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1.
Artigo em Inglês | MEDLINE | ID: mdl-31186149

RESUMO

BACKGROUND: Inflammation and vaso-occlusion play key roles in Sickle Cell Disease (SCD) pathophysiology. Lipoxygenase products of the omega-3 fatty acids (O3FAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, are potent anti-inflammatory mediators modulating pain. O3FAs decrease episodes of vaso-occlusion in SCD. METHODS: We assessed erythrocyte fatty acid composition in two major cell membrane phospholipids, phosphatidylcholine and phosphatidylethanolamine, in children with SCD HbSS-disease (n = 38) and age/race-matched HbAA-controls (n = 18). Ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (FA-Ratio), and its relationship to hs-CRP were evaluated. RESULTS: FA-Ratios were increased in both phosphatidylcholine and phosphatidylethanolamine in HbSS compared to controls. Correlations were noted in HbSS subjects between hs-CRP and FA-Ratios (p = 0.011). FA-Ratios increased with age (p = 0.0007) due to an increase in pro-inflammatory AA with a concomitant decrease in anti-inflammatory DHA. CONCLUSIONS: Findings demonstrate relative deficiencies in HbSS of the anti-inflammatory precursor fatty acids DHA and EPA, which correlates positively with hs-CRP.


Assuntos
Anemia Falciforme/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Ômega-3/sangue , Inflamação/sangue , Adolescente , Anemia Falciforme/diagnóstico , Ácido Araquidônico/sangue , Criança , Pré-Escolar , Eritrócitos/metabolismo , Humanos , Fosfatidilcolinas/sangue , Fosfatidiletanolaminas/sangue , Fatores de Risco
2.
Diab Vasc Dis Res ; 12(1): 13-22, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25303939

RESUMO

AIM: To compare the adhesion, migration and endothelial differentiation potential of peripheral blood-derived mononuclear cells (PBMCs) obtained from drug-naive normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) Asian Indian men. METHODS: Based on the 75-g oral glucose tolerance test, 30 NGT and 31 IGT subjects were recruited into the study. PBMCs were isolated from fasting blood using histopaque density gradient centrifugation. Isolated PBMCs were analysed for their ability to adhere to extracellular matrices, incorporation into tubular structures formed by matured endothelial cells and differentiation into endothelial cells upon 7-day culture in endothelial-specific growth medium. RESULTS: PBMCs obtained from IGT subjects exhibit poor adherence to fibronectin and reduced incorporation into tubular structures. Migration towards stromal cell-derived factor-1α (SDF-1α) in a trans-well filter assembly was also reduced for these cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis revealed decreased expression of CXCR4 and ß2 integrin and increased expression of arginase II in IGT subjects. No differences were observed with regard to endothelial differentiation; however, cultured PBMCs of IGT subjects had decreased intracellular nitric oxide (NO) production. CONCLUSION: In pre-diabetic, Asian Indian men, PBMCs exhibit defective migration and homing potential.


Assuntos
Transtornos Leucocíticos/etiologia , Leucócitos Mononucleares/imunologia , Estado Pré-Diabético/fisiopatologia , Adulto , Arginase/genética , Arginase/metabolismo , Povo Asiático , Antígenos CD18/genética , Antígenos CD18/metabolismo , Adesão Celular , Diferenciação Celular , Movimento Celular , Transdiferenciação Celular , Células Cultivadas , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Humanos , Índia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estado Pré-Diabético/sangue , Estado Pré-Diabético/imunologia , Estado Pré-Diabético/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo
4.
Br J Haematol ; 157(3): 370-80, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22360627

RESUMO

Tissue Factor (TF) initiates thrombin generation, and whole blood TF (WBTF) is elevated in sickle cell disease (SCD). We sought to identify the presence of TF-positive monocytes in SCD and their relationship with the other coagulation markers including WBTF, microparticle-associated TF, thrombin-antithrombin (TAT) complexes and D-dimer. Whether major SCD-related pathobiological processes, including haemolysis, inflammation and endothelial activation, contribute to the coagulation abnormalities was also studied. The cohort comprised children with SCD (18 HbSS, 12 HbSC, mean age 3·6 years). We demonstrated elevated levels of TF-positive monocytes in HbSS, which correlated with WBTF, TAT and D-dimer (P = 0·02 to P = 0·0003). While TF-positive monocytes, WBTF, TAT and D-dimer correlated with several biomarkers of haemolysis, inflammation and endothelial activation in univariate analyses, in multiple regression models the haemolytic markers (reticulocytes and lactate dehydrogenase) contributed exclusively to the association with all four coagulant markers evaluated. The demonstration that haemolysis is the predominant operative pathology in the associated perturbations of coagulation in HbSS at a young age provides additional evidence for the early use of therapeutic agents, such as hydroxycarbamide to reduce the haemolytic component of this disease.


