508 research outputs found
Physiologically-Based Pharmacokinetic (Pbpk) Modeling of Pcdd/Fs and Pfass in Humans
Els models farmacocinètics (PBPK) sĂłn representacions matemĂ tiques del cos humĂ , que tenen com a objectiu calcular la concentraciĂł de compostos quĂmics en els teixits humans. Els models PBPK poden millorar el cĂ lcul del risc per a la salut humana, però de moment no han estat escassament utilitzats. Entre els compostos ambientals mĂ©s perillosos per a la salut humana destaquen les dibenzo-p-dioxines policlorades i dibenzofurans policlorats (PCDD/Fs) i els compostos perfluorats (PFASs).
L’objectiu de la present tesis es el desenvolupament de un model PBPK per calcular la concentració de PCDD/Fs i PFASs en teixits humans.
Prèviament al desenvolupament del model PBPK, es va desenvolupar un Ăndex de risc utilitzant mapes auto-organitzats (SOM), per calcular els compostos ambientals mĂ©s perillosos per a la salut humana. Entre els compostos mĂ©s perillosos es van trobar els PFASs. DesprĂ©s es va desenvolupar el model PBPK per predir les concentracions de PCDD/Fs en sang i en teixit adipĂłs. Els resultats finals van ser altament coincidents amb els resultats experimentals trobats a l’à rea de Tarragona (NE d’Espanya), y per això es va considerar el model com a validat. A continuaciĂł el model es va adaptar per calcular les concentracions de PFASs. Per això, primer es va adaptar el model per PFOS i PFOA, que sĂłn els compostos perfluorats mĂ©s estudiats en la literatura, i desprĂ©s es va estendre el model a 9 PFASs mĂ©s. Finalment, es va fer un anĂ lisis de la incertesa del model PBPK, i la incertesa paramètrica es va estudiar visual i estadĂsticament.Los modelos farmacocinĂ©ticos (PBPK) son representaciones matemáticas del cuerpo humano, que tienen como objetivo calcular la concentraciĂłn de quĂmicos en los tejidos humanos. Los modelos PBPK pueden mejorar el cálculo de riesgo para la salud humana, pero hasta el momento no han sido muy usados. Entre los compuestos ambientales más peligrosos para la salud humana destacan las dibenzo-p-dioxinas policloradas y los dibenzofuranos policlorados (PCDD/Fs) y los compuestos perfluorados (PFASs).
El objetivo de la presente tesis es el desarrollo un modelo PBPK para calcular la concentraciĂłn de PCDD/Fs y PFASs en tejidos humanos.
Previo al desarrollo del modelo PBPK se desarrollĂł un Ăndice de riesgo usando mapas auto-organizados (SOM), para calcular los compuestos ambientales más peligrosos para la salud humana. Los PFASs se encontraron entre los compuestos de más riesgo. DespuĂ©s se desarrollĂł el modelo PBPK para predecir las concentraciones de PCDD/Fs en sangre y en tejido adiposo. Los resultados finales fueron muy coincidentes con los resultados experimentales encontrados en el área de Tarragona (NE de España), y por esta razĂłn el modelo se considerĂł como validado. A continuaciĂłn el modelo se adaptĂł para calcular las concentraciones de PFASs. Para ello, primero se adaptĂł el modelo para PFOS y PFOA, que son los compuestos perfluorados más estudiados en la literatura, y despuĂ©s se extendiĂł el modelo a otros 9 PFASs. Finalmente, se hizo un análisis de la incertidumbre del modelo PBPK, y la incertidumbre paramĂ©trica se estudio visual y estadĂsticamente.Physiologically based pharmacokinetic (PBPK) models are mathematic representations of the human body that aims to assess the time course distribution of chemicals in human tissues. PBPK models may improve the assessment of human health risk but until now were not well studied. Among the most harmful environmental pollutants for human health there are polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) and perfluoroalkyl substances (PFASs).
The objective of the present work is to develop a PBPK model to assess the time course concentration of PCDD/Fs and PFASs in human tissues.
