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2.
Ann Biol Clin (Paris) ; 78(4): 425-432, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32618564

RESUMO

Wilson disease is a rare inherited disorder of copper metabolism that affects liver and brain due to copper tissue accumulation. The mechanism involved is based on mutations of the ATP7B gene. Children have predominant hepatic manifestations while adult are more often diagnosed by neurological and psychiatric symptoms. However, others features are tubulopathy, articular disorders and hemolytic anemia. We report the diagnostic of Wilson disease in a 14 years old girl and her sibling after investigation of hemolytic anemia, hepatic insufficiency, and hypophosphatemia.


Assuntos
Anemia Hemolítica/diagnóstico , Degeneração Hepatolenticular/diagnóstico , Doença Aguda , Adolescente , Anemia Hemolítica/complicações , Criança , Pré-Escolar , ATPases Transportadoras de Cobre/genética , Diagnóstico Diferencial , Família , Feminino , Hemólise/fisiologia , Insuficiência Hepática/complicações , Insuficiência Hepática/diagnóstico , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/genética , Humanos , Hipofosfatemia/complicações , Hipofosfatemia/diagnóstico , Masculino , Irmãos
5.
Haematologica ; 105(3): 610-622, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31413092

RESUMO

Hereditary xerocytosis is a dominantly inherited red cell membrane disorder caused in most cases by gain-of-function mutations in PIEZO1, encoding a mechanosensitive ion channel that translates a mechanic stimulus into calcium influx. We found that PIEZO1 was expressed early in erythroid progenitor cells, and investigated whether it could be involved in erythropoiesis, besides having a role in the homeostasis of mature red cell hydration. In UT7 cells, chemical PIEZO1 activation using YODA1 repressed glycophorin A expression by 75%. This effect was PIEZO1-dependent since it was reverted using specific short hairpin-RNA knockdown. The effect of PIEZO1 activation was confirmed in human primary progenitor cells, maintaining cells at an immature stage for longer and modifying the transcriptional balance in favor of genes associated with early erythropoiesis, as shown by a high GATA2/GATA1 ratio and decreased α/ß-globin expression. The cell proliferation rate was also reduced, with accumulation of cells in G0/G1 of the cell cycle. The PIEZO1-mediated effect on UT7 cells required calcium-dependent activation of the NFAT and ERK1/2 pathways. In primary erythroid cells, PIEZO1 activation synergized with erythropoietin to activate STAT5 and ERK, indicating that it may modulate signaling pathways downstream of erythropoietin receptor activation. Finally, we studied the in-vitro erythroid differentiation of primary cells obtained from 14 PIEZO1-mutated patients, from 11 families, carrying ten different mutations. We observed a delay in erythroid differentiation in all cases, ranging from mild (n=3) to marked (n=8). Overall, these data demonstrate a role for PIEZO1 during erythropoiesis, since activation of PIEZO1 - both chemically and through activating mutations - delays erythroid maturation, providing new insights into the pathophysiology of hereditary xerocytosis.

6.
Hemoglobin ; 43(1): 50-51, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30700173

RESUMO

We report two members of a French family who are carriers of a rare hemoglobin (Hb) variant leading to erythrocytosis: Hb Saint Nazaire [ß103(G5)Phe→Ile; HBB: c.310T>A]. The proband is a 38-year-old woman referred to our institution for a moderate but persistent polycythemia without any clinical consequence. As her mother had a similar blood count, a diagnosis of a Hb variant with high oxygen affinity was proposed. The variant was difficult to detect by capillary electrophoresis (CE) and not distinguishable by high performance liquid chromatography (HPLC) and isoelectric focusing. Finally, a heterozygous mutation on the HBB gene corresponding to Hb Saint Nazaire was identified. This case report illustrates that this rare cause of erythrocytosis can be easily under or misdiagnosed unless several Hb separation techniques are used.


