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Previous studies have shown that subjects with sickle cell trait (SCT), alpha-thalassemia (alpha-t), and the dual hemoglobinopathy (SCT/alpha-t) manifest subtle, albeit significant, differences during exercise. To better understand such differences, we assessed skeletal muscle histomorphological and energetic characteristics in 10 control HbAA subjects (C), 5 subjects with alpha-t (alpha-t), 6 SCT carriers (SCT) and 9 SCT carriers with alpha-t (SCT/alpha-t). Subjects underwent a muscle biopsy and also performed an incremental maximal exercise and a time to exhaustion test. There were no observable differences in daily energy expenditure, maximal power output (Pmax), or time to exhaustion at 110% Pmax (Tex) among the groups. Blood lactate concentrations measured at the end of the Tex, muscle fiber type distribution, and mean phosphofructokinase (PFK), lactate dehydrogenase (LDH), beta-hydroxyacyl-CoA-dehydrogenase (HAD), and citrate synthase (CS) activities were all similar among the four groups. However, SCT was associated with a lower cytochrome-c oxidase (COx) activity in type IIa fibers (P<0.05), and similar trends were observed in fiber types I and IIx. Trends toward lower creatine kinase (CK) activity (P=0.0702) and higher surface area of type IIx fibers were observed in SCT (P=0.0925). In summary, these findings support most of the previous observations in SCT, such as 1) similar maximal power output and associated maximal oxygen consumption (VO2max) values and 2) lower exercise performances during prolonged submaximal exercise. Furthermore, performances during short supramaximal exercise were not different in SCT. Finally, the dual hemoglobinopathy condition does not seem to affect muscle characteristics.

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BACKGROUND: Sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency and alpha-thalassemia trait are common genetic abnormalities among the American Black population. Under oxidative stress, the presence of any of these conditions would predispose the hemoglobin (Hb) to oxidation resulting in accelerated methemoglobin (metHb) formation. It was hypothesized that red cells phenotypic for these genetic variants should have more or different levels of metHb reductase (cytochrome b5 reductase) activity. METHODS: To test this hypothesis, we measured the red cell metHb reductase activity in 558 male subjects (316 Blacks and 242 Whites), by the procedure described by Beutler. All Black patients also had G6PD spot test and Hb electrophoresis. In addition, all patients had a complete blood count (CBC). If the hematocrit was < 35% a reticulocyte count was also done. Patients with corrected reticulocyte (retic count X hematocrit/45) index over 2% were excluded regardless of other findings. RESULTS: The results showed that Blacks had different metHb reductase activity levels than Whites (mean = 3.19 vs 2.89 IU/gHb, respectively with p = 0.03). However, the differences in metHb reductase activities in patients with sickle cell trait, G6PD deficiency, and low MCV < 80 micron3 (presumptively having alpha-thalassemia) in small subgroups did not reach statistical significance (p = 0.2), although, all 3 groups were comprised of small numbers. CONCLUSIONS: It is concluded that American Blacks have significantly different metHb reductase activity. The different metHb reductase activity in Blacks seems to be unrelated to the presence of G6PD deficiency, sickle cell trait, or alpha-thalassemia and it may be the result of genetic polymorphism. However, our study samples do not exactly represent the cross-sections of the Black and White populations. In addition, all patients were male in this study. Therefore, this study should be confirmed using larger and more population-representative samples. The clinical significance of this problem is not clear at this time.

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Routine hematological tests were performed in a family which was at risk for sickle cell disease. Cellulose acetate electrophoresis and Triton PAGE were employed to differentiate between various variants of hemoglobin. Based on the data a pedigree was constructed which indicated that few members of the respectively had received the S gene, some of them were sickle cell disease while few were sickle cell trait. Elevated levels of peroxidase enzyme in affected individuals reflect its involvement in RBCs destruction. Statistical analysis strengthen this statement.

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The activity level of acetylcholinesterase in the erythrocytes of 32 patients homozygous for sickle cell anemia was determined and compared with that of normal AA controls as well as with that of AS individuals. Acetylcholinesterase activity was markedly higher in erythrocyte membrane from SS individuals than in those from AS individuals or AA controls. Additionally, ATPase activities were also significantly higher in sickle cell erythrocytes as compared to normal cells. These higher values of acetylcholinesterase and ATPase activities in SS erythrocytes may be explained as a consequence of the abnormally high cation levels in sickle cell erythrocytes.