Assuntos
Anemia Falciforme/sangue , Hemólise/fisiologia , Monócitos/química , Tromboplastina/análise , Antitrombina III , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Endotélio Vascular/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Citometria de Fluxo/métodos , Humanos , Mediadores da Inflamação/análise , Peptídeo Hidrolases/sangue
5.
J Thromb Haemost ; 6(12): 2202-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18983524

RESUMO

OBJECTIVES: We explored the possibility that heme, an inflammatory mediator and a product of intravascular hemolysis in patients with hemolytic anemia including sickle cell disease, could modulate hemostasis by an effect on endothelial tissue factor (TF) expression. METHODS: Levels of TF mRNA, protein and procoagulant activity were measured in heme-treated endothelial cells. RESULTS: Heme induces TF expression on the surface of both macrovascular and microvascular endothelial cells in a concentration-dependent manner, with 12-fold to 50-fold induction being noted (enzyme-linked immunosorbent assay) between 1 and 100 microm heme (P < 0.05). Complementary flow cytometry studies showed that the heme-mediated endothelial TF expression was quantitatively similar to that of tumor necrosis factor-alpha (TNF-alpha). Heme also upregulated the expression of TF mRNA (8-fold to 26-fold), protein (20-fold to 39-fold) and procoagulant activity (5-fold to 13-fold) in endothelial cells in a time-dependent manner. The time-course of heme-mediated TF antigen expression paralleled the induction of procoagulant activity, with antibody blocking studies demonstrating specificity for TF protein. Interleukin (IL)-1alpha, and TNF-alpha are not involved in mediating the heme effect, as antibodies against these cytokines and IL-1-receptor antagonist failed to block heme-induced TF expression. Inhibition of heme-induced TF mRNA expression by sulfasalazine and curcumin suggested that the transcription factor nuclear factor kappaB is involved in mediating heme-induced TF expression in endothelial cells. CONCLUSIONS: Our results demonstrate that heme induces TF expression by directly activating endothelial cells, and that heme-induced endothelial TF expression may provide a pathophysiologic link between the intravascular hemolytic milieu and the hemostatic perturbations previously noted in patients with hemolytic anemia including sickle cell disease.


Assuntos
Anemia Hemolítica/sangue , Endotélio Vascular/citologia , Heme/farmacologia , Hemostasia , Tromboplastina/genética , Ativação Transcricional/efeitos dos fármacos , Anemia Hemolítica/fisiopatologia , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Células Cultivadas , Hemostasia/efeitos dos fármacos , Humanos , NF-kappa B , RNA Mensageiro/análise , Tromboplastina/análise , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
6.
Transl Res ; 152(4): 165-77, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18940719

RESUMO

Phosphatidylserine (PS)-dependent erythrocyte adhesion to endothelium and subendothelial matrix components is mediated in part via thrombospondin (TSP). Although TSP exhibits multiple cell-binding domains, the PS-binding site on TSP is unknown. Because a cell-binding domain for anionic heparin is located at the amino-terminus, we hypothesized that PS-positive red blood cells (PS(+ve)-RBCs) bind to this domain. We demonstrate that both heparin and its low-molecular-weight derivative enoxaparin (0.5-50 u/mL) inhibited PS(+ve)-RBC adhesion to immobilized TSP in a concentration-dependent manner (21% to 77% inhibition, P < 0.05). Preincubation of immobilized TSP with an antibody against the heparin-binding domain blocked PS(+ve)-RBC adhesion to TSP. Antibodies that recognize the collagen- and the carboxy-terminal CD47-binding domain on TSP had no effect on this process. Although preincubation of PS(+ve)-RBCs with TSP peptides from the heparin-binding domain that contained the specific heparin-binding motif KKTRG inhibited PS(+ve)-erythrocyte adhesion to matrix TSP (P < 0.001), these peptides in the immobilized form supported PS-mediated erythrocyte adhesion. A TSP-peptide that lacks the binding motif neither inhibited nor supported PS(+ve)-RBC adhesion. Additional experiments show that soluble TSP also interacted with PS(+ve)-RBCs via its heparin-binding domain. Our results demonstrate that PS-positive erythrocytes bind to both immobilized and soluble TSP via its heparin-binding domain and that both heparin and enoxaparin, at clinically relevant concentrations, block this interaction. Other studies have shown that heparin inhibited P-selectin- and soluble-TSP-mediated sickle erythrocyte adhesion to endothelial cells. Our results, taken together with the previously documented findings, provide a rational basis for clinical use of heparin or its low-molecular-weight derivatives as therapeutic agents in treating vaso-occlusive pain in patients with sickle cell disease.


