Characterization of the major histocompatibility complex locus association with Behçet’s disease in Iran

© 2015 Xavier et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction: The aim of this study was to characterize the association of human leukocyte antigen (HLA) B alleles and major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) in an Iranian dataset. Methods: The association of three SNPs in the MHC region previously identified as the most associated in high-density genotyping studies was tested in a case-control study on 973 BD patients and 825 controls from Iran, and the association of HLA-B alleles was tested in a subset of 681 patients and 414 controls. Results: We found that HLA-B*51 (P = 4.11 × 10(-41), OR [95% CI] = 4.63[3.66-5.85]) and B*15 confer risk for BD (P = 2.83 × 10(-2), OR [95% CI] = 1.75[1.08-2.84]) in Iranian, and in B*51 negative individuals, only the B*15 allele is significantly associated with BD (P = 2.51 × 10(-3), OR [95% CI] = 2.40[1.37-4.20]). rs76546355, formerly known as rs116799036, located between HLA-B and MICA (MHC class I polypeptide-related sequence A), demonstrated the same level of association with BD as HLA-B*51 (P adj = 1.78 × 10(-46), OR [95% CI] = 5.46[4.21-7.09], and P adj = 8.34 × 10(-48), OR [95% CI] = 5.44[4.20-7.05], respectively) in the HLA-B allelotyped subset, while rs2848713 was less associated (P adj = 7.14 × 10(-35), OR [95% CI] = 3.73[2.97-4.69]) and rs9260997 was not associated (P adj = 1.00 × 10(-1)). Additionally, we found that B*51 genotype-phenotype correlations do not survive Bonferroni correction, while carriers of the rs76546355 risk allele predominate in BD cases with genital ulcers, positive pathergy test and positive BD family history (2.31 × 10(-4) ≤ P ≤ 1.59 × 10(-3)). Conclusions: We found that the HLA-B*51 allele and the rs76546355/rs116799036 MHC SNP are independent genetic risk factors for BD in Iranian, and that positivity for the rs76546355/rs116799036 risk allele, but not for B*51, does correlate with specific demographic characteristics or clinical manifestations in BD patients.This work was supported by the Portuguese Fundação para a Ciência e a Tecnologia (grants PTDC/SAU-GMG/098937/2008, PTDC/IIM-GES/5015/2012 and CMUP-ERI/TPE/0028/2013, fellowships SFRH/BD/43895/2008 to JMX, SFRH/BPD/35737/2007 to PA, SFRH/BPD/70008/2010 to IS, a Ciência and an Investigator-FCT contract to SAO), and the Research Committee of the Tehran University of Medical Sciences (grant 132/714).info:eu-repo/semantics/publishedVersio

Drug induced liver injury associated with TNF-α inhibitors – infliximab, adalimumab and etanercept: the role of the laboratory

Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016Background: Knowing and understanding safety profile of a pharmacological product is a continuous process since preclinical toxicological studies to postmarketing clinical evaluation. Although very uncommon, drug-induced liver injury (DILI) leads to drug discontinuation and withdrawn. Biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the treatment of several diseases. Thus, the main goals of this work was to review clinical reported hepatotoxic events associated with a biologic antirheumatic therapy ( infliximab, etanercept and adalimumab) and to access the importance of the laboratory monitoring in the diagnosis of a drug-induced liver injury. Methods: It was performed a systematic literature revision through analysis of scientific papers and reports, obtained from online databases and websites during the period of April to September 2016. Discussion/Conclusion: The mechanism of drug-induced liver injury is complex and not fully understood. The most common presentation of the hepatotoxicity induced by TNF-α antagonists is an autoimmune phenotype with marked hepatocellular injury, cholestasis can also occurs. After drug discontinuation and corticosteroid therapy, the outcome is positive and progression to severe liver injury is rare. Adverse hepatic events in patients on TNF-α antagonists are lower when comparing with non-biologic disease-modifying antirheumatic drugs. The clinical diagnosis and prediction of DILI is a challenge due to the lack of reliable screening methods, including laboratory markers, and diagnostic standards. In the future, better understanding of the underlying mechanisms of DILI in this group of drugs and identification of genetic or other markers of the hepatotoxicity associated with TNF-α antagonists are imperative for the development of improved preclinical screening assays to be used during clinical trials to evaluate a drug’s potential hepatotoxic effects before its release into the market.Âmbito: Conhecer e perceber o perfil de segurança de um fármaco é um processo contínuo desde os estudos pré-clínicos toxicológicos até à avaliação clínica após a sua comercialização. Apesar de muito incomum, a lesão hepática induzida por fármacos (LHIF) tem impacto na descontinuação e retirada dos fármacos. As terapêuticas biológicas, tais como anticorpos monoclonais e proteínas da fusão revolucionaram o tratamento de várias doenças. Assim, os objetivos principais deste trabalho foi rever os eventos hepatotóxicos reportados clinicamente associados a uma terapêutica biológica anti-reumática (etanercept, infliximab e adalimumab) e avaliar a importância do laboratório no diagnóstico de uma lesão hepática induzida por fármacos. Métodos: Foi feita uma revisão sistemática da literatura, através da análise de artigos científicos e relatórios obtidos através de bases de dados online e sites, entre o período de abril a setembro de 2016. Discussão/Conclusão: O mecanismo da lesão hepática induzida por fármacos é complexo e não compreendido totalmente. A apresentação mais comum da hepatotoxicidade induzida por antagonistas do TNF-α é um fenótipo autoimune com evidente lesão hepatocelular, a colestase também pode ocorrer. Após a descontinuação do fármaco e início da terapêutica corticosteroide, o resultado é positivo, sendo que a progressão a lesão hepática grave é rara. Os efeitos adversos hepáticos em doentes com antagonistas de TNF-α são mais baixos quando comparados com medicamentos anti-reumáticos modificadores da doença não-biológicos. O diagnóstico clínico e a previsão da LHIF é um desafio devido à falta de métodos de avaliação eficazes, incluindo marcadores laboratoriais e diretrizes de diagnósticos. No futuro, compreender melhor os mecanismos subjacentes à LHIF neste grupo de fármacos e a identificação de marcadores genéticos ou outros da hepatotoxicidade associada a antagonistas do TNF-α é imperativo para o desenvolvimento de melhores testes de avaliação pré-clínica para serem utilizados durante os ensaios clínicos para avaliar os efeitos hepatotóxicos potenciais de um fármaco antes da entrada no mercado

