RESUMO
Through studies in mice and in humans, Stuart Orkin showed that GATA-1 is a master transcriptional regulator of hematopoiesis. He has highlighted the role of BCL11A in the fetal-adult hemoglobin switch. The Gairdner Foundation Award recognizes Orkin's contribution to the development of gene therapy of sickle cell disease.
Assuntos
Anemia Falciforme , Distinções e Prêmios , Terapia Genética , Anemia Falciforme/genética , Anemia Falciforme/terapia , Animais , Modelos Animais de Doenças , Hemoglobina Fetal/genética , Hematopoese/genética , Humanos , Camundongos , Proteínas Repressoras/genéticaRESUMO
I was attracted to hematology because by combining clinical findings with the use of a microscope and simple laboratory tests, one could often make a diagnosis. I was attracted to genetics when I learned about inherited blood disorders, at a time when we had only hints that somatic mutations were also important. It seemed clear that if we understood not only what genetic changes caused what diseases but also the mechanisms through which those genetic changes contribute to cause disease, we could improve management. Thus, I investigated many aspects of the glucose-6-phosphate dehydrogenase system, including cloning of the gene, and in the study of paroxysmal nocturnal hemoglobinuria (PNH), I found that it is a clonal disorder; subsequently, we were able to explain how a nonmalignant clone can expand, and I was involved in the first trial of PNH treatment by complement inhibition. I was fortunate to do clinical and research hematology in five countries; in all of them, I learned from mentors, from colleagues, and from patients.
Assuntos
Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/patologia , Células Sanguíneas/patologia , Células Clonais/patologiaRESUMO
Three and a half years after the pandemic outbreak, now that WHO has formally declared that the emergency is over, COVID-19 is still a significant global issue. Here, we focus on recent developments in genetic and genomic research on COVID-19, and we give an outlook on state-of-the-art therapeutical approaches, as the pandemic is gradually transitioning to an endemic situation. The sequencing and characterization of rare alleles in different populations has made it possible to identify numerous genes that affect either susceptibility to COVID-19 or the severity of the disease. These findings provide a beginning to new avenues and pan-ethnic therapeutic approaches, as well as to potential genetic screening protocols. The causative virus, SARS-CoV-2, is still in the spotlight, but novel threatening virus could appear anywhere at any time. Therefore, continued vigilance and further research is warranted. We also note emphatically that to prevent future pandemics and other world-wide health crises, it is imperative to capitalize on what we have learnt from COVID-19: specifically, regarding its origins, the world's response, and insufficient preparedness. This requires unprecedented international collaboration and timely data sharing for the coordination of effective response and the rapid implementation of containment measures.
Assuntos
COVID-19 , Humanos , COVID-19/terapia , SARS-CoV-2/genética , Evolução Molecular , Estudo de Associação Genômica Ampla , GenômicaRESUMO
Glucose-6-phosphate dehydrogenase (G6PD) deficiency in erythrocytes causes acute haemolytic anaemia upon exposure to fava beans, drugs, or infection; and it predisposes to neonatal jaundice. The polymorphism of the X-linked G6PD gene has been studied extensively: allele frequencies of up to 25% of different G6PD deficient variants are known in many populations; variants that cause chronic non-spherocytic haemolytic anaemia (CNSHA) are instead all rare. WHO recommends G6PD testing to guide 8-aminoquinolines administration to prevent relapse of Plasmodium vivax infection. From a literature review focused on polymorphic G6PD variants we have retrieved G6PD activity values of 2291 males, and for the mean residual red cell G6PD activity of 16 common variants we have obtained reliable estimates, that range from 1.9% to 33%. There is variation in different datasets: for most variants most G6PD deficient males have a G6PD activity below 30% of normal. There is a direct relationship between residual G6PD activity and substrate affinity (Km G6P ), suggesting a mechanism whereby polymorphic G6PD deficient variants do not entail CNSHA. Extensive overlap in G6PD activity values of individuals with different variants, and no clustering of mean values above or below 10% support the merger of class II and class III variants.
