RESUMO
BACKGROUND: In recent years, significant advances have been made in the field of rare diseases (RDs). However, there is a large number of RDs without specific treatment and half of these treatments have public funding in Spain. The aim of the FINEERR project was to carry out a multidisciplinary strategic discussion on the challenge of funding and access to RD-targeted drugs in Spain, in order to agree on specific proposals for medium-term improvement and hence support decision-making in the Spanish National Healthcare System (SNHS). RESULTS: The FINEERR Project was organized around a CORE Advisory Committee, which provided an overview, agreed on the design and scope of the project, and selected the members within each of four working groups (WG). Overall, 40 experts discussed and reached a consensus on different relevant aspects, such as conditioning factors for initial funding and access, evaluation and access to RD-targeted therapies, funding of these therapies, and implementation of a new funding and access model. From these meetings, 50 proposals were defined and classified by their level of relevance according to the experts. A descriptive analysis of responses was performed for each proposal. Thereafter, experts completed another questionnaire where they ranked the 25 most relevant proposals according to their level of feasibility of being implemented in the SNHS. The most relevant and feasible proposals were to improve: process of referral of patients with RDs, control over monitoring mechanisms, and communication between healthcare professionals and patients. CONCLUSIONS: The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies in Spain to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs.
Assuntos
Qualidade de Vida , Doenças Raras , Humanos , Consenso , Acessibilidade aos Serviços de Saúde , Doenças Raras/tratamento farmacológico , EspanhaRESUMO
CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hematological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to manage the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process.
Assuntos
Neoplasias Hematológicas , Receptores de Antígenos Quiméricos , Consenso , Humanos , Imunoterapia Adotiva , EspanhaRESUMO
Enteroaggregative Escherichia coli (EAEC) is an emergent bacterial pathogen. The first studies in developing countries with EAEC strains, showed that this bacterium was associated with persistent diarrhea. However, new studies showed that EAEC may be associated also with acute diarrhea, with both nosocomial and community outbreaks worldwide, and as an important pathogen of diarrheal disease in human immunodeficiency virus-infected adults. EAEC strains are recognized by their characteristic aggregative adherence or "stacked-brick" pattern to epithelial cells. Although the pathogenesis of EAEC infection is not well understood, cellular changes observed in animal models and in vitro assays, suggested that the alterations in the intestinal mucosa during EAEC infection are associated with adherence factors and toxins production. The damage has been associated with the release of inflammatory mediators, which may contribute also to the intestinal illness. The dissemination of the high pathogenicity island from Yersinia pestis evolutionary group to EAEC has been show; different studies suggest that it may contribute to the virulence of EAEC strains. Molecular methods to investigate the presence of plasmid and chromosomal EAEC-associated virulence markers, have been used for the characterization and epidemiological studies of EAEC strains. Although the clinical and epidemiological importance of EAEC have been demonstrated in different studies, Escherichia coli strains with adherent agreggative phenotype are commonly isolated from healthy children and environmental sources. This support the necessity to study virulence factors no related with the cells adherence pattern, that show the specific EAEC pathogenic clones associated whit intestinal disease.
Assuntos
Doenças Transmissíveis Emergentes/microbiologia , Infecções por Escherichia coli/microbiologia , Escherichia coli/patogenicidade , Adulto , Animais , Aderência Bacteriana , Proteínas de Bactérias/fisiologia , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Células Cultivadas/microbiologia , Criança , Doenças Transmissíveis Emergentes/epidemiologia , Diarreia/microbiologia , Surtos de Doenças , Células Epiteliais/microbiologia , Escherichia coli/classificação , Escherichia coli/genética , Infecções por Escherichia coli/epidemiologia , Genes Bacterianos , Ilhas Genômicas/genética , Vida Livre de Germes , Saúde Global , Humanos , Mucosa Intestinal/microbiologia , Técnicas de Cultura de Órgãos , Plasmídeos/genética , Sus scrofa/microbiologia , Virulência , Yersinia pestis/genéticaRESUMO
Pet toxin is a serine protease from enteroaggregative Escherichia coli which has been described as causing enterotoxic and cytotoxic effects. In this paper we show that Pet produces spectrin and fodrin (nonerythroid spectrin) disruption. Using purified erythrocyte membranes treated with Pet toxin, we observed degradation of alpha- and beta-spectrin chains; this effect was dose and time dependent, and a 120-kDa protein fraction was observed as a breakdown product. Spectrin degradation and production of the 120-kDa subproduct were confirmed using specific antibodies against the alpha- and beta-spectrin chains. The same degradation effect was observed in alpha-fodrin from epithelial HEp-2 cells, both in purified cell membranes and in cultured cells which had been held in suspension for 36 h; these effects were confirmed using antifodrin rabbit antibodies. The spectrin and fodrin degradation caused by Pet is related to the Pet serine protease motif. Fluorescence and light microscopy of HEp-2 Pet-treated cells showed morphological alterations, which were associated with irregular distribution of fodrin in situ. Spectrin and fodrin degradation by Pet toxin were inhibited by anti-Pet antibodies and by phenylmethylsulfonyl fluoride. A site-directed Pet mutant, which had been shown to abolish the enterotoxic and cytotoxic effects of Pet, was unable to degrade spectrin in erythrocyte membranes or purified spectrin or fodrin in epithelial cell assays. This is a new system of cellular damage identified in bacterial toxins which includes the internalization of the protease, induction of some unknown intermediate signaling steps, and finally the fodrin degradation to destroy the cell.
