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1.
Ann Hematol ; 98(7): 1537-1545, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31025160

RESUMO

The hemoglobinopathies are a group of disorders passed down through families (inherited) in which there is abnormal production or structure of the hemoglobin molecule. They are among the most common inherited diseases around the world. Those that produce abnormal hemoglobin are called structural hemoglobinopathies while thalassemia is another type of disorder that is caused by a defect in the gene production of the globin chains. In a study ambispective comprising 1623 patients, 153 subjects showed an abnormal hemoglobin and 1470 with hypochromic and microcytic anemia, and of these 1470, 23 patients were studied for simultaneously α-thalassemias and structural hemoglobinopathies. Among the α-thalassaemia cases, 1282 cases (87.2%) were deletional α-thalassemia, 172 cases (11.7%) were non-deletional α-thalassemia, and 16 cases (1.1%) were deletional and non-deletional α-thalassamias simultaneously. Thus, approximately 12% of the cases were non-deletional α-thalassaemia. Clinical diagnosis, only 19 severe cases (1 hydrops fetalis and 18 instances of Hb H disease), 1200 thalassamias traits, and 160 thalassaemia silent carriers were recorded within the α-thalassaemia. Regarding structural hemoglobinopathies, there were only 2 cases of hemoglobinopathies with low oxygen affinity and 1 case of hemoglobin M; the remaining 150 were silent hemoglobinopathies. Non-deletional α-thalassaemia represented 12% of all α-thalassemias in our region; the most common deletion in our area was the 3.7-kb deletions, followed by Asian --(SEA) and --(FIL). The alterations responsible for non-deletional α-thalassaemia are most represented by the Hph and Hb Groene Hart and, in the case of structural hemoglobinopathies, Hb Le Lamentin and Hb J-Paris.


Assuntos
Anemia/genética , Sequência de Bases , Hemoglobinas Anormais/genética , Deleção de Sequência , alfa-Globinas/genética , Adulto , Estudos de Coortes , Humanos , Masculino , Espanha
2.
Int J Hematol ; 109(5): 563-571, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30859397

RESUMO

Chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is a rare disease with an indolent clinical course, which is characterized by persistent increase in large granular lymphocytes of NK-cell type. A somatic mutation in signal transducer and activator transcription 3 (STAT3) has been reported in patients with CLPD-NK; however, the details of the mutational profiles and their clinical significance remain unclear. We performed mutation analyses of the STAT3, STAT5B, and TNF-alpha-induced protein 3 (TNFAIP3) genes for mononuclear cell-derived DNA in 17 CLPD-NK patients using allele-specific polymerase chain reaction and amplicon sequencing. Mutations in STAT3 and TNFAIP3 were found in 29% (5/17) and 6% (1/17) of cases, respectively. All patients were negative for STAT5B mutations. In all three STAT3-mutation (+) patients studied, STAT3 mutations were restricted to sorted NK cells. STAT3 mutation (+) patients had a lower hemoglobin level (6.6 g/dL vs. 13.9 g/dL, P = 0.0044) and showed a trend toward reduced neutrophil counts (1.22 × 109/L vs. 3.10 × 109/L, P = 0.070) compared with the STAT3 mutation (-) patients. No mutations in these genes were found in patients with neuropathy. These results suggest that heterogeneity of CLPD-NK and STAT3-mutated NK cells may play a significant role in cytopenia in CLPD-NK patients.


Assuntos
Anemia/genética , Células Matadoras Naturais , Transtornos Linfoproliferativos/genética , Neutropenia/genética , Fator de Transcrição STAT3/genética , Idoso , Idoso de 80 Anos ou mais , Anemia/patologia , Doença Crônica , Feminino , Humanos , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/patologia
3.
Parasitol Res ; 118(4): 1147-1158, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30747294