Assuntos
Alelos , Substituição de Aminoácidos , Hemoglobinas Anormais/genética , Mutação , Policitemia/sangue , Policitemia/genética , Adulto , Criança , Análise Mutacional de DNA , Índices de Eritrócitos , Família , França , Hemoglobinas Anormais/metabolismo , Heterozigoto , Humanos
7.
Haematologica ; 104(8): 1554-1564, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30655378

RESUMO

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.


Assuntos
Anemia Hemolítica Congênita/genética , Canalopatias/genética , Hidropisia Fetal/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais Iônicos/genética , Anemia Hemolítica Congênita/complicações , Anemia Hemolítica Congênita/cirurgia , Edema/etiologia , Família , Feminino , Hemólise , Humanos , Hidropisia Fetal/cirurgia , Sobrecarga de Ferro , Masculino , Mutação , Mutação de Sentido Incorreto , Gravidez , Estudos Retrospectivos , Esplenectomia/efeitos adversos , Trombose
8.
Int J Lab Hematol ; 40(6): 697-703, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30184319

RESUMO

INTRODUCTION: Development of additional parameters for complete blood count has emerged in recent hematology analyzers, leading to many publications. However, few studies have been conducted on advanced RBC parameters and hemolytic anemias. We investigated the interest of Sysmex unique parameters, MicroR and HypoHe, as well as the immature fraction of reticulocytes (IRF) in combination with complete blood and reticulocyte count, for screening hereditary spherocytosis (HS) and pyruvate kinase deficiency. METHODS: We analyzed 182 samples using Sysmex XE-5000 analyzers from a cohort of red cell disorder patients from the Rouen University Hospital. These included 47 HS, 17 pyruvate kinase deficiencies, sickle cell diseases and trait, ß-thalassemia minor, iron deficiencies, and 489 samples from a routine group. RESULTS: Combining five parameters (hemoglobin level, reticulocyte count, IRF, MicroR, and %HypoHe), we developed a specific screening tool for HS allowing a sensitivity of 100% and a specificity of 92.1% and a specific screening tool for pyruvate kinase deficiencies allowing a sensitivity of 100% and a specificity of 96.5%. These parameters were also found accurate in infants and in HS without anemia. CONCLUSION: We propose a costless, easy-to-use, and efficient approach to detect HS and pyruvate kinase deficiencies using Sysmex analyzers. These screening tools may help diagnosis of these disorders, help prevent complications, and result in a better management of these patients.


Assuntos
Anemia Hemolítica Congênita não Esferocítica/sangue , Eritrócitos Anormais/metabolismo , Piruvato Quinase/deficiência , Erros Inatos do Metabolismo dos Piruvatos/sangue , Reticulócitos/metabolismo , Esferocitose Hereditária/sangue , Anemia Hemolítica Congênita não Esferocítica/patologia , Contagem de Células Sanguíneas/instrumentação , Contagem de Células Sanguíneas/métodos , Eritrócitos Anormais/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Piruvato Quinase/sangue , Erros Inatos do Metabolismo dos Piruvatos/patologia , Reticulócitos/patologia , Esferocitose Hereditária/patologia
9.
PLoS One ; 12(3): e0172147, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28257476