Assuntos
Eritrócitos/metabolismo , Heparina/metabolismo , Fosfatidilserinas/metabolismo , Trombospondina 1/metabolismo , Sítios de Ligação , Calcimicina/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Enoxaparina/metabolismo , Eritrócitos/efeitos dos fármacos , Humanos , Ionóforos/farmacologia
7.
Blood ; 111(2): 905-14, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17911385

RESUMO

Phosphatidylserine (PS)-positive erythrocytes adhere to endothelium and subendothelial matrix components. While thrombospondin mediates these inter-actions, it is unknown whether PS-associated erythrocyte-endothelial adhesion occurs in the absence of plasma ligands. Using ionophore-treated PS-expressing control HbAA erythrocytes, we demonstrate that PS-positive erythrocytes adhered to human lung microendothelial cells in the absence of plasma ligands, that this adhesion was enhanced following endothelial activation with IL-1alpha, TNF-alpha, LPS, hypoxia, and heme, and that this adhesive interaction was selective to erythrocyte PS. We next explored whether microendothelial cells express an adhesion receptor that recognizes cell surface-expressed PS (PSR) similar to that expressed on activated macrophages. We demonstrate constitutive expression of both PSR mRNA and protein that were up-regulated in a time-dependent manner following endothelial activation. While minimal PSR expression was noted on unstimulated cells, endothelial activation up-regulated PSR surface expression. In antibody-blocking studies, using PS-positive erythrocytes generated either artificially via ionophore treatment of control erythrocytes or from patients with sickle cell disease, we demonstrate that PSR was functional, supporting PS-mediated erythrocyte adhesion to activated endothelium. Our results demonstrate the existence of a novel functional adhesion receptor for PS on the microendothelium that is up-regulated by such pathologically relevant agonists as hypoxia, cytokines, and heme.


Assuntos
Células Endoteliais/metabolismo , Eritrócitos/metabolismo , Pulmão/metabolismo , Fosfatidilserinas/metabolismo , Receptores de Superfície Celular/biossíntese , Regulação para Cima/fisiologia , Adulto , Adesão Celular/fisiologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Células Cultivadas , Células Endoteliais/citologia , Eritrócitos/citologia , Matriz Extracelular/metabolismo , Feminino , Heme/farmacologia , Hemoglobina A/metabolismo , Humanos , Interleucina-1alfa/farmacologia , Ionóforos/farmacologia , Ligantes , Lipopolissacarídeos/farmacologia , Pulmão/irrigação sanguínea , Pulmão/citologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/fisiologia , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Microcirculação/metabolismo , Fosfatidilserinas/antagonistas & inibidores , RNA Mensageiro/biossíntese , Receptores de Superfície Celular/agonistas , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima/efeitos dos fármacos
8.
Australas Radiol ; 50(5): 507-9, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16981954

RESUMO

Positron emission tomography/CT is an established imaging method in the diagnosis and staging of cancers. (18)F-fluoro-2-deoxy-d-glucose (FDG) is the most commonly used radiotracer in positron emission tomography/CT. It is a tumour viability agent and usually its uptake within a lesion reflects the presence of a viable tumour tissue. However, false-positive FDG uptake is known to occur in benign processes of either inflammatory or infectious aetiology. We describe FDG uptake at the site of laparoscopic scar that mimicked Sister Mary Joseph's nodule in a patient with gastric adenocarcinoma. Here, the knowledge of the patient's history and subtle imaging findings helped in accurate staging of the patient. In this case report, we emphasize the value of the knowledge of the patient history and awareness of different pitfalls of FDG to achieve a correct diagnosis on positron emission tomography/CT.