RESUMO

Trypanosoma carassii is a flagellated bloodstream parasite of cyprinid fish with pathogenesis manifesting primarily as anemia in experimentally infected fish. This anemia is characterized by decreases in the number of circulating red blood cells (RBCs) during peak parasitemia. We examined changes in the key blood metrics and expression of genes known to be important in the regulation of erythropoiesis. Increasing parasitemia was strongly correlated with an overall decrease in the total number of circulating RBCs. Gene expression of key erythropoiesis regulators (EPO, EPOR, GATA1, Lmo2, and HIFα) and proinflammatory cytokines (IFNγ and TNFα) were measured and their expressions differed from those in fish made anemic by injections of phenylhydrazine (PHZ). Significant upregulation of pro-erythropoietic genes was observed in PHZ-induced anemia, but not during peak parasitic infection. Previously, we reported on functional characterization of goldfish erythropoietin (rgEPO) and its ability to induce survival and differentiation of erythroid progenitor cells in vitro. Treatment of goldfish during the infection with rgEPO reduced the severity of anemia but failed to fully prevent the onset of the anemic state in infected fish. Proinflammatory cytokines have been implicated in the suppression of erythropoiesis during trypanosomiasis, specifically the cytokines TNFα, IFNγ, and IL-1ß. Analysis of key proinflammatory cytokines revealed that mRNA levels of IFNγ and TNFα were upregulated in response to infection, but only TNFα increased in response to PHZ treatment. Synergistic activity of the proinflammatory cytokines may be required to sustain prolonged anemia. These findings provide insight into the relationship between T. carassii and host anemia and suggest that T. carassii may directly or indirectly suppress host erythropoiesis.


Assuntos
Anemia/genética , Citocinas/biossíntese , Eritropoese/genética , Regulação da Expressão Gênica/genética , Carpa Dourada/parasitologia , Parasitemia/patologia , Trypanosoma/classificação , Anemia/parasitologia , Animais , Contagem de Eritrócitos , Eritropoetina/biossíntese , Fator de Transcrição GATA1/biossíntese , Interferon gama/biossíntese , Proteínas com Domínio LIM/biossíntese , Fenil-Hidrazinas/farmacologia , RNA Mensageiro/genética , Receptores da Eritropoetina/biossíntese , Tripanossomíase/patologia , Fator de Necrose Tumoral alfa/biossíntese
4.
Eur J Haematol ; 102(3): 203-209, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30578738

RESUMO

The molecular pathogenesis of deletion 5q (del(5q)) myelodysplastic syndrome (MDS) has recently been realized as a result of major advances in our understanding of the mechanisms responsible for clinical phenotype. Identification of commonly deleted genes such as RPS14, miRNA-145, HSPA9, CD78, and CSNK1a1 have elucidated the precise biological changes responsible for the anemia, leukopenia, and thrombocytosis that characterizes del(5q) MDS and highlighted the importance of allelic haploinsufficiency in the hematological phenotype. Recent elegant investigations have also identified a critical role of innate immune signaling in del(5q) pathogenesis. TP53 and Wnt/ß-catenin pathways have also been found to be involved in clonal expansion and progression of the disease as well as resistance and poor outcomes to available therapy. Understanding the molecular pathogenesis of the disease has provided a critical foundation in identifying the biological targets of lenalidomide in del(5q) MDS, which has led to the development of novel therapeutic agents in hematologic malignancies as well as potential alternative targets to exploit in patients who have failed lenalidomide treatment.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas/etiologia , Anemia/diagnóstico , Anemia/genética , Anemia/metabolismo , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Evolução Clonal/genética , Evolução Clonal/imunologia , Progressão da Doença , Haploinsuficiência/genética , Humanos , Imunidade Inata/genética , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/terapia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Ribossômicas/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt
5.
J Oncol Pharm Pract ; 25(1): 16-24, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28814194

RESUMO

OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 µg. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 µg, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types.


