89 research outputs found
Transplante autólogo de células estaminais em leucemiamielóide aguda: factores com Influência na sobrevida: experiência de 13 anos de uma Instituição
© Ordem dos MédicosWe report our results of autologous stem cell transplantation (SCT) in patients with AML during the last 13 years. Between August 1990 and December 2003, 42 patients with acute myeloid leukemia (AML) received an autologous SCT. Patients were classified as standard risk if first complete remission (CR) was induced after one or two chemotherapy regimens and the white blood cell count at presentation was below 50,000/mL (n=12), while patients requiring more than two induction regimens to attain first CR and with CR2 ou more advanced disease and/or had a higher white blood cell count at presentation were defined as high risk (n=30). Twenty one patients were transplanted in first CR. The median patient age was 24 years (range, 2-56 years), and the median time interval from diagnosis to autologous SCT was 9 months (range 3-87 months). The conditioning regimen for SCT consisted of busulfan (BU) 16 mg/kg and melfalan (MEL) 180 mg/m2 (BUMEL) in 17 (40%) patients and busulfan 16 mg/kg and VP-16 60 mg/kg (BUVP16) in 22 (52%) patients. Three patients received a different conditioning regimen with BCNU 300 mg/m2, VP16 2 g/m2 and melphalan 160 mg/m2 (BEM). Twenty five (60%) patients received bone marrow (BM), 11 (26%) patients received peripheral blood stem cells (PBSC) and 6 patients (14%) received BM plus PBSC. With a median follow-up of 7 years, the 13 year overall survival (OS) and diseasefree survival (DFS) of all patients is 52% and 40%, respectively. In univariate analysis, males had a significantly superior DFS than females (55% vs 22%, p=0.003), and patients younger than 15 years of age had significantly superior OS and DFS than older patients (50% vs 35%, p=0.05; and 50% vs 28%, p=0.03, respectively). Patients with FAB M3 subtype also had a superior OS than the other FAB subtypes (100% vs 44%, p=0.05). There was a strong statistical correlation between risk group and survival. In fact, the patients with standard risk had a superior OS and DFS than those with high risk disease (67% vs 23%, p=0.0004; and 50% vs 27%, p=0.01, respectively). When patients with FAB M3 disease were excluded from the analysis, the group with standard risk continue to have a superior OS and DFS (67% vs 13%, p=0.008; and 50% vs 14%, p=0.02, respectively). We conclude that autologous SCT is an effective treatment in AML with the possibility of long survivorship, particularly in patients with standard risk disease.info:eu-repo/semantics/publishedVersio
Transplante alogénico de células estaminais em doentes com síndrome mielodisplásica: análise de acordo com o Índice de Prognóstico Internacional
© Ordem dos MédicosWe determined the outcome of patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML) after allogeneic stem cell transplantation according to their international prognostic scoring system (IPSS) risk categories at diagnosis. A total of 11 females and 7 males, with a median age of 45 years, were transplanted. With a median follow-up of 60 months, the 6-year actuarial event-free survival (EFS) for Less Advanced (Low and Intermediate-1 risk IPSS) and Advanced (Intermediate-2 and High risk IPSS) MDS was 71.4% and 43.6%, respectively (p=0.002). We did not observe a difference in EFS depending on cytogenetics at diagnosis (good risk 53.8% Vs intermediate and high risk 53.3%, p=ns), neither on the type of conditioning regimen used (myeloablative 50% Vs reduced intensity 52.2%, p=ns). Our results support that IPSS score at diagnosis may be used to predict EFS in patients with MDS undergoing allogeneic SCT.Neste estudo avaliámos o valor preditivo do índice prognóstico internacional (IPSS) na altura do diagnóstico em doentes com síndrome mielodisplásica (SMD) e leucemia mielóide aguda secundária submetidos a transplante alogénico de células estaminais. Foram transplantados um total de 11 mulheres e sete homens, com uma mediana de idades de 45 anos. Com um seguimento mediano de 60 meses, a sobrevivência livre de eventos aos 6 anos nos doentes com doença menos avançada (IPSS Risco Baixo e Intermédio 1) e com doença avançada (IPSS Intermédio 2 e Alto Risco) foi de 71.4% e 43.6%, respectivamente (p=0.002). Não observámos diferenças significativas na sobrevivência livre de eventos de acordo com a análise citogenética na altura do diagnóstico (risco bom 53,8% VS risco intermédio e alto 53,3%, p=ns) nem com o tipo de regime de condicionamento utilizado (mieloablativo 50% VS intensidade reduzida 52,2%, p=ns). Os nossos resultados demonstram que o IPSS na altura do diagnóstico pode ser utilizado para predizer a sobrevivência livre de eventos em doentes com SMD submetidos a transplante alogénico de células estaminaisinfo:eu-repo/semantics/publishedVersio
Desenvolvimento e conceção de um novo sistema universal para conversão “Plug and Play” de cadeira de rodas manuais em elétricas
Atualmente, os dados estatísticos indicam que, na Europa, existam cerca de 5 milhões de utilizadores de cadeiras de rodas, sendo que, ultimamente, tem-se verificado um aumento de cerca de 20.000 novos utilizadores, a cada ano.