Assuntos
Adenocarcinoma/patologia , Cicatriz/diagnóstico , Laparoscopia/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias Gástricas/patologia , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Idoso , Cicatriz/etiologia , Meios de Contraste/administração & dosagem , Diagnóstico Diferencial , Fluordesoxiglucose F18 , Humanos , Masculino , Estadiamento de Neoplasias/métodos , Intensificação de Imagem Radiográfica/métodos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgia
9.
J Pediatr Hematol Oncol ; 26(12): 785-90, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15591896

RESUMO

Vaso-occlusive pain is a frequent manifestation of sickle cell disease, but most clinical studies have documented only those pain episodes for which patients seek acute care or require hospitalization. Based on limited previous studies, the authors suggest that pain episodes managed at home are more frequent then those resulting in acute care management but likely share a common pathophysiology. The authors determined the characteristics of vaso-occlusive pain managed at home in 30 subjects (ages 6-19 years) using a self-report diary daily for 6 months. A total of 175 pain episodes were reported in 4,885 days, with 51% lasting 1 day or less. Severe pain, rated as 7 to 10 on a 10-point scale, was reported on 12% of pain days, but most pain was of mild to moderate intensity. A combination of baseline hematologic parameters and biomarkers assessing erythrocyte/endothelial cell adhesion, including hematocrit, fetal hemoglobin, and adhesion ratio, were statistically significant predictors of pain frequency in statistical analyses. Given the overlap in clinical features and predictive hematologic parameters of home-managed and acute care-managed pain, both likely represent a continuum of frequency and severity rather than distinct clinical entities. The higher frequency of these home-managed episodes suggests their potential utility as additional outcome measures in studies of vaso-occlusive pain.


Assuntos
Anemia Falciforme/complicações , Dor/etiologia , Doenças Vasculares Periféricas/etiologia , Doenças Vasculares Periféricas/patologia , Adolescente , Adulto , Biomarcadores/análise , Adesão Celular , Criança , Constrição Patológica , Eritrócitos/fisiologia , Feminino , Serviços de Assistência Domiciliar , Humanos , Masculino , Dor/fisiopatologia , Manejo da Dor , Medição da Dor , Doenças Vasculares Periféricas/complicações
10.
Lancet ; 362(9394): 1450-5, 2003 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-14602439

RESUMO

BACKGROUND: Nocturnal oxyhaemoglobin desaturation might have a role in CNS complications related to sickle cell disease, and rates of painful crises. We attempted to examine the biological relations, and describe the haematological risk factors for oxyhaemoglobin desaturation. METHODS: The study population included children with sickle cell disease and controls. Cellular activation was assessed by measurement of soluble vascular cell adhesion molecule 1, P-selectin, L-selectin, and leukotriene B4. Erythrocyte-endothelial adhesion and routine haematological variables were assessed. Oxygen saturation (SaO2) was measured by pulse oximetry while children were awake and asleep. Children with a mean sleeping SaO2 of < or =93% were identified as hypoxaemic. Children were divided into four groups: controls (ten children), HbSC (nine, all normoxic), HbSS normoxic (13), and HbSS hypoxaemic (15). FINDINGS: Among haematological variables, sleeping SaO2 correlated only with packed-cell volume (r=0.7; p<0.0001). Inverse relations were noted between sleeping SaO2 and adhesion (-0.45; p<0.01), and markers of white-cell (-0.51; p<0.01), platelet (-0.61; p<0.001), and endothelial activation (-0.46; p<0.01). In the HbSS group who had sleeping hypoxaemia, waking SaO2 measurements showed continuing hypoxaemia, with similar correlation between SaO2 and cell activation markers. INTERPRETATION: Our adhesion-related findings suggest a potential mechanism for the increased occurrence of clinical vaso-occlusive crises in individuals with sickle cell disease who have oxyhaemoglobin desaturation. Release of cellular mediators in hypoxaemia, and the relation between anaemia and oxyhaemoglobin desaturation, suggest that risk factors for stroke, including anaemia, might have a role in CNS-vasculopathy through hypoxia-mediated pathways. Further more, hypoxaemia in the older child also occurs during the day; such mild untreated hypoxia could lead to an increased risk of vaso-occlusive episodes.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Biomarcadores/sangue , Transtornos Cerebrovasculares/fisiopatologia , Hipóxia/sangue , Hipóxia/fisiopatologia , Adolescente , Adulto , Anemia Falciforme/complicações , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/etiologia , Criança , Pré-Escolar , Ritmo Circadiano , Feminino , Hemoglobina Falciforme/metabolismo , Hemoglobina Falciforme/fisiologia , Humanos , Masculino , Oximetria , Oxigênio/sangue , Fatores de Risco , Sono/fisiologia , Molécula 1 de Adesão de Célula Vascular/sangue , Molécula 1 de Adesão de Célula Vascular/fisiologia
11.
Contraception ; 67(5): 403-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12742565

RESUMO

Some suitably substituted acrylophenones, quinolines and dithiocarbamate were synthesized as new generation, non-detergent spermicides and were studied for their mechanism of action in comparison with various known spermicides belonging to several different classes of chemical compound. Nonoxynol-9, benzalkonium chloride, Sapindus saponins, verapamil, emetine and tartaric acid were used as reference molecules to study the effect of new spermicides on human sperm motility parameters (using computer-assisted semen analyzer), plasma membrane integrity, lipid peroxidation and defense system against reactive oxygen species (ROS). Results have indicated that sperm plasma membrane remains the primary site of action of most of the spermicides, though the effect may be predominantly on the physiological integrity rather than the structural integrity in case of the new compounds. Lipid peroxidation may play an important role in disrupting sperm membrane physiology that may or may not be accompanied with a detrimental effect on the defense system of the human spermatozoa against the ROS.