Assuntos
Deficiência de Glucosefosfato Desidrogenase , Masculino , Recém-Nascido , Humanos , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Eritrócitos , Polimorfismo Genético , Hemólise , Organização Mundial da SaúdeRESUMO
COVID-19, which is caused by the SARS-CoV-2, has ravaged the world for the past 2 years. Here, we review the current state of research into the disease with focus on its history, human genetics and genomics and the transition from the pandemic to the endemic phase. We are particularly concerned by the lack of solid information from the initial phases of the pandemic that highlighted the necessity for better preparation to face similar future threats. On the other hand, we are gratified by the progress into human genetic susceptibility investigations and we believe now is the time to explore the transition from the pandemic to the endemic phase. The latter will require worldwide vigilance and cooperation, especially in emerging countries. In the transition to the endemic phase, vaccination rates have lagged and developed countries should assist, as warranted, in bolstering vaccination rates worldwide. We also discuss the current status of vaccines and the outlook for COVID-19.
Assuntos
COVID-19 , Influenza Humana , Humanos , Pandemias/prevenção & controle , SARS-CoV-2RESUMO
Glucose 6-phosphate dehydrogenase (G6PD) deficiency is 1 of the commonest human enzymopathies, caused by inherited mutations of the X-linked gene G6PD. G6PD deficiency makes red cells highly vulnerable to oxidative damage, and therefore susceptible to hemolysis. Over 200 G6PD mutations are known: approximately one-half are polymorphic and therefore common in various populations. Some 500 million persons with any of these mutations are mostly asymptomatic throughout their lifetime; however, any of them may develop acute and sometimes very severe hemolytic anemia when triggered by ingestion of fava beans, by any of a number of drugs (for example, primaquine, rasburicase), or, more rarely, by infection. Approximately one-half of the G6PD mutations are instead sporadic: rare patients with these mutations present with chronic nonspherocytic hemolytic anemia. Almost all G6PD mutations are missense mutations, causing amino acid replacements that entail deficiency of G6PD enzyme activity: they compromise the stability of the protein, the catalytic activity is decreased, or a combination of both mechanisms occurs. Thus, genotype-phenotype correlations have been reasonably well clarified in many cases. G6PD deficiency correlates remarkably, in its geographic distribution, with past/present malaria endemicity: indeed, it is a unique example of an X-linked human polymorphism balanced through protection of heterozygotes from malaria mortality. Acute hemolytic anemia can be managed effectively provided it is promptly diagnosed. Reliable diagnostic procedures are available, with point-of-care tests becoming increasingly important where primaquine and its recently introduced analog tafenoquine are required for the elimination of malaria.
Assuntos
Deficiência de Glucosefosfato Desidrogenase , Infecções por HIV , Doadores de Sangue , Segurança do Sangue , Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Primaquina/uso terapêuticoRESUMO
COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics, such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and we call for bypassing local politics in the interest of humankind on all continents.
Assuntos
COVID-19/genética , COVID-19/virologia , Pandemias , Anticorpos Monoclonais/uso terapêutico , COVID-19/prevenção & controle , COVID-19/terapia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Predisposição Genética para Doença , Política de Saúde , Humanos , Saúde da População , SARS-CoV-2 , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Vacinas de mRNARESUMO
PNH is a chronic hemolytic disorder due to an intrinsic red cell abnormality. There is no evidence that either prolonged administration of corticosteroids or chemotherapy are beneficial in PNH. On the other hand, patients can live with PNH for many years with supportive management. At the moment complement inhibitor therapy is indicated in most cases; and it is highly desirable that the current financial barriers to this therapy be overcome.
Assuntos
Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , HemóliseRESUMO
BACKGROUND: Tanzania ranks as the fourth country in the world with respect to the number of sickle cell disease (SCD) births; it is also endemic to the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV). This study was done to determine the prevalence of HIV and HBV infections among SCD patients in Dar es Salaam, Tanzania. METHODS: A multicenter hospital-based descriptive cross sectional study was carried out among participants aged ≥ 16 years with a proven diagnosis of SCD. Socio-demographic and clinical data were recorded. Blood samples were drawn for HIV and HBV diagnosis. All categorical variables were summarized into frequencies. RESULTS: There were 185/325 (56.9 %) females. The mean age (SD) was 23.0 ± 7.5 years. The prevalence of HIV was 1.8 %; the prevalence of HBV was 1.2 %. CONCLUSIONS: The prevalence of both HIV and HBV in SCD patients is no greater than in the general population of Dar es Salaam or Tanzania. For associations, a large study would be needed. From a detailed blood transfusion history of SCD patients we found no evidence that HIV or HBV infection was transmitted through blood transfusion.