O presente trabalho, teve como o objetivo a proposta conceptual e o desenvolvimento de um protótipo de um sistema elétrico motorizado universal e “user friendly”. O referido sistema possibilita a conversão de cadeira de rodas manual em cadeira de rodas com acionamento elétrico, independentemente do modelo desta e sem que, para tal, seja necessário prescindir das principais características e vantagens do modelo convencional - leveza, possibilidade de encartar para fácil transporte, facilidade de utilização, desgaste reduzido dos componentes mecânicos, durabilidade, conforto, segurança e ausência de atravancamentos ao nível da manobrabilidade.
Assim, o presente artigo apresenta um novo conceito de sistema com funcionamento “Plug and Play”, que permite solucionar as necessidades específicas do utilizador e, essencialmente, ser acoplado à maioria dos modelos de cadeira de rodas manuais já existentes. O projeto foi desenvolvido e totalmente validado por ferramentas CAD/CAE e recorreu a uma metodologia de projeto estruturada desde o desenho computacional, técnicas de fabrico, desenvolvimento de protótipo, teste, ensaio e validação em contexto de ensaio clínico.Divmac - Projectos, automatismos e periféricos industriais, S.A
Dispositivo para a reabilitação do sistema articular superior: Do fabrico ao teste em pacientes
This paper presents a static device that was designed to respond to a problem identified in a Portuguese physical rehabilitation hospital for the rehabilitation of the upper limbs function in patients with cerebrovascular problems. Its study, design and construction was carried out at the Department of Mechanical Engineering, at the University of Minho, regarding its future evolution to a (dynamic) robotic device to carry out a better rehabilitation of the upper limbs. The designed and constructed device combines ergonomic support components for the upper limbs, which are placed on a linear guiding system to enable the adjustment of the device to different individuals, and other mechanical components to provide its attachment to wheelchairs, to perform certain postures that will benefit the patient’s recovery. The design of this prototype was carried out using the SOLIDWORKS® software and the support components, the attachments and the other linkages needed were machined, as well as the linear guides, to better adapt to the patient’s upper limbs for rehabilitation. For the proof of concept, this prototype was tested in a hospital environment, especially in patients suffering from cerebrovascular diseases.O presente artigo apresenta um dispositivo estático que nasceu de acordo com um
problema detetado numa unidade hospitalar Portuguesa de reabilitação física – a
reabilitação do sistema articular superior em pacientes de acidentes vasculares cerebrais
(AVC). A conceção, o projeto e a sua construção foram realizadas no Departamento de
Engenharia Mecânica da Universidade do Minho, tendo em vista a sua evolução para um
dispositivo robotizado (dinâmico) para promover uma melhor reabilitação. O dispositivo
estático que foi concebido e construído é composto por componentes de apoio ergonómicos
dos membros superiores, que assentam num sistema de calhas e que permitem o ajuste do
dispositivo a diferentes indivíduos, bem como a sua instalação em cadeiras de rodas, e a
realização de determinadas posturas estáticas que beneficiam a recuperação. A conceção
deste primeiro protótipo estático baseou-se numa modelação realizada em SOLIDWORKS®
e na maquinagem das calhas e das bases de apoio ergonómicas necessárias, adaptáveis
aos membros superiores do indivíduo a reabilitar. Para prova de conceito, o protótipo inicial
foi testado em ambiente hospitalar, especialmente em pacientes vítimas de AVC.Divmac - Projectos, automatismos e periféricos industriais, S.A
Dispositivo para a reabilitação do sistema articular superior: Estudo e concepção de uma solução
One of the most common disabilities, observed in stroke patients, is limb hemiparesis, which is the weakness of the limb contralateral to the damaged hemisphere of the brain. Another problem inherent to this pathology is the appearance of shoulder pain that can negatively affect the rehabilitation process, due to the pain that the patient may feel during rehabilitation, reducing the movement and range autonomy of the articulate upper limbs function.