Assuntos
Motilidade dos Espermatozoides/efeitos dos fármacos , Espermicidas/farmacologia , Espermatozoides/efeitos dos fármacos , Acrilatos/farmacologia , Membrana Celular/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Quinolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tiocarbamatos/farmacologia
12.
J Lab Clin Med ; 139(2): 80-9, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11919546

RESUMO

Neutrophil activation with the release of intracellular granule contents has been observed in sickle cell disease (SCD). Because leukotriene B(4) (LTB(4)), a 5-lipoxygenase metabolite of arachidonic acid in neutrophils, is a chemoattractant and enhances neutrophil adhesion to endothelium, we assessed plasma levels of this metabolite in controls (n = 9) and individuals with SCD, SS genotype, both in basal "steady state" (n = 37) and during episodes of vaso-occlusion (n = 10) and acute chest syndrome (n = 5). Thirteen patients with SCD, SC genotype, in steady state were also studied. Although no significant differences were noted between the control (136 +/- 32 fmol/mL) and SC genotype (177 +/- 83 fmol/mL, P >.15), LTB(4) levels were markedly increased in patients with SS genotype in basal steady state (207 +/- 64 fmol/mL, P <.003) compared with those in controls. Values were further increased during vaso-occlusion (264 +/- 94 fmol/mL) and acute chest syndrome (363 +/- 124 fmol/mL). These levels were significantly different from measurements taken during steady state (P <.04 and P <.0001, respectively). No correlation was noted between LTB(4) level and total white cell or neutrophil count. Additionally, the significant correlation noted in SCD between increased levels of plasma LTB(4) and soluble L-selectin (P <.03) reflects neutrophil activation. We also observed an effect of LTB(4) on red cell-endothelial adhesion at concentrations that appear clinically relevant (1-10 pmol/mL) with concomitant up-regulation of mRNA for the endothelial vitronectin receptor. These properties of LTB(4) are relevant to disease pathophysiology, providing further evidence of the contribution of the neutrophil to the proinflammatory and proadhesive phenotype in SCD.


Assuntos
Anemia Falciforme/metabolismo , Leucotrieno B4/sangue , Leucotrieno B4/urina , Neutrófilos/química , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/genética , Adesão Celular , Dor no Peito , Criança , Pré-Escolar , Endotélio Vascular/química , Endotélio Vascular/patologia , Eritrócitos , Hemoglobina Fetal/análise , Expressão Gênica , Genótipo , Hemoglobinas/análise , Humanos , Selectina L/sangue , Contagem de Leucócitos , Neutrófilos/fisiologia , Dor , RNA Mensageiro/análise , Receptores de Vitronectina/genética , Valores de Referência , Contagem de Reticulócitos , Síndrome , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo
13.
Blood ; 99(5): 1564-71, 2002 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11861269

RESUMO

Phosphatidlyserine (PS) exposure on the erythrocyte surface endows the cell with the propensity of adhering to vascular endothelium. Because individuals with sickle cell disease (SCD) manifest loss of erythrocyte membrane asymmetry with PS exposure, we have assessed the contribution of this marker to the process of sickle erythrocyte-microendothelial adhesion. Assays for plasma-induced adhesion were conducted on unactivated endothelium, in the absence of immobilized ligands, such that PS was compared to the erythrocyte adhesion receptor CD36. Blocking studies with erythrocytes pretreated with annexin V (to cloak PS) or anti-CD36 or both revealed an inhibitory effect on adhesion of 36% +/- 10% and 23% +/- 8% with blocking of both sites suggestive of an additive effect. We next evaluated 87 blood samples from patients with SCD and grouped them into 4 categories based on adhesion marker (CD36 and PS) levels. Results revealed a striking correlation between erythrocyte PS positivity and adhesion. Analyses of the individual patient data demonstrated a positive correlation between PS and adhesion (R = 0.52, P <.000 001), whereas none was noted between adhesion and CD36 (R = 0.2, P >.07). The effect of PS on adhesion appears to be related to the quantitative differences in erythrocyte markers in SCD, with PS the predominant marker when compared to CD36 both in the total erythrocyte population, and when the adherence-prone erythrocyte, the CD71(+) stress reticulocyte, was evaluated. Our study signals the entrance of an important new contributor to the field of sickle erythrocyte-endothelial adhesion. The implications of erythrocyte PS exposure in relation to the vascular pathology of SCD need to be assessed.