Assuntos
Anemia , Antineoplásicos/efeitos adversos , Darbepoetina alfa , Neoplasias/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/genética , Antineoplásicos/classificação , Darbepoetina alfa/administração & dosagem , Darbepoetina alfa/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Eritropoese/efeitos dos fármacos , Feminino , Hematínicos/administração & dosagem , Hematínicos/farmacocinética , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/classificação , Neoplasias/patologia , Estudos Retrospectivos , Estados Unidos
6.
J Sci Food Agric ; 99(1): 473-481, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30014470

RESUMO

BACKGROUND: Iron (Fe) plays a crucial role in several fundamental processes, including erythropoiesis, cellular metabolism, and in cardiovascular disease. The aim of this work was to contribute to a better understanding of the physiology of and recovery from Fe deficiency by studying how fermented milk consumption affects vascular biomarkers during Fe repletion. RESULTS: The deleterious cardiovascular biomarkers cytokine-induced neutrophil chemoattractant 1, connective tissue growth factor (CTGF), interleukin-6, monocyte chemoattractant protein-1 (MCP-1), inhibitor of tissue plasminogen activator 1 total, metallopeptidase inhibitor 1 (TIMP-1), tumor necrosis factor alpha, vascular endothelial growth factor (VEGF), sE-selectin, and soluble intercellular adhesion molecule 1 (sICAM-1) decreased after fermented goat milk consumption in groups of fed animals either with normal Fe or Fe overload with respect to rats fed with fermented cow milk. The beneficial cardiovascular biomarkers caveolin-1 and adiponectin were higher in both control and anemic rats fed fermented goat milk either with normal Fe or Fe overload with respect to fermented cow milk. Anemia decreased TIMP-1 in rats fed fermented goat milk with Fe overload, whereas there was increased CTGF and MCP-1 in animals fed fermented cow milk with either normal or Fe overload. In addition, Fe overload increased VEGF. CONCLUSION: Fermented goat milk consumption improves hematological status and promotes beneficial metabolic responses, which may attenuate cardiovascular risk factors during anemia recovery and iron overload to lessen the inflammatory response, macrophages activation and atherosclerosis development. © 2018 Society of Chemical Industry.


Assuntos
Anemia/dietoterapia , Sistema Cardiovascular/metabolismo , Produtos Fermentados do Leite/análise , Leite/metabolismo , Anemia/genética , Anemia/metabolismo , Anemia/fisiopatologia , Animais , Sistema Cardiovascular/fisiopatologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Produtos Fermentados do Leite/microbiologia , Fermentação , Cabras , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lactobacillus delbrueckii/metabolismo , Masculino , Leite/química , Leite/microbiologia , Ratos Wistar , Streptococcus thermophilus/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Malar J ; 17(1): 467, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545357

RESUMO

BACKGROUND: Evolutionary pressure by Plasmodium falciparum malaria is known to have favoured a large number of human gene adaptations, but there is surprisingly little investigation of the effect of malaria on human mitochondrial sequence variation. Plasmodium falciparum infection can cause severe malaria anaemia (SMA) with insufficient tissue oxygenation, lactic acidosis and death. Despite equal degrees of severe anaemia, some individuals develop lactic acidosis while others do not. A case-control study design was used to investigate whether differences in host mitochondrial gene sequences were associated with lactic acidosis in SMA. Full mitochondrial sequences were obtained from 36 subjects with SMA complicated by lactic acidosis and 37 subjects with SMA without lactic acidosis. The two groups were matched for age, sex, and degree of anaemia. RESULTS: Compared with the reference sequence, a median of 60 nucleotide variants per individual (interquartile range 4-91) was found, with an average frequency of 3.97 variants per 1000 nucleotides. The frequency and distribution of non-synonymous DNA variants in genes associated with oxidative phosphorylation were not statistically different between the two groups. Non-synonymous variants predicted to have the most disruptive effect on proteins responsible for oxidative phosphorylation were present at a similar frequency in both groups. CONCLUSIONS: Lactic acidosis in SMA does not appear to be consistently associated with the high prevalence of any mitochondrial gene variant.