This paper presents the study, design and development of an universal, lightweight, compact, versatile, strong, compact, modular and low-cost device (with 4 degrees of freedom). This device enables the improvement of the stroke patient’s posture, promoting an active and therapeutic positioning of the entire upper member. This device can also be attached to wheelchairs, sofa arms, beds, etc., and it can follow the patient to all places he moves in the hospital.
It is currently being tested in several hospitals, and patients have accepted this device as a good rehabilitation apparatus (in terms of ergonomics and comfort), as well as the health professionals, providing a greater range of movements, and a correct positioning of the patient’s shoulder during all day.Uma das incapacidades mais comummente verificadas nos doentes vítimas de Acidente
Vascular Cerebral (AVC) trata-se da hemiparésia contralateral ao local onde ocorreu a lesão
cerebral. Outra complicação desta patologia é o aparecimento do ombro doloroso, afectando
negativamente o processo de reabilitação, tornando-se um processo mais doloroso e
diminuindo a amplitude e variedade de movimentos de toda a articulação superior.
O presente trabalho apresenta o estudo, a concepção e o desenvolvimento de um
dispositivo universal, leve, fiável, robusto, compacto, modular e de baixo custo (com 4 graus
de liberdade). Este dispositivo permite assim corrigir a postura do doente vítima de AVC,
promovendo um posicionamento terapêutico e activo do ombro. O dispositivo pode ser acoplado em cadeiras de rodas, em sofás em cadeirões, em camas, etc., acompanhando o
doente em todos os locais em que este se movimenta, dentro da Unidade Hospitalar.
Este dispositivo está a ser testado em várias unidades hospitalares, tendo revelado uma
grande aceitação por parte dos doentes (em termos de ergonomia e conforto), e por parte
dos profissionais (aumento da variedade/qualidade e amplitude de movimentos e melhor
posicionamento do membro durante todo o dia).Divmac - Projectos, automatismos e periféricos industriais, S.A
Paving the way for predictive diagnostics and personalized treatment of invasive aspergillosis
Invasive aspergillosis (IA) is a life-threatening fungal disease commonly diagnosed among individuals with immunological deficits, namely hematological patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation. Vaccines are not available, and despite the improved diagnosis and antifungal therapy, the treatment of IA is associated with a poor outcome. Importantly, the risk of infection and its clinical outcome vary significantly even among patients with similar predisposing clinical factors and microbiological exposure. Recent insights into antifungal immunity have further highlighted the complexity of host-fungus interactions and the multiple pathogen-sensing systems activated to control infection. How to decode this information into clinical practice remains however, a challenging issue in medical mycology. Here, we address recent advances in our understanding of the host-fungus interaction and discuss the application of this knowledge in potential strategies with the aim of moving toward personalized diagnostics and treatment (theranostics) in immunocompromised patients. Ultimately, the integration of individual traits into a clinically applicable process to predict the risk and progression of disease, and the efficacy of antifungal prophylaxis and therapy, holds the promise of a pioneering innovation benefiting patients at risk of IA.CC is supported by the Fundação para a Ciência e Tecnologia,
Portugal (SFRH/BPD/96176/2013
Alpha-thalassemia due to novel deletions and complex rearrangements in the subtelomeric region of chromosome 16p
2º Dia do Jovem Investigador do Instituto Nacional de Saúde Doutor Ricardo Jorge, INSA, 8 maio 2017Introduction: Inherited deletions removing the α-globin genes and/or their upstream regulatory elements (MCSs) give rise to alpha-thalassemia, one of the most common genetic recessive disorders worldwide. The pathology is characterized by microcytic hypochromic anemia due to reduction of the α-globin chain synthesis, which are essential for hemoglobin tetramerization.
Material and Methods: In order to clarify the suggestive α-thalassemia phenotype in eleven patients, we performed Multiplex Ligation-dependent Probe Amplification with commercial and synthetic engineered probes, gap-PCR, and Sanger sequencing to search for deletions in the subtelomeric region of chromosome 16p.