Assuntos
Anemia Falciforme/patologia , Endotélio Vascular/citologia , Eritrócitos/patologia , Fosfatidilserinas/sangue , Fosfatidilserinas/fisiologia , Adolescente , Adulto , Biomarcadores/sangue , Antígenos CD36/sangue , Antígenos CD36/imunologia , Estudos de Casos e Controles , Adesão Celular , Comunicação Celular , Criança , Pré-Escolar , Membrana Eritrocítica/química , Membrana Eritrocítica/fisiologia , Membrana Eritrocítica/ultraestrutura , Eritrócitos/química , Eritrócitos/ultraestrutura , Humanos , Lactente
14.
Blood ; 98(12): 3228-33, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11719358

RESUMO

Complex pertubations of hemostasis occur in sickle cell disease (SCD). Although the procoagulant property of sickle erythrocytes in vitro is tied to exposure of phosphatidylserine (PS), no study has directly linked this PS positivity to in vivo thrombin generation. This study was designed to determine if thrombin generation in SCD correlates with erythrocyte PS, or whether platelets play a significant role. PS was quantified on erythrocytes and platelets from 40 patients with SCD (SS genotype = 25; SC genotype = 15) and 11 controls. Markers of thrombin generation (prothrombin fragment F1.2; thrombin-antithrombin or TAT complexes) and fibrin dissolution (D-dimer; plasmin-antiplasmin or PAP complexes) were also evaluated. Thrombin generation and activation of fibrinolysis occurred with elevations in F1.2, TAT, and D-dimer. Although numbers of both PS-positive erythrocytes and platelets were elevated, there was no correlation between PS-positive platelets and any hemostatic markers. In contrast, correlations were noted between PS-positive erythrocytes and F1.2 (P <.0002), D-dimer (P <.000002), and PAP (P <.01). Correlations between F1.2 and D-dimer (P <.0001) demonstrated that fibrinolysis was secondary to thrombin generation. In patients with the SC genotype, abnormalities in coagulation, although present, were of a lesser magnitude than in SS disease. This study suggests that the sickle erythrocyte is the cell responsible for the thrombophilic state in SCD because associations between erythrocyte PS and thrombin generation were observed. No such relationship with platelet PS was noted. The use of erythrocyte PS as a surrogate marker in trials testing new therapeutic modalities may provide insights into the vascular complications of SCD.


Assuntos
Anemia Falciforme/complicações , Trombofilia/complicações , Adolescente , Adulto , Anemia Falciforme/sangue , Antitrombina III , Biomarcadores/sangue , Plaquetas/química , Criança , Pré-Escolar , Eritrócitos/química , Fibrina/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinolisina/análise , Fibrinólise , Hemostasia , Humanos , Lactente , Estudos Longitudinais , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/sangue , Fosfatidilserinas/sangue , Protrombina , Trombina/metabolismo , Trombofilia/sangue , alfa 2-Antiplasmina/análise
15.
Blood ; 97(9): 2568-73, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11313243

RESUMO

To assess whether fetal hemoglobin (HbF) modulates the adhesion of sickle erythrocytes to endothelium, children with homozygous sickle cell anemia (SS disease) were studied, using this physiologically crucial period to evaluate the relationships between HbF and the major erythrocyte adhesion markers. The mean level of CD36(+) erythrocytes was 2.59% +/- 2.15% (+/- SD, n = 40) with an inverse relationship between CD36 positivity and F cells (R = -0.76, P < .000 00 002). In univariate analyses, significant correlations with various hematologic parameters and age were noted. Multiple regression analyses, however, revealed a relationship solely with F cells. Minimal levels of very late activation antigen-4(+) (VLA4(+)) erythrocytes (0.31% +/- 0.45%, n = 40) with relationships similar to those noted for CD36(+) cells were also observed. The subpopulation of strongly adhesive stress reticulocytes was further assessed, using CD71 as their marker. The mean level of CD71(+) erythrocytes was 5.81% +/- 4.21%, with statistical correlates in univariate and multivariate analyses similar to those discussed above. When adhesion ratios were evaluated, inverse correlations were noted between basal and plasma-induced adhesion and F-cell numbers (R = -0.54, P < .0005; R = -0.53, P < .0006, n = 39). In addition, in analyses where basal or plasma-induced adhesion was the dependent variable and the independent variables included F cells and the various adhesion-related parameters, significant relationships solely with F cells were noted. The results demonstrate that SS patients with higher levels of F cells have concomitant decreases in the numbers of CD36(+), VLA4(+), and CD71(+) erythrocytes and that these findings translate into less adherent erythrocytes. These findings extend knowledge regarding the protective effects of HbF in the pathophysiology of sickle cell disease.


