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Biomedical subjects

M E Fabry

Publications and source records attributed to M E Fabry.

At least 91 records · Page 5Linked to original sources
PubMed1985

Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients.

We have studied 42 homozygous beta-thalassemia patients from Algeria and 34 sickle cell anemia patients from Senegal and Benin, determining the relationship between haplotypes, Hb F, and G gamma-globin/A gamma-globin ratios. Populations selected have a high frequency of haplotype homozygotes because of consanguinity (Algeria) and geographic homogeneity (West Africa). We find in beta-thalassemia patients, that haplotype IX in haplotypic homozygotes and heterozygotes, haplotype III in heterozygotes, and the Senegal haplotype in sickle cell anemia patients are all linked to high G gamma-globin expression. In addition, haplotypes IX and Senegal, but not haplotype III, have high Hb F levels. All of these haplotype have a common subhaplotype (+- ) in the gamma-globin gene region. In addition, haplotypes IX, III, and Senegalese sickle cell anemia patients exhibit hematological amelioration of their disease. Conversely, haplotypes I, V, and A in thalassemia patients, which also have a common subhaplotype (-----), and the Benin subhaplotype (--++-) in sickle cell anemia patients are all associated with low G gamma-globin and low Hb F levels. Low G gamma-globin expression in the adult is associated with two haplotypes that are not common between thalassemia and sickle cell anemia patients. We conclude that the determinant for high G gamma-globin expression is haplotype-linked to common and genetically dominant subhaplotypes in the two diseases. The total Hb F level, unlike the high G gamma-globin expression, however, is linked to haplotypes but not to subhaplotypes, thus dissociating the two genetic effects.

Anemia, Sickle Cell↗
PubMed1985

Red cell distribution width parallels dense red cell disappearance during painful crises in sickle cell anemia.

We reported previously that painful crises in patients with sickle cell anemia are accompanied by striking decreases in the percent of densest red cells (fraction 4) when studied with isopyknic Percoll-Stractan gradients. We report that an alternative to density gradients is the red cell distribution width (RDW), an estimate of red cell size variation measured with a Coulter counter. In 17 painful crises in 12 patients with homozygous sickle cell anemia the RDWs decreased in each crisis, from an initial mean of 16.2 +/- 1.8 SD to 12.8 +/- 1.3 (P less than 0.001). In patients in whom serial measurements of both RDW and fraction 4 (very dense) red cells were taken during crisis, the two measurements declined in parallel. The decrease of RDW is a readily observable and objective laboratory concomitant of painful sickle crisis.

Anemia, Sickle Cell↗
PubMed1984

On the mechanism for the red-cell accumulation of mefloquine, an antimalarial drug.

The accumulation of the antimalarial drug mefloquine by human red blood cells has been studied by 19F-NMR spectroscopy. The uptake process was nonlinearly dependent on the external drug concentration. Concentrations inside cells as high as 60-times greater than those in the extracellular phosphate-buffered-saline were observed. Red-cell ghosts were also found to accumulate mefloquine with high-affinity binding sites for the drug. Hemoglobin was found to bind mefloquine with low affinity, but due to the high concentration of this protein it is a significant drug compartment in the red cell. Analysis of the 19F-NMR chemical shifts and linewidths of mefloquine in the presence of red cells, red-cells ghosts and hemoglobin indicates restricted mobility of the drug in the membrane-bound state and slow exchange with the extracellular medium. This is a significant characteristic of the reaction in connection with the prophylactic activity of the drug. Exchange of the drug between hemoglobin and the red-cell membrane, however, is fast and may play an important role in the bioavailability of the drug to the parasite.

Antimalarials↗
PubMed1984

Dense cells in sickle cell anemia: the effects of gene interaction.