Results: We have identified five distinct large deletions, two of them novel, and one indel. The deletions range from approximately 3.3 to 323 kb, and i) remove the whole α-globin cluster; or ii) remove exclusively the upstream regulatory elements leaving the α-globin genes structurally intact. The indel consists in the loss of MCS-R2 (HS-40), which is the most important distal regulatory element for the α-globin gene expression, and the insertion of 39 bp, seemingly resulting from a complex rearrangement involving two DNA segments (probably from chromosome 3q) bridging the deletion breakpoints with a CC-bp orphan sequence in between. Finally, in one patient no α-globin deletion or point mutation were found. This patient revealed to be a very unusual case of acquired alpha-thalassemia associated with a myelodysplastic syndrome.
Conclusions: Our study widens the spectrum of molecular lesions by which α-thalassemia may occur and emphasizes the importance of diagnosing large α-zero-deletions to provide patients with appropriate genetic counseling.info:eu-repo/semantics/publishedVersio
Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis
© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Reactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10-6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.This study was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 847507 (HDM-FUN). MGN was supported by an ERC Advanced grant (833247) and a Spinoza grant of the Netherlands Association for Scientific Research. VK was supported by a Research Grant [2017] of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Hypatia tenure track grant. AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003. CC was supported by FCT (CEECIND/04058/2018 and PTDC/SAU-SER/29,635/2017) and the Gilead Research Scholars Program – Antifungals. SMG was the recipient of a PhD fellowship funded by FCT (SFRH/BD/136,814/2018). MSG was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) Emmy Noether Program (project no. 434385622/GR 5617/1-1).info:eu-repo/semantics/publishedVersio
Naive and Stem Cell Memory T Cell Subset Recovery Reveals Opposing Reconstitution Patterns in CD4 and CD8 T Cells in Chronic Graft vs. Host Disease
The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of hematological malignancies remains hampered by life-threatening chronic graft vs. host disease (cGVHD). Although multifactorial in nature, cGVHD has been associated with imbalances between effector and regulatory T cells (Treg). To further elucidate this issue, we performed a prospective analysis of patients undergoing unrelated donor allo-HSCT after a reduced intensity conditioning (RIC) regimen containing anti-thymocyte globulin (ATG) and the same GVHD prophylaxis, at a single institution. We studied T cell subset homeostasis over a 24-month follow-up after HSCT in a comparative analysis of patients with and without cGVHD. We also quantified naive and memory T cell subsets, proliferation and expression of the apoptosis-related proteins Bcl-2 and CD95. Finally, we assessed thymic function by T cell receptor excision circle (TREC) quantification and T cell receptor (TCR) diversity by TCRVβ spectratyping. While the total number of conventional CD4 (Tcon) and CD8 T cells was similar between patient groups, Treg were decreased in cGVHD patients. Interestingly, we also observed divergent patterns of Naive and Stem Cell Memory (SCM) subset recovery in Treg and Tcon compared to CD8. Patients with cGVHD showed impaired recovery of Naive and SCM Tcon and Treg, but significantly increased frequencies and absolute numbers of Naive and SCM were observed in the CD8 pool. Markedly increased EMRA CD8 T cells were also noted in cGVHD. Taken together, these results suggest that Naive, SCM and EMRA CD8 play a role in the emergence of cGHVD. Reduced Naive and recent thymic emigrant Tcon and Treg in cGVHD was likely due to impaired thymic output, as it was accompanied by decreased CD4 TREC and TCR diversity. On the other hand, CD8 TCR diversity was similar between patient groups. Furthermore, no correlation was observed between CD8 TREC content and Naive CD8 numbers, suggesting limited thymic production of Naive CD8 T cells in patients after transplant, especially in those developing cGVHD. The mechanisms behind the opposing patterns of CD4 and CD8 subset cell recovery in cGVHD remain elusive, but may be linked to thymic damage associated with the conditioning regimen and/or acute GVHD
Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation
BACKGROUND:
The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single-nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown.
METHODS:
We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients.
RESULTS:
Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus.
CONCLUSIONS:
Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others) .with HSCT.Supported by grants from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) (to Dr. Carvalho); the German Ministry for Education and Science (03Z2JN21, to Dr. Kurzai); the European Commission (FP7-HEALTH-2009-260338, to Dr. Romani; FP7-HEALTH-2011-280873, to Dr. Mantovani), the European Research Council (ERC-2008-AdG-233417, to Dr. Mantovani; ERC-2011-AdG-293714, to Dr. Romani), Associazione Italiana per la Ricerca sul Cancro (99629, to Dr. Mantovani); and Fundacao para a Ciencia e Tecnologia, Portugal (SFRH/BPD/46292/2008, to Dr. Carvalho; SFRH/BD/65962/2009, to Dr. Cunha; and SFRH/BPD/70783/2010, to Dr. Almeida)
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