Assuntos
Anemia Falciforme/sangue , Eritrócitos/metabolismo , Hemoglobina Fetal/metabolismo , Adolescente , Anemia Falciforme/patologia , Antígenos CD/sangue , Antígenos de Diferenciação de Linfócitos B/sangue , Antígenos CD36/sangue , Criança , Pré-Escolar , Agregação Eritrocítica , Eritrócitos/patologia , Humanos , Lactente , Receptores da Transferrina
16.
Curr Opin Hematol ; 8(2): 111-22, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11224686

RESUMO

The pulmonary findings of acute chest syndrome of sickle cell disease have been well characterized in numerous studies. Whereas a third of patients have a documented infection associated with this syndrome, and fat embolism from necrotic marrow is the etiologic factor in another approximately 10%, no cause is discovered in the majority of patients. In most patients, however, the underlying pathophysiology is the presence of a hypoxia-driven, adhesion-related occlusive event in the pulmonary microcirculation. This may be accompanied by a decrease in the levels of normal cytoprotective and anti-adhesive mediators such as nitric oxide. In the patient with sickle cell disease, the lung is also a uniquely vulnerable target organ because its vasculature constricts with hypoxia in contrast to other vascular beds. This review will establish the links between known etiologic agents and the pathophysiology of this syndrome. An additional section of this review will deal with experimental therapies. The use of inhaled nitric oxide will be explored in depth because advances in this area are current and uniquely relevant to acute chest syndrome.


Assuntos
Anemia Falciforme/fisiopatologia , Pneumopatias/fisiopatologia , Doença Aguda , Anemia Falciforme/complicações , Animais , Infecções Bacterianas/complicações , Humanos , Pneumopatias/etiologia , Óxido Nítrico/fisiologia , Síndrome
17.
Pediatr Pathol Mol Med ; 20(1): 27-46, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-12673843

RESUMO

The protean manifestations of sickle cell disease (SCD), especially, microvessel involvement in the vaso-occlusive process, is classically ascribed to the phenomena of erythrocyte sickling and enhanced red cell-endothelial adherence. Pertubations in various hemostatic systems occurs in SCD, both in steady state and during vaso-occlusion, with the intravascular generation of thrombin. The etiology(s) of thrombin generation in SCD will be described. Whether the activation of the cellular and plasmatic phases of hemostasis is causative or occurs as a result of vascular injury will be discussed.


Assuntos
Anemia Falciforme/sangue , Trombofilia/etiologia , Anemia Falciforme/complicações , Anemia Falciforme/fisiopatologia , Animais , Anticorpos Antifosfolipídeos/imunologia , Adesão Celular , Modelos Animais de Doenças , Endotélio Vascular/lesões , Endotélio Vascular/patologia , Deformação Eritrocítica , Membrana Eritrocítica/imunologia , Eritrócitos Anormais/patologia , Fibrinólise , Hemoglobinopatias/sangue , Hemoglobinopatias/genética , Humanos , Lipídeos de Membrana/sangue , Lipídeos de Membrana/imunologia , Camundongos , Camundongos Knockout , Fosfatidilserinas/sangue , Fosfatidilserinas/imunologia , Ativação Plaquetária , Trombina/biossíntese , Trombofilia/sangue , Trombose/etiologia , Talassemia beta/sangue , Talassemia beta/complicações
18.
Blood ; 96(3): 1119-24, 2000 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-10910931

RESUMO

In sickle cell disease (SCD), loss of erythrocyte membrane phospholipid asymmetry occurs with the exposure of phosphatidylserine (PS), which provides a docking site for coagulation proteins. In vivo sickling/desickling, with resulting red cell membrane changes and microvesicle formation, appears to be one of the factors responsible for PS exposure. We evaluated children with SCD homozygous for sickle hemoglobin (SS disease) and controls (n = 65) and demonstrate that high levels of fetal hemoglobin (assessed as F cells) are associated with decreased microvesicle formation, PS exposure, and thrombin generation. F cells correlated inversely with both microvesicles and PS positivity (P <.000001) in SS disease. Multiple regression analyses using various hematologic parameters as independent variables, and either microvesicles or PS positivity as the dependent variable, showed a strong relationship only with F cells. Additionally, plasma prothrombin fragment F1.2 levels (a marker for thrombin generation) correlated with both PS positivity (P <.001) and F cells (P <.01). An F-cell level of approximately 70% was associated with normal levels of prothrombin fragment F1.2 and with microvesicle formation indistinguishable from control values. We suggest that the use of such surrogate biologic markers in conjunction with F-cell numbers may provide valuable insights into the biology and consequences of in vivo sickling.