In an attempt to uncover potential genetic sources of the clinical diversity of sickle cell anemia, we have characterized homozygous SS patients in the following ways: percentage of dense red blood cells (% F4) as determined from Percoll-Stractan continuous density gradients, alpha gene deletion, average percentage of hemoglobin F (% HbF), hemoglobin in g/dL, age, and sex. We find that alpha 4 individuals have a higher % F4 (mean 24% +/- 15%) than alpha 3 individuals (mean 12% +/- 8%) (P less than .005). Multivariate analysis demonstrated a significant correlation among % F4 levels and alpha-gene number and % HbF, and an interaction between the last two variables. The other variables considered did not significantly alter this model. As reported before, with fewer samples, we find that in the first ten years of life of SS individuals, the frequency of alpha gene deletion is 17%, which is comparable to that in the general black population, while in the group over 20 years of age, the frequency rises to 49%, implying that alpha thalassemia is associated with longer survival. These results indicate that it is necessary to consider sickle cell anemia not only as a single gene defect, but also as a disease whose clinical expression is the result of a group of genes capable of interacting at the phenotypic level.

Adult↗
PubMed1984

An objective sign in painful crisis in sickle cell anemia: the concomitant reduction of high density red cells.

The etiopathologic basis of painful crisis in sickle cell anemia is largely unknown, and no objective criteria for its diagnosis and follow-up exist at present. We have studied 11 patients through 14 painful crises and observed a significant decrease of the densest fraction of red cells in 12 of the 14 crises as determined by isopycnic Percoll-Stractan continuous density gradients. If the first observation is normalized to 100%, the average decrease in dense cells was 77% with a range of 36% to 94%. The time needed for the percentage of dense cells to return to the steady-state level varied from seven to more than 30 days. These findings were in sharp contrast to the stability of the density pattern observed in another group of sickle cell patients, who were studied during crisis-free periods. The mechanism of the disappearance of dense cells could involve selective destruction by the reticuloendothelial (RE) system, selective sequestration in the areas of vasoocclusion, or a combination of both factors.

Adult↗
PubMed1983

Erythrocytes in sickle cell anemia are heterogeneous in their rheological and hemodynamic characteristics.

To understand the contribution to the pathophysiology of sickle cell anemia of the different erythrocyte density types present in the blood of these patients, we have studied the viscosimetric and hemodynamic characteristics of four major classes of hemoglobin SS erythrocytes. We have isolated reticulocytes, discocytes, dense discocytes, and irreversibly sickled cells (fractions I-IV) on Percoll-Renografin density gradients. Bulk viscosity was studied in a coneplate viscosimeter and the hemodynamic studies were performed on the isolated, artificially perfused mesoappendix vasculature of the rat (Baez preparation). Bulk viscosity measurements at shear rates of 230 S-1 demonstrate that when the cells are oxygenated, fraction I (reticulocyte rich) has a higher viscosity than expected from its low intracellular hemoglobin concentration. The rest of the fractions exhibit moderate increases in bulk viscosity pari-passu with the corresponding increases in density (mean corpuscular hemoglobin concentration). When deoxygenated, all cell fractions nearly doubled their bulk viscosity and the deoxy-oxy differences remained constant. The Baez preparation renders a different picture: oxygenated fractions behave as predicted by the viscosimetric data, but, when deoxygenated, cell fractions exhibit dramatically increased peripheral resistance and the deoxy-oxy difference are directly proportional to cell density, thus, the largest increases were observed for fractions III and IV. The differences between the rheological and the hemodynamic measurements are most probably due to the different sensitivity of the two methods to the extent of intracellular polymerization. These results also demonstrate that the hitherto unrecognized fraction III cells (very dense discocytes that change shape very little on deoxygenation) are as detrimental to the microcirculation as the irreversibly sickled cell-rich fraction IV. They may, however, induce obstruction by a different mechanism. As the extent to which these fractions are populated by erythrocytes varies considerably from patient to patient, the distribution function of cell densities in each sickle cell anemia patient might have consequences for the type of pathophysiological events occurring in their microcirculation.

Adult↗
PubMed1982

SC erythrocytes have an abnormally high intracellular hemoglobin concentration. Pathophysiological consequences.

We have examined 20 SC patients on Percoll-Stractan continuous density gradients and find that they have an elevated mean corpuscular hemoglobin concentration (MCHC). Reduction of the MCHC to normal values results in amelioration of four physiologically important blood abnormalities: decreased oxygen affinity, viscosity of deoxygenated erythrocyte suspensions, rate of sickling, and deoxygenation induced K+ efflux. These observations suggest that the rehydration of SC cells to normal values should be considered a potential approach in the therapeutic manipulation of this disease.

Anemia, Sickle Cell↗
PubMed1982

Heterogeneity of red cells in the sickler: a characteristic with practical clinical and pathophysiological implications.

