Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activities of orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (ODC) were significantly elevated (P less than 0.001) in erythrocytes (RBC) from five patients with prednisone-responsive congenital hypoplastic anaemia (CHA). (OPRT: patients - 10.1--64.2 nmol/h/10(9) RBC; controls - 2.8 +/- 0.3 (mean +/- SEM, n = 37); ODC: patients = 30--124 nmol/h/10(9) RBC; controls = 10.2 +/- 0.7 (mean SEM, n = 37).) Two patients had a less pronounced, but significant, increase of aspartate transcarbamylase activity and three patients had marginal increases of dihydroorotase activity. Dihydroorotate dehydrogenase activity was not detected in any CHA patient or control. In one patient prior to prednisone therapy, the OPRT and ODT activities were elevated 10-fold and remained elevated 3-fold after 16 months of therapy. An elevated enzyme pattern similar to that of RBC from CHA patients was observed in three parents of three CHA patients, but not in three parents of two other CHA patients. The activities of all five pyrimidine enzymes were normal for one patient with transient erythroblastopenia of childhood. In contrast, the activities of all the pyrimidine biosynthetic enzymes were elevated in blood from patients with a young RBC population: sickle cell anaemia, sickle-beta-thalassaemia, hereditary spherocytosis, and DiGuglielmo syndrome and from the newborn. It is postulated that factors which affect the activities of pyrimidine enzymes in CHA may also result in diminished erythropoiesis.
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PMID:Elevation of pyrimidine enzyme activities in the RBC of patients with congenital hypoplastic anaemia and their parents. 3 27

Indirect left ventricular filling pressures were measured via balloon-tipped catheters in 11 studies of 10 patients with sickle cell anemia and cardiorespiratory symptomatology. Pulmonary capillary wedge pressures exceeded 12 mm Hg in 8 of 11 studies (8 of 10 patients). Mean pressures in mm Hg were: pulmonary capillary wedge, 16.5 +/- 4.2 (SEM); pulmonary artery, 38 +/- 16; brachial artery, 104 +/- 128; and right atrium, 11 +/- 4. The mean cardiac output was 8.8 +/- 3.1 L/min. The mean pulmonary vascular resistance was 237 +/- 122 dynes sec cm-5 and was significantly increased in 4 patients. In addition to further documentation of significantly elevated pulmonary artery pressures in sickle cell anemia patients with cardiopulmonary symptomatology, these data indicate that a contributory role for elevated left ventricular filling pressures must be considered in the pathogenesis of pulmonary hypertension in sickle cell anemia. Elevation of the pulmonary artery pressure was usually associated with elevation of the pulmonary capillary wedge pressure.
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PMID:Left ventricular filling pressure in sickle cell anemia. 157 56

Interferon-gamma (IFN-gamma) has been shown to influence globin gene expression in cord blood and normal adult progenitor-derived erythroblasts. To explore the influence of IFN-gamma on fetal hemoglobin (HbF) synthesis in the hemoglobinopathies, erythroid progenitors (BFU-E, burst forming unit-erythroid) from patients with sickle cell anemia (SCA) and thalassemia were co-cultured with or without IFN-gamma. Hemoglobin content in progenitor-derived erythroblasts was assessed by radioligand assay (RIA). Co-culture of erythroid progenitors from 12 SCA patients with 200-400 U/ml of IFN-gamma resulted in a significant decrease in picograms of HbF and percent HbF per BFU-E-derived erythroblast. The mean decrease (+/- SEM) of picograms of HbF per cell and percent of HbF was by 42 +/- 9% and 35 +/- 8% of control cultures, respectively. Co-culture of erythroid progenitors from 10 patients with thalassemia major or thalassemia variant (HPFH/thalassemia, sickle/beta 0-thalassemia) with 200 U/ml IFN-gamma also resulted in a significant decrease in picograms and percent of HbF per BFU-E-derived erythroblast. IFN-gamma treatment also inhibited the enhancement in gamma-globin synthesis induced in culture by butyric acid. Erythroid progenitors from 2 patients with SCA, 1 patient with sickle/beta 0-thalassemia, and 1 patient with HbE/beta 0-thalassemia were co-cultured with IFN-gamma, L-alpha-amino-n-butyric acid, or both. HbF content (expressed as picograms HbF/cell) was decreased in samples co-cultured with IFN, increased in cultures with L-alpha-amino-n-butyric acid, but remained at control values in cultures treated with IFN plus L-alpha-amino-n-butyric acid. These data demonstrate that IFN-gamma is an environmental factor that influences gamma-globin gene expression in the beta hemoglobinopathies in vitro.
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PMID:Interferon-gamma modulates fetal hemoglobin synthesis in sickle cell anemia and thalassemia. 170 29