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The amount and activity of superoxide dismutase (SOD) (EC 1.15.1.1) were measured in red cells collected from 50 white controls, 101 black controls, 50 patients with sickle hemoglobin (SS Hb), 12 with sickle trait, and 11 with other sickling hemoglobinopathies. Red cells from normal black subjects had more SOD amount and activity than normal whites (1.77 U/mg Hb and 2.96 micrograms/mg Hb vs. 1.47 U/mg Hb and 2.64 micrograms/mg Hb, respectively) or blacks with SS Hb or other sickling hemoglobinopathies. Patients with more severe manifestations of SS Hb had lower levels of SOD activity than those with milder symptoms but had the same amount of enzyme protein. Individuals with sickle trait had amounts and activities of SOD comparable to black controls. An alteration in defense to free radical oxygen may play a role in the severity of symptoms experienced by patients with homozygous sickle cell disease.

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The relationship between the number of units of blood transfused and indicators of iron status in 37 patients with sickle cell anaemia (Hb SS), SC disease (Hb SC) or S beta-thalassaemia has been studied. The correlation coefficient between serum ferritin and the number of units transfused was good (r = 0.86), provided that ferritin samples taken within one week following a crisis were excluded. The relationship of transfusion history to serum ferritin in the steady state showed a similar relationship to that previously observed for other multiply transfused patients. The serum ferritin taken within 7 days of a painful crisis was significantly greater than the serum ferritin from the same patients in the steady state (p less than 0.025). The serum alanine transaminase did not rise as consistently as the serum ferritin during crises; it correlated with the serum ferritin but not the transfusion burden in the steady state. Transferrin iron saturation correlated less clearly with transfusion history than serum ferritin (r = 0.62). Patients who had received exchange transfusions were less likely to be iron-overloaded (ferritin increment per unit of blood = 9.9 +/- 3.8 micrograms/l) than patients who had received an equivalent number of units by conventional transfusion (ferritin increment per unit of blood transfused = 25.1 +/- 2.42 micrograms/l).

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The formation of pyridoxal and its phosphate from pyridoxamine phosphate by red cell haemolysates was measured in a centrifugal analyser by the formation of the fluorescent adduct with semicarbazide. Pyridoxal phosphate was found to react more rapidly than pyridoxal, thus permitting a distinction between the two products, and hence the measurement of phosphatase activity. Activity of the enzyme, pyridoxamine phosphate:oxygen oxidoreductase (deaminating) EC 1.4.3.5 (PPO) was measured in haemolysates from 72 Gambian women with evidence of riboflavin deficiency, and was repeated after 6 weeks of placebo or riboflavin supplementation. Those who received the riboflavin supplement responded with a marked increase in PPO activity, which was matched by a decrease in the activation coefficient (AC) of erythrocyte NAD(P)H2:glutathione oxidoreductase, EC 1.6.4.2 (glutathione reductase, EGR). No difference between the supplemented and unsupplemented groups was observed in the capacity of haemolysates to hydrolyse pyridoxal 5-phosphate, nor in the extent of activation of erythrocyte L-aspartate:2-oxoglutarate aminotransferase EC 2.6.1.1. by pyridoxal phosphate. Although the three subjects with low levels of D-glucose 6-phosphate: NADP 1-oxidoreductase EC 1.1.1.49 (G6P-D) had, as expected, correspondingly low AC's of EGR, their unsupplemented activities of PPO were in the same low range as those of the G6P-D-normal subjects, and they responded as G6P-D-normal subjects did to riboflavin supplementation. PPO thus does not appear to resemble EGR in retaining its flavin coenzyme during riboflavin depletion.(ABSTRACT TRUNCATED AT 250 WORDS)

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In a group of 27 sickle cell disease patients ranging in age from 2 yr 3 months to 43 yr, 13 (48%) were found to have depressed erythrocyte glutathione reductase activity suggesting riboflavin deficiency. Glutathione reductase activity coefficients did not correlate with riboflavin intakes which were calculated from 3-day diet records returned by 16 patients. Other causes of riboflavin deficiency including decreased absorption, altered metabolism, or increased excretion of the vitamin must be considered. The potential effect of depressed erythrocyte glutathione reductase activity in the sickle cell disease process is discussed.

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401 subjects of both sexes and with ages ranging from 5 to 50 years were investigated for haemoglobin phenotypes by starch-gel electrophoresis. Concentrations of blood haemoglobin, serum total protein, albumin, globulin, total cholesterol and serum transaminases (SGOT and SGPT) were determined to examine the influence of the sickle cell gene on these biochemical parameters. The carriers of sickle cell trait had higher levels of SGOT and SGPT compared to those with haemoglobin A and homozygous sickle cell haemoglobin. The carriers of homozygous sickle cell had lower levels of haemoglobin, total cholesterol and transaminases. No significant difference was observed in serum protein concentration in relation to the presence of sickle cell gene.