Assuntos
Acidose Láctica , Anemia , DNA Mitocondrial/genética , Malária Falciparum , Acidose Láctica/etiologia , Acidose Láctica/genética , Anemia/etiologia , Anemia/genética , Estudos de Casos e Controles , Pré-Escolar , Feminino , Humanos , Lactente , Ácido Láctico/sangue , Malária Falciparum/complicações , Malária Falciparum/genética , Masculino , Fosforilação Oxidativa , Análise de Sequência de DNA , Uganda/epidemiologia
8.
Mutat Res ; 777: 52-63, 2018 Jul - Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30115430

RESUMO

Anemia is defined by a deficiency of hemoglobin, an iron-rich protein that binds oxygen in the blood. It can be due to multiple causes, either acquired or genetic. Alterations of genes involved in iron metabolism may be responsible, usually at a young age, for rare forms of chronic and often severe congenital anemia. These diseases encompass a variety of sideroblastic anemias, characterized by the presence of ring sideroblasts in the bone marrow. Clinical expression of congenital sideroblastic anemia is either monosyndromic (restricted to hematological lineages) or polysyndromic (with systemic expression), depending on whether iron metabolism, and especially heme synthesis, is directly or indirectly affected. Beside sideroblastic anemias, a number of other anemias can develop due to mutations of key proteins acting either on cellular iron transport (such as the DMT1 transporter), plasma iron transport (transferrin), and iron recycling (ceruloplasmin). Contrasting with the aforementioned entities which involve compartmental, and sometimes, systemic iron excess, the iron refractory iron deficiency anemia (IRIDA) corresponds to a usually severe anemia with whole body iron deficiency related to chronic increase of plasma hepcidin, the systemic negative regulator of plasma iron. Once clinically suggested, these diseases are confirmed by genetic testing in specialized laboratories.


Assuntos
Anemia/genética , Ferro/metabolismo , Mutação , Doenças Raras/genética , Anemia/etiologia , Animais , Heme/biossíntese , Humanos , Absorção Intestinal , Sobrecarga de Ferro/genética , Mitocôndrias/fisiologia , Doenças Raras/etiologia
9.
Food Funct ; 9(6): 3195-3201, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29872815

RESUMO

In spite of the crucial role of the inflammatory state under anemic conditions, to date, no studies have directly tested the modulation of cytokines during iron overload. The aim of this work was to contribute to a better understanding of the pathophysiology and recovery from iron deficiency, by studying how fermented goat milk consumption affects inflammatory signalling during iron repletion. Eighty male Wistar rats were used for a pre-experimental period of 40 days, by dividing them into two groups (the control group receiving a normal-Fe diet and the Fe-deficient group receiving a low-Fe diet). Later, the rats were fed with a fermented goat or cow milk-based diet, with a normal-Fe content or Fe-overload (450 mg kg-1) for 30 days. After feeding the fermented milk, the anti-inflammatory and pro-inflammatory cytokines were assessed. The anti-inflammatory cytokines (IL-13, IL-10 and IL-4) were higher in both groups of animals (control and anemic) fed fermented goat milk either with normal Fe or Fe-overload with respect to the fermented cow milk. With regard to pro-inflammatory signalling, fermented goat milk consumption decreased the pro-inflammatory cytokines (IL-2, TNF-α, IL-1ß, IL-12p70 and IP-10). The Fe overload increased the anti-inflammatory cytokines together with IL-1ß and IP-10. Fermented goat milk consumption improves the hematological status and promotes the beneficial metabolic responses related to the inflammatory signaling in nutritional ferropenic anemia recovery, which may be a dietary strategy to lessen the evoked inflammation during iron repletion. Additionally, the parameters of inflammation should therefore be incorporated as routine biomarkers of iron deficiency or overload severity.


Assuntos
Anemia/dietoterapia , Produtos Fermentados do Leite/análise , Ferro/metabolismo , Leite/metabolismo , Anemia/genética , Anemia/imunologia , Anemia/metabolismo , Animais , Cabras , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Masculino , Leite/química , Ratos Wistar
10.
Biomed Res Int ; 2018: 9405617, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29516014