Assuntos
Anemia Falciforme , Infecções por HIV , Hepatite B , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Estudos Transversais , Feminino , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Hepatite B/epidemiologia , Vírus da Hepatite B , Humanos , Masculino , Prevalência , Tanzânia/epidemiologia , Adulto JovemRESUMO
In the UK, early work on paroxysmal nocturnal haemoglobinuria (PNH) was conducted by John Dacie who, at the Hammersmith Hospital, first hypothesised that the PNH abnormality might arise through a somatic mutation; and who outlined with S.M. Lewis the relationship between PNH and aplastic anaemia. When the phosphatidylinositol glycan anchor biosynthesis Class A (PIGA) gene was identified by Taroh Kinoshita's group, jointly with him the Hammersmith group proved that PNH is caused in most patients by a single somatic mutation in the PIGA gene. At the same time, after Bruno Rotoli had spent a sabbatical at the Hammersmith, the 'immune escape model' for the pathogenesis of PNH was developed. Early this century, Peter Hillmen, formerly at the Hammersmith and now in Leeds, spearheaded the use of the complement-blocking (anti-C5) antibody eculizumab. This new medicine radically changed the management and the clinical course of patients with PNH. Recently a derivative of eculizumab with more favourable pharmacokinetics has been introduced. In view of the fact that these agents are associated with C3-dependent extravascular haemolysis, it is important that a number of inhibitors of the proximal complement pathway are now in the offing and may further improve the life of patients with PNH.
Assuntos
Hemoglobinúria Paroxística/terapia , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/etiologia , Humanos , Resultado do Tratamento , Reino UnidoRESUMO
Patients with sickle cell disease (SCD) with high fetal haemoglobin (HbF) tend to have a lower incidence of complications and longer survival due to inhibition of deoxyhaemoglobin S (HbS) polymerisation by HbF. HbF-containing cells, namely F cells, are strongly influenced by genetic factors. We measured the percentage of F cells (Fcells%) in 222 patients with SCD to evaluate the association of (i) Fcells% with genetic HbF-modifier variants and (ii) Fcells% with haematological parameters. There was a different distribution of Fcells% in females compared to males. The association of the B-cell lymphoma/leukaemia 11A (BCL11A) locus with Fcells% (ß = 8·238; P < 0·001) and with HbF% (ß = 2·490; P < 0·001) was significant. All red cell parameters except for Hb and mean corpuscular Hb concentration levels in males and females were significantly different. The Fcells% was positively associated with mean cell Hb, mean cell volume and reticulocytes. To explain the significant gender difference in Fcells%, we tested for associations with single nucleotide polymorphisms on the X chromosomal region Xp22.2, where a genetic determinant of HbF had been previously hypothesised. We found in males a significant association with a SNP in FERM and PDZ domain-containing protein 4 (FRMPD4) and adjacent to male-specific lethal complex subunit 3 (MSL3). Thus, we have identified an X-linked locus that could account for a significant fraction of the Fcells% variation in patients with SCD.