RESUMO

The risk and clinical significance of cardiac iron overload due to chronic transfusion varies with the underlying disease. Cardiac iron overload shortens the life expectancy of patients with thalassemia, whereas its effect is unclear in those with myelodysplastic syndromes (MDS). In patients with sickle cell anemia (SCA), iron does not seem to deposit quickly in the heart. Our primary objective was to assess through a multicentric study the prevalence of cardiac iron overload, defined as a cardiovascular magnetic resonance T2*<20 ms, in patients with thalassemia, SCA, or MDS. Patient inclusion criteria were an accurate record of erythrocyte concentrates (ECs) received, a transfusion history >8 ECs in the past year, and age older than 6 years. We included from 9 centers 20 patients with thalassemia, 41 with SCA, and 25 with MDS in 2012-2014. Erythrocytapharesis did not consistently prevent iron overload in patients with SCA. Cardiac iron overload was found in 3 (15%) patients with thalassemia, none with SCA, and 4 (16%) with MDS. The liver iron content (LIC) ranged from 10.4 to 15.2 mg/g dry weight, with no significant differences across groups (P = 0.29). Abnormal T2* was not significantly associated with any of the measures of transfusion or chelation. Ferritin levels showed a strong association with LIC. Non-transferrin-bound iron was high in the thalassemia and MDS groups but low in the SCA group (P<0.001). Hepcidin was low in thalassemia, normal in SCA, and markedly elevated in MDS (P<0.001). Two mechanisms may explain that iron deposition largely spares the heart in SCA: the high level of erythropoiesis recycles the iron and the chronic inflammation retains iron within the macrophages. Thalassemia, in contrast, is characterized by inefficient erythropoiesis, unable to handle free iron. Iron accumulation varies widely in MDS syndromes due to the competing influences of abnormal erythropoiesis, excess iron supply, and inflammation.


Assuntos
Anemia Falciforme/sangue , Coração/fisiopatologia , Sobrecarga de Ferro/sangue , Síndromes Mielodisplásicas/sangue , Talassemia/sangue , Adolescente , Adulto , Anemia Falciforme/fisiopatologia , Transfusão de Sangue , Criança , Feminino , Humanos , Ferro/sangue , Quelantes de Ferro , Sobrecarga de Ferro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/fisiopatologia , Miocárdio/metabolismo , Talassemia/fisiopatologia
12.
Stroke ; 43(4): 1129-30, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22198986

RESUMO

BACKGROUND AND PURPOSE: Large vessels are also affected in sickle cell disease. The aim of this study was to assess several parameters in adult patients with sickle cell disease compared with control subjects and in patients with sickle cell disease with stroke. METHODS: Carotid arterial stiffness, intima-media thickness, and transcranial Doppler ultrasonography were measured. RESULTS: Arterial stiffness and transcranial Doppler velocity were significantly increased in 49 patients with sickle cell disease compared with 47 control subjects (P<0.05) and especially in patients with stroke (P<0.05). CONCLUSIONS: These data suggest that transcranial Doppler and arterial stiffness might be associated to stroke in adult patients with sickle cell disease.


Assuntos
Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/fisiopatologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Ultrassonografia Doppler Transcraniana , Rigidez Vascular , Adolescente , Adulto , Anemia Falciforme/complicações , Feminino , Humanos , Masculino , Acidente Vascular Cerebral/etiologia
13.
Hypertension ; 48(6): 1088-94, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17075035

RESUMO

Whether NO is involved or not in sustained conduit artery flow-mediated dilatation in humans remains unclear. Moreover, the role of endothelium-derived hyperpolarizing factor (EDHF), synthesized by cytochrome epoxygenases and acting through calcium-activated potassium channels, and its relationship with NO during flow-mediated dilatation have never been investigated previously. In 12 healthy subjects we measured radial artery diameter (echotracking) and blood flow (Doppler) during flow-mediated dilatation induced by gradual distal hand skin heating (34 to 44 degrees C), during the local infusion of saline and inhibitors of NO synthase (N(G)-monomethyl-l-arginine [l-NMMA]: 8 to 20 micromol/min per liter), calcium-activated potassium channels (tetraethylammonium chloride: 9 micromol/min per liter), and cytochrome epoxygenases (fluconazole: 0.4 to 1.6 micromol/min per liter), alone and in combination. Mean wall shear stress, the flow-mediated dilatation stimulus, was calculated at each level of flow, and the diameter-wall shear stress relationship was constructed. During heating, compared with saline, the diameter-shear stress relationship was shifted downward by l-NMMA, tetraethylammonium, fluconazole, and, in a more pronounced manner, by the combinations of l-NMMA with tetraethylammonium or with fluconazole. Therefore, maximal radial artery flow-mediated dilatation, compared with saline (0.62+/-0.03 mm), was decreased under our experimental conditions by l-NMMA (-39+/-4%), tetraethylammonium chloride (-14+/-4%), fluconazole (-18+/-6%), and to a greater extent, by the combinations of l-NMMA with tetraethylammonium (-64+/-4%) or with fluconazole (-71+/-3%). This study demonstrates that NO and a cytochrome-related EDHF are involved in peripheral conduit artery flow-mediated dilatation in humans during sustained flow conditions. Moreover, the synergistic effects of the inhibitors strongly suggest a functional interaction between NO and EDHF pathways.