RESUMO

Erythrocytes play an important role in oxygen and carbon dioxide transport. Although erythrocytes possess no nucleus or mitochondria, they fulfil several metabolic activities namely, the Embden-Meyerhof pathway, as well as the hexose monophosphate shunt. Metabolic processes within the erythrocyte contribute to the morphology/shape of the cell and important constituents are being kept in an active, reduced form. Erythrocytes undergo a form of suicidal cell death called eryptosis. Eryptosis results from a wide variety of contributors including hyperosmolarity, oxidative stress, and exposure to xenobiotics. Eryptosis occurs before the erythrocyte has had a chance to be naturally removed from the circulation after its 120-day lifespan and is characterised by the presence of membrane blebbing, cell shrinkage, and phosphatidylserine exposure that correspond to nucleated cell apoptotic characteristics. After eryptosis is triggered there is an increase in cytosolic calcium (Ca2+) ion levels. This increase causes activation of Ca2+-sensitive potassium (K+) channels which leads to a decrease in intracellular potassium chloride (KCl) and shrinkage of the erythrocyte. Ceramide, produced by sphingomyelinase from the cell membrane's sphingomyelin, contributes to the occurrence of eryptosis. Eryptosis ensures healthy erythrocyte quantity in circulation whereas excessive eryptosis may set an environment for the clinical presence of pathophysiological conditions including anaemia.


Assuntos
Cálcio/metabolismo , Morte Celular/genética , Eriptose/genética , Eritrócitos/metabolismo , Anemia/genética , Anemia/patologia , Apoptose/genética , Eritrócitos/patologia , Humanos , Estresse Oxidativo/genética , Canais de Potássio/genética
11.
BMC Res Notes ; 11(1): 43, 2018 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343300

RESUMO

OBJECTIVE: By measuring the associations between the presence of sickle cell and ß-thalassemia genes, we assessed the extent to which these hemoglobinopathies contribute to the high prevalence of anemia observed in preschool-aged children and women of reproductive age in Sierra Leone. RESULTS: The prevalence of anemia was statistically significantly higher in children with homozygous sickle cell genes (HbSS) than in children with normal hemoglobin genes (HbAA or HbAC), but there was no difference in anemia prevalence in those with heterozygous sickle cell trait (HbAS or HbSC) compared with those with normal hemoglobin genes. In women, there was no difference in anemia prevalence by sickle cell status. In both children and women, there was no difference in the anemia prevalence for individuals with or without the ß-thalassemia gene. For both sickle cell and ß-thalassemia, there was no significant difference in hemoglobin concentrations by sickle cell or ß-thalassemia status. Anemia prevalence was higher in children and women with homozygous sickle cell (HbSS). However, as the prevalence of HbSS children (5.4%) and women (1.6%) was quite small, it is unlikely that these hemoglobinopathies substantially contributed to the high anemia prevalence found in the 2013 national micronutrient survey.


Assuntos
Anemia Falciforme/genética , Anemia/epidemiologia , Anemia/genética , Hemoglobinas/análise , Hemoglobinas/genética , Talassemia beta/genética , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Serra Leoa/epidemiologia
12.
Exp Parasitol ; 185: 29-38, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29309785

RESUMO

Understanding the pathophysiology and associated host parasite interactions of the malaria infection is the prerequisite for developing effective prevention and treatment strategies. The exact mechanism underlying malaria associated ineffective and dyserythropoiesis is not yet fully understood. Being an important protein, haemoglobin serves as the main amino acid reservoir available to the intra-erythrocytic plasmodium. It is important to check the expression profiling of globin genes which may help us to understand host parasite interactions and its potential contribution to both infection and disease. Here, an in-vitro culture system was used to study the effect of different doses of Plasmodium falciparum on haematopoietic stem cell expansion, differentiation and expression of globin genes. Upon exposure to the different doses of P. falciparum parasites of strains 3D7, Dd2 and RKL9 (intact and lysed form) at different stages of erythroid development, cells demonstrated suppression in growth and differentiation. At almost all stages of erythroid development upon parasite exposure, the γ globin gene was found to be downregulated and the α/ß as well as α/non- α globin mRNA ratios in late stage erythroid cells were found to be reduced (p < .01) compared to the untreated controls. The imbalance in globin chain expression might be considered as one of the factors involved in malaria associated inappropriate erythropoietic responses.