The role of heterogeneity of red cells and its relation to the severity of sickle cell anemia has been examined by the use of spontaneously formed continuous density gradients. We have found that sicklers have a more heterogeneous distribution of cell densities than normals; that this heterogeneity varies greatly from patient to patient; and that this heterogeneity is functionally significant because it involves changes in MCHC and O2 affinity. Extrapolation of HbS solution data to clinical situations will have to account for heterogeneity, and previous efforts to correlate ISC's with severity might have ignored the role of cells with high density but without the classical morphological features associated with these types of cells.

Anemia, Sickle Cell↗
PubMed1981

Some aspects of the pathophysiology of homozygous Hb CC erythrocytes.

We have studied erythrocytes from homozygous CC patients in vitro and in perfused rat mesoappendix vasculature to answer some long-standing questions. By examination of wet whole blood preparations, and by comparing the cell distribution on isopycnic continuous density gradients of whole blood samples from a splenectomized CC patient with those from three intact CC patients, we have demonstrated the presence of a distinct crystal-containing band of cells that is present in the former, but totally absent from the latter. We conclude that Hb CC cells containing crystals circulate in Hb CC individuals, but in intact patients they are effectively removed by the spleen. By use of 31P nuclear magnetic resonance and viscosity measurements on cells, we have demonstrated that intracellular aggregation of hemoglobin C occurs on deoxygenation even when no crystal formation is detectable by morphological methods. These two observations are in apparent contradiction with the absence of clinical microcirculatory impairment found in both intact and splenectomized CC patients. The contradiction was resolved by rheological studies on isolated rat mesoappendix preparations and erythrocyte diameter measurements that lead to the conclusion that the hemorheological properties of CC cells in the microcirculation are nearly normal because their increased viscosity is offset by their smaller diameter and size.

Blood Viscosity↗
PubMed1981

Impairment of the growth of Plasmodium falciparum in HbEE erythrocytes.

HbE is a beta-chain mutant frequently found among inhabitants of Southeast Asia and surrounding territories. We find that Plasmodium falciparum multiplies more slowly in erythrocytes from individuals homozygous for HbE than in cells from HbA individuals. In contrast, this parasite grows normally in erythrocytes heterozygous for HbE. This is the first direct evidence that suggests what has been suspected on the basis of circumstantial data, that HbE-containing erythrocytes might be advantageous to the carrier in regions with endemic malaria.

Erythrocytes↗
PubMed1978

Water exchange across red cell membranes: II. Measurements by nuclear magnetic resonance T1, T2, and T12 hybrid relaxation. The effects of osmolarity, cell volume, and medium.

We have used the nuclear magnetic relaxation of water protons to measure the diffusional permeability (Pw) of human red blood cells to water as a function of concentration of nonpermeable and permeable solutes. Measurements of T1, T2, and a hybrid of the two were made and yielded the same Pw. In the presence of the nonpermeable electrolyte NaCl, membrane permeability is constant between the volumes of 70 and 105 micron3 and increases both as the cells swell and shrink beyond these limits. Changes in both the internal and external osmolarity, using the permeable solutes urea and ammonium chloride, do not affect membrane permeability. The composition of the suspending medium also has a significant effect on membrane permeability. Cells suspended in plasma have a cell water lifetime about 30% longer than cells of the same volume suspended in serum, or isotonic saline with human serum albumin. Addition of a crude preparation of fibrinogen in physiological amounts to isotonic saline and human serum albumin restores the cell water lifetime to a value similar to that observed in plasma.

Ammonium Chloride↗
PubMed1975

Water exchange between red cells and plasma. Measurement by nuclear magnetic relaxation.

Water exchange between human red blood cells and the plasma phase was measured by water proton nuclear magnetic resonance relaxation in the presence of low concentrations of Mn(II) and by 17O relaxation of H217O in the absence of added Mn(II). The results were analyzed as a classic case of two-compartment exchange. The half-life for cell water at 25 degrees C was found to be 15 ms +/- 2 ms, longer than the time determined by other techniques. The T1 of the hemoglobin protons in the red cell and the volume of exchangeable water were also measured. The method appears to be a sensitive tool for the study of membrane permeability to water and other small molecules undergoing rapid exchange.

Erythrocytes↗