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1.
Hum Genomics ; 15(1): 27, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33966626

RESUMO

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.

2.
Blood Adv ; 5(5): 1403-1411, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33666650

RESUMO

Imatinib is the mainstay of treatment of patients with chronic myeloid leukemia (CML) in Tanzania. Monitoring molecular response to therapy by real-time polymerase chain reaction at defined milestones is necessary for early detection of treatment failure. However, this assay is not routinely performed in Tanzania; therefore, the depth of molecular response among patients with CML is not known. A total of 158 patients with previously diagnosed CML who received imatinib treatment were recruited from January 2019 and followed up through October 2020 at Ocean Road Cancer Institute. Information was obtained at the time of diagnosis and follow-up. Blood samples were collected in EDTA tubes to measure the BCR/ABL ratio on the Gene Xpert system for molecular response determination. The median age of the 158 adult patients was 45 years (range, 18-86). By reference to established treatment milestones, only 37 (23.4%) achieved optimal molecular response. Signs of advanced-stage disease, in particular the need for red cell transfusions before diagnosis (adjusted odds ratio [AOR], 3.4; 95% CI, 1.32-9.17) and cytopenias (AOR, 2.26; 95% CI, 1.03-4.96) necessitating drug interruptions were statistically validated predictors of treatment failure on multivariate, multinomial logistic regression. Patient survival at the 22-month follow-up was lowest, with 78.6% (95% CI, 69.4-85.4) in the failure-to-respond category and highest in patients achieving optimal response 97.0% (95% CI, 80.9-99.6). In summary, the majority of patients with CML treated with imatinib in Tanzania do not obtain deep molecular response. This outcome can be attributed to late diagnosis, the development of cytopenias requiring multiple drug interruptions, and poor adherence to treatment.

3.
Br J Haematol ; 191(4): 579-586, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33190263

RESUMO

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.

4.
Br J Haematol ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073380

RESUMO

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.

7.
Blood ; 136(11): 1225-1240, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32702756

RESUMO

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.

8.
Malar J ; 19(1): 165, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32334583

RESUMO

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.

9.
Br J Haematol ; 189(5): 802-805, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32166737
11.
Nat Genet ; 51(10): 1518-1529, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570891

RESUMO

RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2'-O-methylation (2'-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2'-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2'-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure. We identify NPM1 germline mutations in patients with dyskeratosis congenita presenting with bone marrow failure and demonstrate that they are deficient in small nucleolar RNA binding. Mice harboring a dyskeratosis congenita germline Npm1 mutation recapitulate both hematological and nonhematological features of dyskeratosis congenita. Thus, our findings indicate that impaired 2'-O-Me can be etiological to human disease.


Assuntos
Disceratose Congênita/genética , Epigenômica/métodos , Mutação em Linhagem Germinativa , Proteínas Nucleares/genética , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Ribossômico/genética , Animais , Disceratose Congênita/patologia , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/química , RNA Nucleolar Pequeno , Transcriptoma
13.
Future Microbiol ; 14: 1261-1279, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31596137

RESUMO

Malaria puts more than 3 billion people at risk of infection and causes high morbidity and mortality. Plasmodium vivax forms hypnozoites, which may initiate recurrences, even in the absence of reinfection or superinfection. Until recently, the only drug available for eliminating hypnozoites was primaquine (PQ), which, given its short half-life, requires a relatively long course of treatment. Tafenoquine (TQ) is a PQ analog with a longer half-life. This enables radical cure of malaria with a single dose and overcomes adherence issues associated with PQ, thereby increasing effectiveness in real-life settings. Clinical studies have provided sound evidence for TQ's safety and efficacy against malaria, which recently led to its approval by the US FDA. Here, we review aspects of TQ, including how to avoid hemolytic anemia in G6PD deficient patients. We believe that TQ promises to be a major advance toward malaria elimination.


Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Aminoquinolinas/farmacocinética , Animais , Antimaláricos/farmacocinética , Avaliação de Medicamentos , Humanos , Plasmodium vivax/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
BMC Pregnancy Childbirth ; 19(1): 237, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288789

RESUMO

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 Jovem
16.
Recenti Prog Med ; 110(5): 221-229, 2019 05.
Artigo em Italiano | MEDLINE | ID: mdl-31140454

RESUMO

The incentives provided by Orphan Drugs Regulations have promoted the development of drugs that effectively ameliorate the course of serious conditions that had previously been neglected. However, the treatment of each individual patient with any of these drugs - the so-called 'orphan drugs' - is so expensive, that the total burden for publicly funded Health care Service is enormous and may become unsustainable. Italy is no exception, if it is to abide by its basic tenet of providing access to essential medicines - free of charge - to the entire population. We do not see any glimpses of improvement on the horizon: therefore we suggest that radical change must be introduced. First, price negotiation ought to take place at the European level, not at the member state level. Second, pricing should take into account not only value for patients, but also costs of research and development (R&D) plus production. Italian Medicines Agency (AIFA) should also support research focused on optimizing the effective use of orphan drugs in clinical practice. The challenges are complex: but AIFA is recognized as an authoritative body, and may be able to coagulate the agreement of other regulatory agencies for the ultimate purpose of achieving, for each of the orphan drugs a more reasonable 'European price'.


Assuntos
Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Doenças Raras/tratamento farmacológico , Custos de Medicamentos , Desenvolvimento de Medicamentos/economia , Desenvolvimento de Medicamentos/legislação & jurisprudência , Indústria Farmacêutica/economia , Indústria Farmacêutica/legislação & jurisprudência , Humanos , Itália , Produção de Droga sem Interesse Comercial/economia , Doenças Raras/economia
17.
Lancet ; 393(10181): 1595-1596, 2019 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31007199
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