Assuntos
Anemia/etiologia , Regulação da Expressão Gênica/genética , Globinas/genética , Células-Tronco Hematopoéticas/parasitologia , Malária Falciparum/genética , Anemia/genética , Anemia/metabolismo , Antígenos CD34/sangue , Biomarcadores/metabolismo , Células Cultivadas , Eritrócitos/parasitologia , Eritrócitos/patologia , Células Eritroides/imunologia , Sangue Fetal/citologia , Globinas/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Hemólise , Interações Hospedeiro-Parasita/genética , Humanos , Malária Falciparum/complicações , Reação em Cadeia da Polimerase em Tempo Real
13.
Hematology ; 23(3): 187-191, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28945175

RESUMO

OBJECTIVES: To report the hematological and molecular features as well as diagnostic aspects of the hitherto un-described interactions of two rare α-globin chain variants with α0-thalassemia commonly found among Southeast Asian populations. METHODS: The study was done on two adult Thai patients (P1 and P2) who had hypochromic microcytic anemia. Hb analysis was carried out using high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Mutations were identified by PCR and related techniques. RESULTS: Hb analysis of P1 using HPLC showed a normal Hb pattern, but CE demonstrated an abnormal peak at zone 7. DNA sequencing identified a CCG-CTG mutation at codon 95 of the α2 globin gene corresponding to the Hb G-Georgia [α95(G2)Pro → Leu(α2)] previously undescribed in the Thai population. In contrast, Hb analysis of P2 demonstrated an abnormal peak not fully separated from Hb A on HPLC, but not on CE. DNA analysis identified the rarely described Hb Nakhon Ratchasima [α63(E12)Ala → Val(α2)] mutation. Routine DNA analysis detected the SEA deletion α0-thalassemia in trans to the Hb variants in both cases. Hematological parameters were compared with those of patients with compound heterozygote for other α-globin variants and α0-thalassemia previously documented. CONCLUSIONS: Identification of the patients confirmed that interaction of these rare Hb variants with α0-thalassemia does not lead to the Hb H disease. Differentiation of these two Hb variants from other clinically relevant hemoglobinopathies in a routine setting is, however, necessary. This can be accomplished using a combined Hb-HPLC and CE analysis followed by PCR-RFLP assays.


Assuntos
Hemoglobinas Anormais/genética , Deleção de Sequência , alfa-Globinas/genética , Talassemia alfa/genética , Adulto , Anemia/sangue , Anemia/genética , Anemia Hipocrômica/sangue , Anemia Hipocrômica/genética , Hemoglobinopatias/sangue , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/genética , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Tailândia , Talassemia alfa/sangue
14.
Transfusion ; 58(1): 196-199, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29047116

RESUMO

BACKGROUND: Mutation in the KLF1 gene is the cause of the In(Lu) (Inhibitor of Lutheran) Lu(a-b-) phenotype and more than 60 alleles have been associated with this phenotype. Here we describe findings from investigation of seven cases: six presenting with a Lu(a-b-) phenotype including the historical index case and one referred from a patient with chronic anemia. STUDY DESIGN AND METHODS: Serologic testing was by standard methods. DNA testing included amplification and sequencing of KLF1 and LU coding regions. A StuI polymerase chain reaction-restriction fragment length polymorphism was designed to target c.304T>C in KLF1. RESULTS: Five different KLF1 alleles were identified. Three are new: KLF1*90A (p.Trp30Ter), KLF*911A (p.Thr304Lys), and KLF1*304C,318G (p. Ser102Pro, Tyr106Ter) present in two unrelated individuals. Two, including the index case, had c.954dupG (p.Arg319Glufs*34), that is, KLF1*BGM06. The child with unexplained anemia had c.973G>A (p.Glu325Lys), associated with congenital dyserythropoietic anemia. The common c.304T>C was found in two of the seven samples investigated and in 60 of 100 blood donors. CONCLUSION: Mutations in KLF1 are pleiotropic and although most are benign, others are associated with hematologic abnormalities. We report three new KLF1 alleles associated with benign In(Lu) and document both the molecular basis of the original In(Lu) phenotype using a frozen sample stored for more than 50 years and the cause of unexplained anemia in a child. We also confirm previous observations that c.304C (p.102Pro) is not, by itself, associated with an In(Lu) phenotype in donors self-identified as U.S. minorities.