Previously to the PBPK model development, a ranking index was developed using self-organizing maps (SOM) to assess the most harmful environmental contaminants, being PFASs among the most harmful compounds. After that, the PBPK model was developed to assess and predict the concentration of PCDD/Fs in human blood and adipose tissue. The final outcomes were very coincident with the experimental data found in Tarragona County (NE of Spain), and the model was considered as a validated. After that, the model was adapted to assess the concentrations of PFASs. Firstly the model was developed for PFOS and PFOA, that are the most studied compounds in the research literature, and then the model was expended to 9 PFASs more. Finally the uncertainty analysis of the PBPK model was conducted, and the parametric uncertainty was visually and statistically studied
Material didà ctic per a Tecnologia a la ESO orientat a alumnes d’Aula d’Acollida
Aquest treball final de mà ster s’ha dut a terme a partir de la proposta de realitzar un
conjunt d’activitats i materials didà ctics destinats a alumnes nouvinguts amb dificultats per
la llengua catalana a un Institut de Secundà ria. L’objectiu principal és facilitar la integració
d’aquests alumnes a les aules ordinà ries, realitzant activitats de tipus visual relacionats
amb la terminologia.
Actualment, els centres d’educació primà ria i secundà ria tenen un gran nombre d’alumnes
de diferents procedències. Aquests alumnes, que sovint poden recórrer a l’aula d’acollida
del seu centre per a l’aprenentatge de l’idioma i per a la integraciĂł al nostre paĂs, en
moltes altres hores assisteixen a les aules ordinĂ ries on, en molts casos, desaprofiten
aquestes hores ja que al desconèixer la llengua els Ă©s totalment difĂcil poder integrar-se al
grup i seguir les classes amb normalitat.
Amb aquest treball es vol aconseguir facilitar la integraciĂł en el major grau possible
aquests alumnes a les aules ordinĂ ries de Tecnologia, proporcionant-los-hi material
d’introducció a la terminologia de tecnologia del seu nivell basat principalment en activitats
i jocs de vocabulari, i a poder ser, entrant en continguts i conceptes mĂ©s especĂfics.
Per desenvolupar aquest treball, s’ha començat per realitzar un anĂ lisis del currĂculum de
Tecnologies de la ESO i s’han estudiat les diferents unitats didà ctiques per extreure’n el
vocabulari o terminologia principal.
S’ha realitzat també un anà lisis de les tipologies d’activitats que es podrien realitzar per
facilitar l’aprenentatge d’aquests alumnes i s’ha creat material per la unitat d’Energies
integrada en el BLOC d’Electricitat de 2n ESO.
Finalment, s’ha posat en prà ctica a un grup reduït d’alumnes d’Aula d’Acollida i els
resultats obtinguts han estat satisfactoris. Es pot concloure que els alumnes necessiten un
reforç en el vocabulari i que estarien disposats i motivats a fer activitats d’aquest tipus per
millorar el seu aprenentatge i integrar-se de manera més natural a les aules
A new scoring system for the diagnosis of BRCA1/2 associated breast-ovarian cancer predisposition.