Assuntos
Fatores Biológicos/fisiologia , Óxido Nítrico/fisiologia , Artéria Radial/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Resistência ao Cisalhamento , Vasodilatação/efeitos dos fármacos
14.
Eur J Pharmacol ; 502(1-2): 21-30, 2004 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-15464086

RESUMO

Although dehydroepiandrosterone (DHEA) is widely used in the elderly to prevent some adverse effects of ageing, possible deleterious side effects have not been fully assessed. We evaluated the direct actions of DHEA and DHEA sulphate on angiogenesis, a critical event in pathologies that are common in the elderly (cancer, atherosclerosis, inflammation... etc.). At physiological concentrations found in human plasma following DHEA therapy (1-50 nM), DHEA had no action on angiogenesis in vitro. In contrast, higher concentrations of DHEA (10-100 microM), which can be found in tissues after local administration or storage, inhibited in vitro endothelial cell proliferation (blockage in G2/M), migration and capillary tube formation and in vivo angiogenesis in the Matrigel plug assay. This inhibition might be due to a decreased glucose-6-phosphate dehydrogenase activity and to a modification of the tubulin network involved in cell proliferation and migration. The sulphate ester form of DHEA had no effect on angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacologia , Sulfato de Desidroepiandrosterona/farmacologia , Desidroepiandrosterona/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/citologia , Humanos
15.
Am J Physiol Heart Circ Physiol ; 282(4): H1262-9, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11893560

RESUMO

To assess the influence of initial diameter on the gender difference in flow-dependent dilatation (FDD) of the conduit artery, we measured radial artery internal diameter (echotracking), flow (Doppler) and total blood viscosity in 24 healthy (25 +/- 0.8 yr) men and women during reactive hyperemia (RH) and during a gradual hand skin heating (SH). At baseline, mean diameter (men, 2.76 +/- 0.09 vs. women, 2.32 +/- 0.07 mm, P < 0.05), flow (men, 21 +/- 4 vs. women, 10 +/- 1 ml/min, P < 0.05), and blood viscosity (men, 4.13 +/- 0.07 vs. women, 3.92 +/- 0.13 cP, P < 0.05) were higher in men but mean shear stress (MSS) was not different between groups. During RH, the percent increase in diameter was lower in men (men, 9 +/- 1 vs. women, 13 +/- 1%, P < 0.05). This difference was suppressed after correction for baseline diameter. During SH, the increase in diameter with flow was higher in women (P < 0.01). However, the increase in MSS was higher in women because of their smaller diameter at each level of flow (P < 0.01) and there was no difference between groups for the increase in diameter at each level of MSS. These results demonstrate in a direct manner that initial diameter influences the magnitude of FDD of conduit arteries in humans by modifying the value of the arterial wall shear stress at each level of flow and support the interest of the heating method in presence of heterogeneous groups.


Assuntos
Hemodinâmica/fisiologia , Músculo Liso Vascular/fisiologia , Artéria Radial/fisiologia , Caracteres Sexuais , Temperatura Cutânea/fisiologia , Pele/irrigação sanguínea , Vasodilatação/fisiologia , Análise de Variância , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Índice de Massa Corporal , Feminino , Temperatura Alta , Humanos , Hiperemia/fisiopatologia , Masculino , Artéria Radial/diagnóstico por imagem , Fluxo Sanguíneo Regional , Análise de Regressão , Reprodutibilidade dos Testes , Ultrassonografia
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