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In normal erythrocytes, a membrane-bound (Ca2+ + Mg2+)-ATPase is stimulated by a soluble activator, calmodulin. Since cells containing Hb S accumulate excessive Ca2+, the defect could lie in either the (Ca2+ + Mg2+)-ATPase or calmodulin. To decide between these two possibilities, we prepared (Ca2+ + Mg2+)-ATPase from erythrocytes of normal (AA), sickle cell trait (AS) and sickle cell disease (SS) individuals. Calmodulin was prepared from haemolysates from AA and SS erythrocytes. The enzyme prepared from SS ghosts had lower specific activity than that from AA membranes. Furthermore, calmodulin from either source did not stimulate the ATPase of SS erythrocytes. Enzyme from AS cells had specific activity similar to that of enzyme prepared from SS membranes. The enzymatic activity of a mixed cell population obtained from an SS patient 8 d following exchange-transfusion was proportional to the per cent Hb A. These results indicate that calmodulin is unable to interact with the enzyme site on the SS membrane. This inability is believed to be due to a specific property of the membrane and not an abnormality of calmodulin itself.

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Serum alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) levels were determined in 28 children with homozygous sickle cell disease (SCD) during the steady state, crisis, and postcrisis periods. Serum alpha-HBDH levels were also studied in 20 patients with infection. In patients during the steady state, serum alpha-HBDH levels were significantly above control values. During the vaso-occlusive crisis there was a significant further increase in the alpha-HBDH levels. In patients with infection, however, there was no significant increase in serum alpha-HBDH levels. These findings clearly indicate that the level of serum alpha-HBDH in patients with SCD permits differentiation between vaso-occlusive crises, infection, and spurious symptoms.

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The relationship between D-glucose-6-phosphate: NADP oxido-reductase (E.C.1.1.1.49; glucose-6-phosphate dehydrogenase; G6PD) deficiency and homozygous sickle cell (SS) disease was examined in 120 patients. The proportions of hemizygotes (22.6%) was slightly more than that observed, and the combined proportions of heterozygotes and homozygotes (28.3%) were slightly less than would be expected, in the general population, but the differences were not significant. However, the proportion of patients of abnormal G6PD status in the 10-19 years age group was 41.7%, significantly more than that found in the 20-29 years age group (0.02 less than P less than 0.05), or expected in the general population (P=0.05). Possible reasons for this are discussed. Difference in G6PD status did not affect the total haemoglobin concentration, reticulocyte count, unconjugated serum bilirubin or Hb F concentration, irreversibly sickled cell counts or plasma haemoglobin concentration, and there was no demonstrable correlation between clinical severity or leg ulceration and abnormal G6PD status.

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The relationship between D-glucose-6-phosphate: NADP oxide-reductase (E.C.1.1.1.49; glucose-6-phosphate dehydrogenase; G6PD) deficiency and homozygous sickle cell (SS) disease was examined in 120 patients. The proportion of hemizygotes (22.6 percent) was slightly more than that observed, and the combined proportions of heterozygotes and homozygotes (28.3 percent) were slightly less than would be expected, in the general population, but the differences were not significant. However, the proportion of patients of abnormal G6PD status in the 10-19 years age group was 41.7 percent, significantly more than that found in the 20-29 years age group (0.02

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The low molecular weight cobra venom factor (CoVF) was used to activate the terminal sequence of the alternative complement pathway in thirty-one sera from patients with sickle cell disease (SCD). The SCD sera were compared with normal sera as a source of the alternative complement pathway factors C3 proactivator (C3PA) and C3PA convertase. These factors are required for formation of the enzymatically active CoVF-C3PA complex which is capable of cleaving C3 and thus initiating generation of the cytolytic C5b-9 complex. CoVF cofactor activity was significantly less than normal in SCD sera as measured in an indirect lysis assay, indicating reduced C3PA or C3PA convertase activity in these sera. Qualitative (immunoelectrophoresis) and quantitative (radial immunodiffusion) measurement of C3PA showed, however, that this protein is normal or elevated in SCD sera. Taken together, the reduced CoVF cofactor activity and normal or elevated C3PA in SCD sera suggests that sera from patients with sickle cell disease have reduced C3PA convertase activity.

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