Relatório de estágio em farmácia comunitária

Relatório de estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia da Universidade de Coimbr

Avaliação da complexidade terapêutica em doentes hipertensos

Monografia realizada no âmbito da unidade Estágio Curricular do Mestrado Integrado em Ciências Farmacêuticas, apresentada à Faculdade de Farmácia da Universidade de CoimbraA hipertensão arterial (HTA) é a doença crónica mais prevalente na população idosa e afeta mais de metade dos idosos portugueses. Os idosos, além de estarem sujeitos a uma polimedicação para controlar a HTA, estão também suscetíveis à toma de outra grande diversidade de medicamentos devido às particularidades associadas ao envelhecimento. Apesar dos efeitos benéficos associados à polimedicação, esta também aumenta a complexidade terapêutica, predispondo o idoso a um maior risco de desenvolver interações medicamentosas e efeitos adversos bem como a uma maior probabilidade de não aderirem à terapêutica. A complexidade terapêutica pode ser avaliada utilizando o Índice de Complexidade da Farmacoterapia (ICFT), que tem em conta a forma farmacêutica, a frequência das doses e as instruções adicionais subjacentes à toma da medicação. Estudos epidemiológicos demonstram que doentes hipertensos têm regimes terapêuticos com elevados níveis de complexidade farmacoterapêutica. Deste modo, fazendo uso da proximidade à comunidade desenvolvida ao longo destes últimos 5 meses durante o estágio curricular em farmácia comunitária, foi avaliada a complexidade terapêutica em doentes hipertensos, utentes habituais da Farmácia São José (Coimbra). Verificou-se que o ICFT aumentou com a idade, tendo apresentado um score médio de 20,6 pontos, sendo a componente “instruções especiais” a que mais contribuiu para este valor. Valores de ICFT mais elevados correspondiam aos doentes que apresentavam a pressão arterial (PA) normal-alta ou HTA de grau 1 e 2. Assim, na população em estudo, valores mais elevados de ICFT parecem estar associados a uma HTA não controlada.Hypertension is the most frequent chronic disease in the elderly and affects more than a half of Portuguese old people. The elderly, in addition to being exposed to polypharmacy to control hypertension, are also more sensitive to other drugs co-administered due to the alterations underlying the ageing. Despite its benefits, polypharmacy can increase medication regimen complexity, predisposing patients to higher risks of developing drug-drug interactions and adverse effects and it may also hamper the medication adherence. The medication regimen complexity can be evaluated using Medication Regimen Complexity Index (MRCI) which is based on the dosage form, dosage frequency and administration instructions. Epidemiological studies show that hypertensive patients have complex regimen medications. Thus, during the experience achieved in the community pharmacy during the last five months, the medication regimen complexity of hypertensive patients was evaluated on hypertensive patients from Farmácia São José (Coimbra). MRCI increased with age and its average was 20.6, being the “special instructions” the major contribution to that value. Higher MRCI values were founded in patients who had normal-high blood pressure or hypertension type 1 and 2. Consequently, regarding this hypertensive population, higher MRCI values seemed to be associated to uncontrolled hypertension disease

