RESUMO
In April 2009 the first pandemic of the 21st century developed within a few weeks starting from Mexico. Its first wave reached Germany in autumn 2009 and was responsible for 1.8-3.5 million additional medical consultations. For the public health sector, this pandemic was one of the largest challenges of the last few decades. As a contribution to broader evaluations on national and international level, the Robert Koch Institute invited representatives from different professions involved in the pandemic response to participate in a workshop on 22-23 March 2010. This workshop was structured in short presentations, group work, and plenary discussions. Main experiences were that (a) pandemic preparedness was helpful, (b) the early warning systems were reliable, (c) vaccines were available within a few months, however, in limited amounts. Need for improvement was discussed for (a) effectiveness of vaccination logistics, (b) mechanisms for the reimbursement of the cost of vaccination, (c) availability of surveillance and monitoring systems, (d) integration of physicians in decision-making processes and health education, and (e) proactive communication strategies. Investments in the above mentioned areas can help to improve public health protection in the future.
Assuntos
Surtos de Doenças , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Comportamento Cooperativo , Estudos Transversais , Previsões , Alemanha , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/provisão & distribuição , Influenza Humana/prevenção & controle , Comunicação Interdisciplinar , Programas Nacionais de Saúde/tendências , Vigilância da População , Encaminhamento e Consulta/estatística & dados numéricos , Mecanismo de ReembolsoRESUMO
This review summarizes scientific, ethical and regulatory aspects of Phase I clinical trials with monoclonal antibodies. The current standard requirements for pre-clinical testing and for clinical study design are presented. The scientific considerations discussed herein are generally applicable, the view on legal requirements for clinical trials refer to the German jurisdiction only. The adverse effects associated with the TGN1412 Phase I trial indicate that the predictive value of pre-clinical animal models requires reevaluation and that, in certain cases, some issues of clinical trial protocols such as dose fixing may need refinement or redesign. Concrete safety measures, which have been proposed as a consequence of the TGN1412 event include introduction of criteria for high-risk antibodies, sequential inclusion of trial participants and implementation of pre-Phase I studies where dose calculation is based on the pre-clinical No Effect Level instead of the No Observed Adverse Effect Level. The recently established European clinical trials database (EUDRACT Database) is a further safety tool to expedite the sharing of relevant information between scientific authorities.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Ensaios Clínicos Fase I como Assunto/legislação & jurisprudência , Aprovação de Drogas/legislação & jurisprudência , Experimentação Humana/legislação & jurisprudência , Legislação de Medicamentos , Projetos de Pesquisa , Sistemas de Notificação de Reações Adversas a Medicamentos , Animais , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados , Antineoplásicos/toxicidade , Ensaios Clínicos Fase I como Assunto/ética , Ensaios Clínicos Fase I como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Revisão Ética , Alemanha , Guias como Assunto , Experimentação Humana/ética , Humanos , Nível de Efeito Adverso não Observado , Valores de Referência , Medição de Risco , Testes de ToxicidadeRESUMO
Regulation of nucleo-cytoplasmic export of viral transcripts by a viral protein (Rev/Rex) is a characteristic feature in the replication cycle of complex retroviruses. We recently reported that the endogenous retrovirus family HTDV/HERV-K encodes a protein, Corf, that is a cellular Counterpart of Rev/Rex function and thus a new component of nucleo-cytoplasmic pathways. In HTDV/HERV-K-expressing cells, Corf is localized within the nucleoli. Here we describe the nuclear localization signal (NLS) of the Corf protein. Mutations in the NLS lead to cytoplasmic accumulation of the mutated protein and abrogate Corf function in a trans-dominant way.
Assuntos
Arginina/fisiologia , Retrovirus Endógenos , Sinais de Localização Nuclear/fisiologia , Proteínas Virais/fisiologia , Sequência de Aminoácidos , Arginina/genética , Arginina/metabolismo , Sequência de Bases , Transporte Biológico , Linhagem Celular , Núcleo Celular/metabolismo , DNA Complementar , Ácidos Graxos Insaturados/farmacologia , Produtos do Gene rev , Produtos do Gene rex , Genes Dominantes , Humanos , Dados de Sequência Molecular , Mutagênese , Sinais de Localização Nuclear/genética , Fenótipo , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/fisiologia , Transfecção , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
The human endogenous retrovirus HTDV/HERV-K, which resides in moderate copy numbers in the human genome, is expressed in a cell-type-specific manner, predominantly in teratocarcinoma cells. We have analyzed the regulatory potential of the 5' enhancer of the HERV-K long terminal repeat. Protein extracts of HERV-K-expressing teratocarcinoma cell lines (GH and Tera2) and nonexpressing HeLa and HepG2 cells form different protein complexes on the enhancer sequence as detected by electrophoretic mobility shift assays (EMSA). Using competition EMSAs, DNase I footprinting, and supershift experiments, we localized the binding site of these complexes to a 20-bp sequence within the enhancer and showed that the transcription factor YY1 is one component of the HERV-K enhancer complex. Replacement of the YY1 binding site with unrelated sequences reduced expression of the luciferase gene as a reporter in transient-transfection assays.