International audienceCriteria have been proposed for genetic testing of breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Using simulations, this study evaluates the efficiency (sensitivity, positive predictive value [PPV] and specificity) of the various criteria used in France. The efficiency of the criteria published in 1998, which are largely used, is not optimal. We show that some extensions of these criteria provide an increase in sensitivity with a low decrease in specificity and PPV. The study shows that scoring systems (Manchester, Eisinger) have similar efficiency that may be improved. In this aim, we propose a new scoring system that takes into account unaffected individuals and kinship coefficients between family members. This system increases sensitivity without affecting PPV and specificity. Finally, we propose a two-step procedure with a large screening by the physician for recommending genetic counselling, followed by a more stringent selection by the geneticist for prescribing genetic testing. This procedure would result in an increase of genetic counselling activity but would allow the identification of almost 80% of mutation carriers among affected individuals, with a mutation detection rate of 15% and a specificity of 88%
BRCA1 mutations in women with familial or early-onset breast cancer and BRCA2 mutations in familial cancer in Estonia
<p>Abstract</p> <p>Background</p> <p>The aim of this study was to identify BRCA1 and BRCA2 mutations in the Estonian population. We analyzed genetic data and questionnaire from 64 early-onset (< 45 y) breast cancer patients, 47 familial cases (patients with breast or ovarian cancer and a case of these cancers in the family), and 33 predictive cases (patients without breast or ovarian cancer, with a family history of such diseases) from Estonia for mutations in the BRCA1 gene. A sub-set of familial cases and predictive cases were also analyzed for mutations in the BRCA2 gene.</p> <p>Methods</p> <p>For mutation detection, we used the Polymerase Chain Reaction-Single Stranded Conformation Polymorphism Heteroduplex Analysis (PCR-SSCP-HD), followed by direct DNA sequencing.</p> <p>Results</p> <p>We identified three clinically important mutations in the BRCA1 gene, including seven occurrences of the c.5382insC mutation, three of c.4154delA, and one instance of c.3881_3882delGA. We also detected six polymorphisms: c.2430T>C, c.3232A>G, c.4158A>G, c.4427T>C, c.4956A>G, and c.5002T>C. Four sequence alterations were detected in introns: c.560+64delT, c.560+ [36-38delCTT, 52-63del12], c.666-58delT, and c.5396+60insGTATTCCACTCC. In the BRCA2 gene, two clinically important mutations were found: c.9610C>T and c.6631delTTAAATG. Additionally, two alterations (c.7049G>T and c.7069+80delTTAG) with unknown clinical significance were detected.</p> <p>Conclusions</p> <p>In our dataset, the overall frequency of clinically important BRCA1 mutations in early-onset patients, familial cases, and predictive testing was 7.6% (144 cases, 11 mutation carriers). Pathogenic mutations were identified in 4 of the 64 early-onset breast cancer cases (6.3%). In familial cases, clinically important mutations in the BRCA1 gene were found in 6 of the 47 individuals analyzed (12.8%). In predictive cases, 1 clinically important mutation was detected in 33 individuals studied (3%). The occurrence of clinically important mutations in BRCA2 in familial cases of breast cancer was 2 of the 16 individuals analyzed (12.5%).</p
Favourable ten-year overall survival in a Caucasian population with high probability of hereditary breast cancer
<p>Abstract</p> <p>Background</p> <p>The purpose of our study was to compare differences in the prognosis of breast cancer (BC) patients at high (H) risk or intermediate slightly (IS) increased risk based on family history and those without a family history of BC, and to evaluate whether ten-year overall survival can be considered a good indicator of <it>BRCA1 </it>gene mutation.</p> <p>Methods</p> <p>We classified 5923 breast cancer patients registered between 1988 and 2006 at the Department of Oncology and Haematology in Modena, Italy, into one of three different risk categories according to Modena criteria. One thousand eleven patients at H and IS increased risk were tested for <it>BRCA1/2 </it>mutations. The overall survival (OS) and disease free survival (DFS) were the study end-points.</p> <p>Results</p> <p>Eighty <it>BRCA1 </it>carriers were identified. A statistically significantly better prognosis was observed for patients belonging to the H risk category with respect to women in the IS and sporadic groups (82% vs.75% vs.73%, respectively; p < 0.0001). Comparing only <it>BRCA1 </it>carriers with <it>BRCA-</it>negative and sporadic BC (77% vs.77% vs.73%, respectively; p < 0.001) an advantage in OS was seen.</p> <p>Conclusions</p> <p>Patients belonging to a population with a high probability of being <it>BRCA1 </it>carriers had a better prognosis than those with sporadic BC. Considering these results, women who previously had BC and had survived ten years could be selected for <it>BRCA1 </it>analysis among family members at high risk of hereditary BC during genetic counselling. Since only 30% of patients with a high probability of having hereditary BC have <it>BRCA1 </it>mutations, selecting women with a long term survival among this population could increase the rate of positive analyses, avoiding the use of expensive tests.</p
Survival in Norwegian BRCA1 mutation carriers with breast cancer
Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers
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