Relatório de Estágio em Farmácia Comunitária

Relatório de estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia da Universidade de Coimbr

KDNA genetic signatures obtained by LSSP-PCR analysis of Leishmania (Leishmania) infantum isolated from the new and the old world

Submitted by Nuzia Santos ([email protected]) on 2014-02-18T19:26:57Z No. of bitstreams: 1 ARCA.pdf: 2256108 bytes, checksum: aa9d60804bf341d044b75d5b8d895dd8 (MD5)Made available in DSpace on 2014-02-18T19:26:57Z (GMT). No. of bitstreams: 1 ARCA.pdf: 2256108 bytes, checksum: aa9d60804bf341d044b75d5b8d895dd8 (MD5) Previous issue date: 2012Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Parasitologia. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Morfologia. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, BrasilUniversidade Nova de Lisboa. Instituto de Higiene e Medicina Tropical. Unidade de Leishmanioses. Lisboa, PortugalUniversidade Nova de Lisboa. Instituto de Higiene e Medicina Tropical. Unidade de Leishmanioses. Lisboa, PortugalUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Morfologia. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Parasitologia. Belo Horizonte, MG, BrasilBackground Visceral Leishmaniasis (VL) caused by species from the Leishmania donovani complex is the most severe form of the disease, lethal if untreated. VL caused by Leishmania infantum is a zoonosis with an increasing number of human cases and millions of dogs infected in the Old and the New World. In this study, L. infantum (syn. L.chagasi) strains were isolated from human and canine VL cases. The strains were obtained from endemic areas from Brazil and Portugal and their genetic polymorphism was ascertained using the LSSP-PCR (Low-Stringency Single Specific Primer PCR) technique for analyzing the kinetoplastid DNA (kDNA) minicircles hypervariable region. Principal Findings KDNA genetic signatures obtained by minicircle LSSP-PCR analysis of forty L. infantum strains allowed the grouping of strains in several clades. Furthermore, LSSP-PCR profiles of L. infantum subpopulations were closely related to the host origin (human or canine). To our knowledge this is the first study which used this technique to compare genetic polymorphisms among strains of L. infantum originated from both the Old and the New World. Conclusions LSSP-PCR profiles obtained by analysis of L. infantum kDNA hypervariable region of parasites isolated from human cases and infected dogs from Brazil and Portugal exhibited a genetic correlation among isolates originated from the same reservoir, human or canine. However, no association has been detected among the kDNA signatures and the geographical origin of L. infantum strains

KDNA signatures of the 447-bp minicircle fragment of <i>L. infantum</i> (<i> = L. chagasi</i>) strains isolated from the canine reservoir.

<p>Five µ l of the LSSP-PCR reaction products, were loaded in each lane of a 6% polyacrylamide gel and silver stained. Lanes 2 to 11: genotype I (lanes 2–3: CB2 and CP3); genotype II (lane 4: CP5); genotype III (lanes 5–6: CB7 and CP2); genotype IV (lane 7: CP6); genotype V (lane 8: CB3); genotype VI (lane 9: IPT1); genotype VII (lane 10: CB10); genotype VIII (lane 11: CB4). Migration of the markers of the 1 Kb DNA ladder (Life Technologies, Inc., Gaithersburg, MD) is shown in lane 1, with the following molecular sizes (from the bottom up): 75, 134, 154, 201, 220, 298, 344, 396, 506, 517, 1018 and 1636 bp. Genotypes are indicated by roman numbers.</p

KDNA signatures of the 447-bp minicircle fragment of <i>L. infantum</i> (<i> = L. chagasi</i>) strains isolated from human patients.

<p>Five µ l of the LSSP-PCR reaction products, were loaded in each lane of a 6% polyacrylamide gel and silver stained. Lanes 2 to 17: genotype I (lanes 2–4: HP7, HB5 and HB9); genotype II (lanes 5–6: HP10 and HP1); genotype III (lanes 7–8: HP6 and HB6); genotype VI (lane 9: HP5); genotype VII (lane 10: HB8); genotype VIII (lane 11: HP3); genotype IX (lane 12: HP8); genotype IV (lanes 13–14: HB4 and HB9); genotype V (lanes 15–16: HP4 and PP75); lane 17 the negative control of the LSSP-PCR reaction. Migration of the markers of the 1 Kb DNA ladder (Life Technologies, Inc., Gaithersburg, MD) is shown in lane 1, with the following molecular sizes (from the bottom up): 75, 134, 154, 201, 220, 298, 344, 396, 506, 517, 1018 and 1636 bp. Genotypes are indicated by roman numbers.</p