Assuntos
Pleiotropia Genética , Fatores de Transcrição Kruppel-Like/genética , Sistema do Grupo Sanguíneo Lutheran/genética , Mutação de Sentido Incorreto , Mutação Puntual , Adolescente , Adulto , Alelos , Anemia/genética , Anemia Diseritropoética Congênita/genética , Doadores de Sangue , Preservação de Sangue , Criança , Criopreservação , Feminino , Estudos de Associação Genética , Humanos , Isoanticorpos/sangue , Isoanticorpos/imunologia , Sistema do Grupo Sanguíneo Lutheran/sangue , Sistema do Grupo Sanguíneo Lutheran/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
15.
Pediatr Hematol Oncol ; 34(8): 449-454, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29227722

RESUMO

After a thirty-year lag, we serendipitously reestablished contact with a patient with glucose phosphate isomerase deficiency and hydrops fetalis first reported in 1987. We now provide a clinical update and provide results of mutation analysis in this patient, from Southern India. The patient now an adult female of 36 years of age has moderate anemia but requires no transfusions except with some intercurrent illnesses. Exome sequencing studies showed a homozygous c.1018C>T (Pro340Ser) mutation in exon 12 of the glucose phosphate isomerase gene and later confirmed by direct sequencing. This mutation has not been previously described. To our knowledge, this is also the first known homozygous mutation in the hydrophobic core of the protein and is a highly deleterious mutation by in silico analysis and by clinical history in the family. Flow cytometry studies of band 3 content with eosin maleimide showed a unique tail of red cells on histograms, reflecting the dense red cells (presumably ATP depleted) seen on blood smears; similar findings were seen in patients with pyruvate kinase and phosphoglycerate kinase deficiency.


Assuntos
Anemia/genética , Homozigoto , Hidropisia Fetal/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Anemia/sangue , Anemia/terapia , Citocinas/deficiência , Feminino , Glucose-6-Fosfato Isomerase , Humanos , Hidropisia Fetal/sangue
16.
Clin J Am Soc Nephrol ; 12(12): 1974-1983, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29146700

RESUMO

BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ciliopatias/genética , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Fenótipo , Adolescente , Anemia/genética , Antígenos de Neoplasias/genética , Proteínas de Ligação a Calmodulina/genética , Proteínas de Transporte/genética , Criança , Ciliopatias/complicações , Estudos Transversais , Feminino , Taxa de Filtração Glomerular/genética , Homozigoto , Humanos , Rim/diagnóstico por imagem , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Falência Renal Crônica/fisiopatologia , Cinesina/genética , Estudos Longitudinais , Masculino , Proteínas de Neoplasias/genética , Doenças do Sistema Nervoso/genética , Poliúria/genética , Proteínas/genética , Ultrassonografia , Adulto Jovem
17.
Ann Biol Clin (Paris) ; 75(6): 689-694, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29043985

RESUMO

Mast cell leukemia is an extremely rare disease, which belongs to the systemic mastocytosis group (WHO 2016). We are reporting the case of a 79-year-old woman, without any hematological particular history consulting for hyperthermia, repeated malaise and subacute anemia. Her clinical examination was normal. Unusual cells were seen on blood and bone marrow smears. They represent more than 10% of blood nucleated cells end more than 20% of the bone marrow nucleated cells. Bone marrow immunophenotyping was performed to characterize these cells. It revealed a cell subset expressing the surface antigens CD117, CD2 and CD25. This immunophenotypic profile is the hallmark of malignant mast cells. Then mast cell leukemia diagnosis could have been made and KIT gene sequencing highlighted the N822Y mutation in exon 17. The patient was initially treated with midostaurin, a tyrosine kinase inhibitor. Lack of therapeutic response and absence of the KIT D816V mutation led to switch to imatinib, following the latest scientific recommendations.