Erythroid progenitors circulating in peripheral blood and their response to erythropoietin (EPO), interleukin-3 (IL3), and phytohemagglutinin-stimulated, lymphocyte-conditioned medium (PHALCM) were assessed in sickle cell anemia (SCA) patients and controls. SCA patients have significantly higher numbers of circulating burst-forming unit-erythroid (BFU-E) compared with controls (mean +/- SEM, 940.27 +/- 129.11 per ml and 86.56 +/- 19.74 per ml, respectively; P less than 0.0001). At low doses of EPO, BFU-E-derived colonies were significantly increased in SCA patients compared with controls (each P less than 0.05). The EPO dose required to produce 50% of maximum colony numbers was 47 times greater in control subjects than in SCA patients. Moreover, in 11 of 17 patients with SCA, spontaneous BFU-E-derived colonies were formed without added erythropoietin. This phenomenon was not observed in control subjects (P = 0.035). PHALCM developed from mononuclear cells of SCA patients had significantly greater stimulatory effect than did that derived from controls regardless of the source of target cells (each P less than 0.05). A two-step study of IL3 sensitivity of erythroid progenitors was conducted. First, in a liquid culture system, circulating erythroid progenitors of SCA patients and controls were incubated in the presence of varying doses of IL3. During a second step, CFU-E-like colonies were observed in methylcellulose cultures of these cells. The mean numbers of colony-forming unit-erythroid (CFU-E)-like colonies was significantly higher in SCA patients compared with control subjects at low doses of IL3 (each P less than 0.02). The increased response of erythroid progenitors to IL3 and the increased production of hemopoietic growth factors (IL3 or non-IL3) contribute to the hemopoietic response in SCA patients. These mechanisms and increased sensitivity of the BFU-E to EPO may explain lower than expected EPO levels in SCA patients.
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PMID:Increased response of erythroid progenitors to interleukin-3 in sickle cell anemia: CFU-E-like behavior of circulating erythroid progenitors in liquid culture. 195 Dec 99

Recent studies suggest that intravascular coagulation occurs in sickle cell anemia. There is also some evidence that decreased fibrinolytic activity may be associated with the disorder. In the current study we measured tissue plasminogen activator levels (t-PA) in seven asymptomatic patients with sickle cell anemia. The mean level of releasable t-PA was only 0.01 IU/mL +/- 0.005 (SEM) as compared to 118 healthy volunteers with levels of 0.70 +/- 0.10 (SEM). Despite the small sample size, the difference between the two groups was statistically significant (P less than .001). These data suggest that defective release of t-PA may contribute to a hypercoagulable state in sickle cell anemia.
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PMID:Defective release of tissue plasminogen activator in patients with sickle cell anemia. 314 Jun 56

Ear oximetry was used to monitor arterial oxygenation in seven patients who had a history of frequent admissions for sickle cell crisis and were taking narcotic analgesics. Five full-night studies and seven daytime "nap" studies were performed in which sleep state was monitored by electroencephalography, and respiratory rate and tidal volume were monitored by inductance plethysmography. For all patients the mean (+/- SEM) of the median oxygenation values was 93.3% +/- 0.4% during wakefulness and 91.4% +/- 0.8% during sleep. During wakefulness the lowest saturation was 90% +/- 0.5%; during sleep there was a fall in the lowest oxygen saturation to 86.5% +/- 0.9%. In all patients a fall in oxygen saturation was associated with a decrease in respiratory depth without a change in respiratory frequency. The results indicate that in sickle cell disease oxygen saturation is lower during sleep than during wakefulness and that hypoxemia can be attributed to a fall in tidal volume.
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PMID:Oxygen saturation with sleep in patients with sickle cell disease. 396 54

Twelve units of red cells (RBCs) from patients with sickle cell disease were glycerolized and frozen for periods of 1 to 3 years. The freeze-thaw hemolysis (mean 11.6% +/- 2.1% SEM) and in vitro process recovery (mean 74.4% +/- 3.7% SEM) were similar to those of sickle RBCs frozen for shorter periods of time. There was a weak positive correlation between duration of frozen storage and cell losses during deglycerolization. The adenosine triphosphate and 2,3-diphosphoglycerate levels of the thawed RBCs were within an acceptable range (mean 3.4 +/- 0.2 mumol/g Hb and 18.0 +/- 0.8 mumol/g Hb, respectively). Long-term cryopreservation of sickle (Hb SS) RBCs opens the possibility of exploring autologous transfusion to treat sickle cell disease patients during anemic episodes that are not due to sickling.
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PMID:Long-term cryopreservation of red cells from patients with sickle cell disease. 396 5