Assuntos
Anemia Falciforme/sangue , Anemia Falciforme/etiologia , Eritrócitos/metabolismo , Hemoglobina Fetal/metabolismo , Fosfatidilserinas/sangue , Adolescente , Adulto , Coagulação Sanguínea , Criança , Pré-Escolar , Humanos , Lactente
19.
J Med Primatol ; 29(6): 411-4, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11168832

RESUMO

Daily sperm production (DSP) rate was estimated in adult male rhesus and bonnet monkeys to evaluate seasonal changes in the gametogenic activity of the testes. Three monkeys of each species were castrated during breeding and non-breeding seasons and DSP rate was estimated by enumerating the homogenization-resistant spermatid nuclei of steps 13 and 14. Results indicated a significant reduction in the DSP rate per testis during the non-breeding season in two species, along with a marked decline in the testis weight. However, the gametogenic capacity of seminiferous tubules did not appear to be markedly affected during non-breeding season, as the DSP rate per gram parenchyma of testis was only marginally reduced. The seasonal changes in DSP were much more pronounced in the rhesus than in the bonnet monkey. The feasibility of circanual rhythm in DSP of sub-human primates to form a baseline for the study of reproductive function in male is discussed.


Assuntos
Macaca mulatta/fisiologia , Macaca radiata/fisiologia , Estações do Ano , Contagem de Espermatozoides/veterinária , Testículo/fisiologia , Animais , Masculino , Tamanho do Órgão , Reprodução
20.
Pediatr Pulmonol ; 28(6): 423-8, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10587417

RESUMO

Pulse oximetry is a noninvasive method of measuring oxyhemoglobin saturation. The validity of pulse oximetry in sickle cell disease (SCD) has been questioned. We evaluated pulse oximetry, arterial blood gas analysis, and co-oximetry in patients with SCD, and we assessed the effect of dyshemoglobin and altered blood-oxygen affinity on their accuracy. Sixteen patients with SCD aged 7-21 years had arterial and venous blood drawn and transcutaneous pulse oximetry performed. Oxyhemoglobin dissociation curves were plotted from the venous blood of 15 patients. Oxyhemoglobin saturation estimated by arterial blood gas analysis (SaO(2)) and measured by pulse oximetry (SpO(2)) were both higher than the saturation by co-oximetry (FO(2)Hb) (mean +/- SD = 96.3 +/- 1.6%, 94 +/- 3.1%, and 89.1 +/- 3.8%, respectively). There was a significant, positive correlation between SpO(2) and FO(2)Hb (r = 0.7, P = 0.002). The patients had elevated levels of methemoglobin (MetHb) and carboxyhemoglobin (COHb) (2.3 +/- 1.4% and 4.7 +/- 1.3%, respectively). The oxyhemoglobin dissociation curves were frequently shifted to the right with oxygen tensions elevated when hemoglobin was 50% saturated with oxygen (P(50)) (32.5 +/- 4.5 mm Hg). There was a strong correlation between the amounts of dyshemoglobin (MetHb + COHb) and the difference between SaO(2) and FO(2)Hb (r = 0.7, P = 0.002). There was no correlation between the difference between SaO(2) and FO(2)Hb and the P(50) (r = 0.27, P = 0.33) There was also a strong positive correlation between SaO(2)-SpO(2) and dyshemoglobin fraction (r = 0.77, P = 0.001). We conclude that pulse oximetry and arterial blood gas analysis overestimate oxygen saturation when compared to co-oximetry, but that SpO(2) is consistently closer than SaO(2) to FO(2)Hb. SpO(2) is partially affected by MetHb and COHb. The discrepancy between SaO(2) and FO(2)Hb is due to the presence of dyshemoglobin and a shifted oxyhemoglobin dissociation curve, but the effect from dyshemoglobin predominates.


Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/metabolismo , Oximetria , Oxigênio/sangue , Oxiemoglobinas/metabolismo , Adolescente , Adulto , Análise de Variância , Gasometria , Criança , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria
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