Assuntos
Anemia/diagnóstico , Células Sanguíneas/patologia , Leucemia de Mastócitos/diagnóstico , Mastócitos/patologia , Mastocitose Sistêmica/diagnóstico , Idoso , Substituição de Aminoácidos , Anemia/sangue , Anemia/genética , Citodiagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Leucemia de Mastócitos/sangue , Leucemia de Mastócitos/genética , Mastocitose Sistêmica/sangue , Mastocitose Sistêmica/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-kit/genética
18.
Nature ; 550(7677): 524-528, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-29045386

RESUMO

Sphingosine-1-phosphate (S1P), a potent signalling lipid secreted by red blood cells and platelets, plays numerous biologically significant roles. However, the identity of its long-sought exporter is enigmatic. Here we show that the major facilitator superfamily transporter 2b (Mfsd2b), an orphan transporter, is essential for S1P export from red blood cells and platelets. Comprehensive lipidomic analysis indicates a dramatic and specific accumulation of S1P species in Mfsd2b knockout red blood cells and platelets compared with that of wild-type controls. Consistently, biochemical assays from knockout red blood cells, platelets, and cell lines overexpressing human and mouse Mfsd2b proteins demonstrate that Mfsd2b actively exports S1P. Plasma S1P level in knockout mice is significantly reduced by 42-54% of that of wild-type level, indicating that Mfsd2b pathway contributes approximately half of the plasma S1P pool. The reduction of plasma S1P in knockout mice is insufficient to cause blood vessel leakiness, but it does render the mice more sensitive to anaphylactic shock. Stress-induced erythropoiesis significantly increased plasma S1P levels and knockout mice were sensitive to these treatments. Surprisingly, knockout mice exhibited haemolysis associated with red blood cell stomatocytes, and the haemolytic phenotype was severely increased with signs of membrane fragility under stress erythropoiesis. We show that S1P secretion by Mfsd2b is critical for red blood cell morphology. Our data reveal an unexpected physiological role of red blood cells in sphingolipid metabolism in circulation. These findings open new avenues for investigating the signalling roles of S1P derived from red blood cells and platelets.


Assuntos
Plaquetas/metabolismo , Eritrócitos/metabolismo , Lisofosfolipídeos/metabolismo , Proteínas de Membrana/metabolismo , Esfingosina/análogos & derivados , Anemia/genética , Anemia/metabolismo , Animais , Transporte Biológico , Forma Celular , Contagem de Eritrócitos , Eritrócitos/citologia , Deleção de Genes , Células HEK293 , Humanos , Lisofosfolipídeos/sangue , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Esfingosina/sangue , Esfingosina/metabolismo
19.
Blood ; 130(23): 2537-2547, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29018082

RESUMO

The orphan nuclear receptors TR4 (NR2C2) and TR2 (NR2C1) are the DNA-binding subunits of the macromolecular complex, direct repeat erythroid-definitive, which has been shown to repress ε- and γ-globin transcription during adult definitive erythropoiesis. Previous studies implied that TR2 and TR4 act largely in a redundant manner during erythroid differentiation; however, during the course of routine genetic studies, we observed multiple variably penetrant phenotypes in the Tr4 mutants, suggesting that indirect effects of the mutation might be masked by multiple modifying genes. To test this hypothesis, Tr4+/- mutant mice were bred into a congenic C57BL/6 background and their phenotypes were reexamined. Surprisingly, we found that homozygous Tr4 null mutant mice expired early during embryogenesis, around embryonic day 7.0, and well before erythropoiesis commences. We further found that Tr4+/- erythroid cells failed to fully differentiate and exhibited diminished proliferative capacity. Analysis of Tr4+/- mutant erythroid cells revealed that reduced TR4 abundance resulted in decreased expression of genes required for heme biosynthesis and erythroid differentiation (Alad and Alas2), but led to significantly increased expression of the proliferation inhibitory factor, cyclin dependent kinase inhibitor (Cdkn1c) These studies support a vital role for TR4 in promoting erythroid maturation and proliferation, and demonstrate that TR4 and TR2 execute distinct, individual functions during embryogenesis and erythroid differentiation.


Assuntos
Diferenciação Celular/genética , Células Eritroides/citologia , Células Eritroides/metabolismo , Membro 2 do Grupo C da Subfamília 2 de Receptores Nucleares/genética , Anemia/sangue , Anemia/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proliferação de Células/genética , Eritropoese/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Heterozigoto , Homozigoto , Linfopoese/genética , Camundongos , Camundongos Knockout , Mutação , Mielopoese/genética , Membro 2 do Grupo C da Subfamília 2 de Receptores Nucleares/metabolismo
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