Assuntos
Toxinas Bacterianas/toxicidade , Proteínas de Transporte/metabolismo , Membrana Celular/efeitos dos fármacos , Enterotoxinas/toxicidade , Proteínas de Escherichia coli , Escherichia coli/patogenicidade , Proteínas dos Microfilamentos/metabolismo , Serina Endopeptidases/toxicidade , Sequência de Aminoácidos , Animais , Toxinas Bacterianas/química , Toxinas Bacterianas/isolamento & purificação , Linhagem Celular , Enterotoxinas/química , Enterotoxinas/isolamento & purificação , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Membrana Eritrocítica/efeitos dos fármacos , Escherichia coli/enzimologia , Infecções por Escherichia coli/fisiopatologia , Humanos , Dados de Sequência Molecular , Coelhos , Serina Endopeptidases/química , Serina Endopeptidases/isolamento & purificação , Espectrina/metabolismoRESUMO
The pathogenic mechanisms of enteroaggregative Escherichia coli (EAggEC) infection are not fully elucidated. In this work we show that an ammonium sulfate precipitate of culture supernatant of EAggEC strain 049766 increased the potential difference (PD) and the short-circuit current (Isc) in rat jejunal preparations mounted in Ussing chambers. The precipitate contained two major proteins of 108 and 116 kDa, which were partially copurified by chromatography in DEAE-cellulose. This chromatographic fraction (peak I) increased jejunal PD and Isc in a dose-dependent manner, accompanied by a decrease in tissue electrical resistance. These effects were inhibited by incubation of peak I at 75 degreesC for 15 min or for 1 h with proteinase K at 37 degreesC. Rabbit polyclonal antibodies against peak I containing both the 108- and 116-kDa proteins inhibited the enterotoxic effect. Specific polyclonal antibodies raised against the 108-kDa but not against the 116-kDa protein inhibited the enterotoxic effect, suggesting that the 108-kDa protein is the active toxic species. Moreover, another EAggEC strain (065126) producing the 116-kDa protein but not the 108-kDa protein had no effect on rat jejunal mucosa in the Ussing chamber. The >100-kDa fraction derived from prototype EAggEC strain 042, which also expressed both 108- and 116-kDa proteins, also produced an enterotoxic effect on rat jejunal preparations in Ussing chambers; however, the same strain cured of its 65-MDa adherence plasmid did not. A subclone derived from the 65-MDa plasmid expressing the 108-kDa toxin (and not the 116-kDa protein) elicited rises in Isc. Tissue exposed to any preparation containing the 108-kDa toxin exhibited similar histopathologic changes, characterized by increased mucus release, exfoliation of cells, and development of crypt abscesses. Our data suggest that some EAggEC strains produce a ca. 108-kDa enterotoxin/cytotoxin which is encoded on the large virulence plasmid.
Assuntos
Toxinas Bacterianas/toxicidade , Enterotoxinas/toxicidade , Proteínas de Escherichia coli , Escherichia coli/patogenicidade , Animais , Toxinas Bacterianas/genética , Enterotoxinas/genética , Mucosa Intestinal/patologia , Masculino , Peso Molecular , Ratos , Ratos Sprague-DawleyRESUMO
We report the use of cultures of mosquito cells (TRA-284) to detect dengue virus in serum from cases of dengue fever in the state of Puebla, México. Using the conventional procedure 56 of 171 samples (32.7%) were positive. The negative sera (67.3%) were passaged 'blind' in mosquito cell cultures but no virus was detected. However, when these sera were incubated in the presence of actinomycin D (an inhibitor of deoxyribonucleic acid transcription) 20 of the 115 samples (17.4%) became positive. This procedure increased the virus detection rate from 32.7% to 44.4%. Serotypes 1 and 4 were identified for the first time in the state of Puebla, where the transmission of dengue virus is increasing. The addition of actinomycin D to mosquito cell cultures may improve the detection of dengue virus and could be a useful tool for virological surveillance in endemic countries.
Assuntos
Dactinomicina/farmacologia , Vírus da Dengue/isolamento & purificação , Animais , Células Cultivadas , Culicidae , Dengue/sangue , Humanos , Transcrição Gênica/efeitos dos fármacos , Virologia/métodosRESUMO
In eight patients with chronic and stable psoriasis, the usefulness of topical cyclosporine solution using 50% dimethylsulfoxide as a vehicle was assessed in a randomly chosen plate and compared with a similar solution without cyclosporine in a contralateral plate. After six months of treatment, the plates involuted in two patients, and in the rest there was a 1 to 3 points reduction in the local psoriasis area severity index score. Plasma cyclosporine levels were negligible and no changes in blood chemistry were detected. It is concluded that topical cyclosporine is effective in the treatment of psoriasis, but only after a prolonged application period.
Assuntos
Ciclosporina/administração & dosagem , Psoríase/tratamento farmacológico , Administração Tópica , Adulto , Doença Crônica , Dimetil Sulfóxido/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Veículos FarmacêuticosRESUMO
Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) are the severe and/or fatal clinical manifestations of dengue fever. Epidemics of DHF/DSS occur mainly in the southeast Asian countries where children are seriously affected and high case-fatality ratio is annually reported. Recently significant epidemics of DHF/DSS have been reported in Cuba, Venezuela and Brazil, which means that reinforcements of the epidemiological surveillance in the countries of the American region that show high virus transmission, are urgently needed. The main purpose of the present article is to review relevant information regarding the clinical manifestations, pathology, diagnostic procedures, treatment of cases, pathophysiologic mechanisms and some data related with specific DHF/DSS epidemics.