Previous studies have shown an association of sickle cell disease with generalized connective tissue disorders such as pseudoxanthoma elasticum. We recently documented an unexpectedly high prevalence of mitral valve prolapse, a connective tissue disorder, in sickle cell disease. To investigate this association, skin biopsies were analyzed from 32 sickle cell disease patients, 11 of whom had mitral prolapse. Total and type III collagen, collagen solubility, and uronic acid were not different between the patients with or without mitral prolapse (p greater than 0.05). Computerized morphometric quantitation of the volume fraction of elastic fibers was greater in sickle cell disease patients than in 10 normals (3.1 +/- 0.1 mean +/- SEM vs 2.0 +/- 0.3%; p less than 0.01) but less than in three patients with pseudoxanthoma elasticum (9.7 +/- 0.6%; p less than 0.001). Desmosine radioimmunoassay (an index of elastic fibers) was greater in sickle cell disease patients with mitral prolapse than those without (239.3 +/- 9.3 vs 171.7 +/- 25.4 ng/mg wet weight; p less than 0.02). Histopathologic grading showed a similar trend (p = 0.07). The combined probabilities of these three independent tests of elastic fiber quantity showed an increased elastic fiber concentration in mitral prolapse patients compared to those without mitral prolapse (p less than 0.02). Thus, there is no evidence for a specific collagen defect; rather, sickle cell disease appears to be associated with a spectrum of elastic tissue disorders, a feature that could predispose to mitral valve prolapse.
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PMID:Mitral valve prolapse in sickle cell disease: manifestation of a generalized connective tissue disorder. 398 3

Although numerous studies have provided indirect evidence for enhanced platelet activity in sickle cell anaemia, little attention has been directed to examination of platelet alpha and dense granule release in the sickling disorders. We simultaneously measured by radioimmunoassay plasma levels of the alpha granule constituents beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in 43 children with sickle cell anaemia in steady state and 24 patients during severe vaso-occlusive crisis. beta-TG levels during steady state (50 +/- 3.6 ng/ml, mean +/- SEM) were greater (P less than 0.001) than in normal controls (36 +/- 1.6), but there was no additional significant rise during crisis (55 +/- 5.9). PF4 levels were similar (P = 0.12) in both steady state (10 +/- 1.2 ng/ml) and crisis (9.3 +/- 2.3) to those of normal controls (6.0 +/- 0.8). The similarity of beta-TG/PF4 ratios in normal and sickle cell anaemia patients as well as the positive correlation (P less than 0.05) between platelet count and beta-TG and PF4 suggested that an artefactual in vitro platelet activation was responsible for some of the observed increased beta-TG and PF4 levels. Further evidence against enhanced platelet activity in these sickle cell patients included normal intraplatelet content of the dense granule constituent 5-HT and a normal ATP/ADP ratio. From this data we conclude that platelet activation in children with sickle cell anaemia appears minimal.
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PMID:Evidence against enhanced platelet activity in sickle cell anaemia. 622 55

The role of platelet-activating factor (PAF) in the pathogenesis of microvascular vaso-occlusion in sickle cell disease (SCD) is not known. In order to assess a role for PAF in vaso-occlusion in patients with SCD in steady state conditions, we measured plasma PAF level and plasma PAF acetylhydrolase activity as indices of PAF metabolism in vivo. We also studied PAF synthesis, from (3H)-acetate, by purified platelets stimulated with A23187. PAF was extracted from plasma of ten patients with SCD in steady state and from age-matched controls. PAF, purified by thin-layer chromatography, was quantitated by radioimmunoassay. PAF level (mean +/- SEM, pg/ml) in plasma of controls was 393 +/- 65, which was significantly lower than the 797 +/- 62 measured in plasma of patients with SCD. There was no difference in acetylhydrolase activity between the two groups. PAF synthesis (mean +/- SEM, nmol/10(6) cells) by platelets of controls without exogenous lyso-PAF was 1.69 +/- 0.24, higher than the 0.59 +/- 0.038 synthesized by platelets of patients with SCD. Incubation of platelets with 1.0 micromol/L lyso-PAF increased PAF synthesis by controls to 8.93 +/- 1.76, still higher than the 4.59 +/- 0.98 synthesized by platelets of patients with SCD. Our data show that patients with SCD are susceptible to a higher circulating levels of PAF in vivo during steady-state conditions. We speculate that higher levels of PAF may be a contributing factor to the persistent stress and inflammatory state of the microcirculation of patients with SCD.
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PMID:Platelet-activating factor in plasma of patients with sickle cell disease in steady state. 928 Jan 46


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