Assuntos
Anemia Falciforme , Cromossomos Humanos X/genética , Eritrócitos Anormais/metabolismo , Genes Ligados ao Cromossomo X , Polimorfismo Genético , Proteínas Repressoras/genética , Reticulócitos/metabolismo , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/genética , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Inativadores do Complemento , Hemoglobinúria Paroxística , Hemólise , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento/fisiologia , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise/efeitos dos fármacos , Hemólise/fisiologia , HumanosRESUMO
BACKGROUND: Patients with sickle cell disease (SCD), an inherited haemoglobinopathy, have increased risk of malaria, at least in part due to impaired splenic function. Infection with Plasmodium falciparum in SCD patients can trigger painful vaso-occlusive crisis, increase the severity of anaemia, and contribute to early childhood mortality. CASE PRESENTATION: A 17 year-old Tanzanian male with known SCD was admitted to Muhimbili National Hospital, a tertiary referral centre in Dar-es-Salaam, following an attack of malaria. From 2004 to 2007 the patient had lived in USA, and from 2010 to 2016 in France where, on account of hypersplenism and episodes of splenic sequestrations, in 2014 the spleen was removed. After appropriate clinical and laboratory assessment the patient was re-started on hydroxyurea; and anti-malarial-prophylaxis with proguanil was instituted. The patient has remained well and malaria-free for the following 15 months. CONCLUSION: SCD patients are highly vulnerable to malaria infection, and impaired splenic function is a feature of SCD patients, even in those who still anatomically have a spleen. This patient had a surgical splenectomy and, in addition, had probably lost some of the acquired malaria-immunity by having lived for several years in malaria-free areas. This patient is a compelling reminder that long-term anti-malarial prophylaxis should be offered to all patients with SCD who live in malaria-endemic areas.
Assuntos
Anemia Falciforme/complicações , Antimaláricos/administração & dosagem , Antidrepanocíticos/administração & dosagem , Hidroxiureia/administração & dosagem , Malária Falciparum/tratamento farmacológico , Proguanil/administração & dosagem , Adolescente , Humanos , Malária Falciparum/parasitologia , Masculino , Esplenectomia , TanzâniaRESUMO
BACKGROUND: Abnormalities of blood cell counts and of cytokine profiles in women with hypertensive disorders of pregnancy (HDP) have been reported in several studies. Although their cause-effect relationships to HDP are not yet clear, detecting and monitoring these alterations can be of use for prognosis and management of HDP. This study aimed to determine hematological, coagulation and cytokine profiles in hypertensive as compared to normotensive pregnancy and to identify correlations between these profiles. METHODS: This was a hospital-based comparative cross-sectional study conducted from September 2017 to February 2018. There were two groups: the comparison group consisted of 77 normotensive pregnant women attending the antenatal clinic of Muhimbili National Hospital (MNH); the index group consisted of 76 hypertensive pregnant women admitted to the maternity block of the same hospital. Hematological and cytokine parameters were compared between the hypertensive and the normotensive group. We analyzed the data using Student's independent t-test when the data were normally distributed; and the Mann-Whitney U-test when the data were not normally distributed. Kruskal Wallis with Dunn's multiple comparison tests was run for subgroup analysis and correlation studies were done using Spearman ranking. RESULTS: Hemoglobin levels were slightly but significantly lower, (P < 0.01) in women with HDP compared to normotensive (N) women; the same was true for platelet counts (P < 0.001). The red cell distribution width (RDW) was slightly but significantly higher in HDP than in N. Neutrophil counts and Interleukin 6 (IL-6) levels were significantly (P < 0.001) higher in HDP than in N; and within HDP IL-6 levels increased with increasing severity of HDP. A novel remarkable finding was that eosinophil counts, normal in N, were lower and lower with increasing severity of HDP, to the point that they were nearly absent in women with eclampsia. CONCLUSION: There are significant changes in hematological, cytokine and coagulation parameters in pregnant women with hypertensive disorders compared to normotensive pregnant women. The picture that emerges is that of an inflammatory state associated with hypertensive disorders of pregnancy.
Assuntos
Citocinas/sangue , Hipertensão Induzida pela Gravidez/sangue , Interleucina-6/sangue , Testes para Triagem do Soro Materno/estatística & dados numéricos , Trimestres da Gravidez/sangue , Adulto , Contagem de Células Sanguíneas , Pressão Sanguínea , Estudos Transversais , Eclampsia/sangue , Eosinófilos , Índices de Eritrócitos , Feminino , Hemoglobinas/análise , Humanos , Inflamação , Neutrófilos , Gravidez , Cuidado Pré-Natal , Índice de Gravidade de Doença , Adulto JovemRESUMO
This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno-suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol -specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto-immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre-leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.