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Biomedical subjects

S B Shohet

Publications and source records attributed to S B Shohet.

At least 73 records · Page 4Linked to original sources
PubMed1982

Hydration of sickle cells using the sodium ionophore Monensin. A model for therapy.

Mean cell hemoglobin concentration (MCHC) is thought to have an important influence in sickle cell disease, both through the strong dependence of sickling rates on hemoglobin S concentration, and through the profoundly limiting effect of high MCHC on the rheologic competence of oxygenated, irreversibly sickled cells (ISC). Recent studies have tested the ability of antidiuretic hormone to reduce sickle cell MCHC by reducing plasma sodium (Na) and osmolality. An alternative means of reducing MCHC is to elevate intracellular cation content, rather than to depress extracellular cation concentration. In an effort to do this, we have treated sickle cells with Monensin, an antibiotic that selectively enhances membrane Na permeability. At submicromolar concentrations, Monensin substantially reduced the MCHC of whole sickle blood and isolated ISC, causing an improvement in cell deformability. Monensin's effectiveness in producing a controlled increase in erythrocyte water content suggests that agents that selectively increase membrane Na permeability could be therapeutically useful.

Anemia, Sickle Cell↗
PubMed1982

Interaction of amphipathic drugs with erythrocytes from various species.

Changes in morphology of human erythrocytes exposed to certain amphipathic drugs can be predicted by the bilayer couple hypothesis as proposed by Sheetz and Singer (Proc Natl Acad Sci USA 71:4456-4461, 1975). When we tested that hypothesis, using erythrocytes from other mammals, we found that most but not all, underwent the predicted changes. Both camel and llama erythrocytes showed minimal morphologic changes when exposed to anionic and cationic phenothiazines. The spicules formed by anionic drug in different species were numerically related to cell sizes. We conclude that structural rigidity of the erythrocyte membrane can alter the response predicted by the bilayer couple hypothesis.

Animals↗
PubMed1982

Hereditary plasma lecithin-cholesterol acyl transferase deficiency: a heterozygous variant with erythrocyte membrane abnormalities.

LCAT esterifies cholesterol to cholesterol ester. This study describes a family with plasma LCAT deficiency with a heterozygous variant. It was found that both parents and one son had half the normal plasma LCAT activity whereas their only daughter and other son exhibited zero plasma LCAT activity, suggesting an autosomal co-dominant inheritance of the enzyme deficiency. Erythrocyte membrane abnormalities (e.g., increased erythrocyte PC and cholesterol) that were associated with patients with zero plasma LCAT were also observed in family members with half the LCAT. Additionally, erythrocytes from LCAT-deficient individuals were more susceptible to peroxidant threat and had membranes that were more mechanically unstable than those from individuals with normal plasma LCAT activity.

Adult↗
PubMed1981

Study on the dehydrating effect of the red cell Na+/K+-pump in nystatin-treated cells with varying Na+ and water contents.

Using the antibiotic Nystatin, we have developed a systematic method for the preparation of red blood cells with independently selected levels of intracellular Na+ concentrations and water content. Such cells provided an experimental model to study the effect of Na+/K+ pump stimulation on red cell water content. Even in initially dehydrated cells, stimulation of the Na+/K+ pump by elevated intracellular Na+ caused subsequent further loss of cell water. Cell water loss was reflected in decreased monovalent cation content per unit mass of hemoglobin and by a shift in the density distribution of the cell populations to higher densities on discontinuous Stractan gradients. We conclude that the 3 Na+out : 2 K+in stoichiometry of the Na+/K+ pump results in a net desalting effect with increased pump activity. Under the conditions of these experiments, the cell appears to have no effective mechanism to compensate for a net loss of ions and water.

Adenosine Triphosphate↗
PubMed1981

Calcium potentiates the peroxidation of erythrocyte membrane lipids.

To explore the possible role of intracellular calcium in membrane lipid peroxidation, we subjected red cells to conditions designed to increase intracellular calcium levels and then measured lipid peroxidation after exposure to a peroxidant threat. Human erythrocytes were pretreated for 3 h with either very high levels of CaCl2, or with low levels in the presence of the ionophore A23187. The erythrocytes were subsequently exposed to a peroxide-generating system consisting of xanthine and xanthine oxidase, or H2O2 for 1 h at 37 degrees C. As measured by a malonyldialdehyde assay, the calcium-treated cell showed up to a 2-fold increase in lipid peroxidation in comparison to untreated cells. In experiments with the ionophore, calcium concentration-dependent effects were detected at levels as low as 10 microM and were maximal at 50 microM. A significant loss of phosphatidylserine and phosphatidylethanolamine was observed in calcium- and peroxide-treated erythrocytes. This potentiation of membrane lipid peroxidation and lipid loss could be prevented by either lipid antioxidants or EGTA. The present study shows that pretreatment of erythrocytes with calcium increases their sensitivity to lipid peroxidation. This suggests that increased calcium concentration may be a factor in the potentiation of membrane lipid peroxidation of erythrocytes known to have increased calcium levels such as sickled and senescent red cells.

Antioxidants↗
PubMed1981

Hemolytic anemia associated with leptospirosis. Morphologic and lipid studies.

A case of fulminant hemolytic anemia associated with a leptospiral infection is presented with morphologic and erythrocyte lipid studies. Both the frequency and pathogenesis of anemia in human leptospirosis is poorly understood. The anemia frequently observed in Weil's syndrome has been ascribed on clinical impression to blood loss, renal failure, and/or an ill-defined hemolytic process. However, hemolytic anemia associated with leptospirosis in animals is well documented and is due to hemolysins with phospholipase activity. Our patient's erythrocyte morphologic abnormalities on bright light and electron microscopy included particles of cells and cells with a thorny or spiculated surface suggesting that the hemolytic process was due to membrane injury. Measurement of the erythrocyte membrane lipids showed reductions in sphingomyelin and phosphatidylethanolamine suggesting that the observed hemolysis and morphologic changes resulted from phospholipases produced by the infecting leptospirae.

Anemia, Hemolytic↗
PubMed1981

Separate mechanisms of deformability loss in ATP-depleted and Ca-loaded erythrocytes.

Membrane rigidity has been widely accepted as the dominant cause of reduced deformability both of ATP-depleted erythrocytes and erythrocytes containing excess calcium (Ca). However, recent studies have shown normal membrane deformability in ATP-depleted erythrocytes. In addition, Ca accumulation causes massive ion and water loss, and it has been shown that extensive dehydration causes an increase in intracellular viscosity with attendant loss of whole cell deformability. To obtain a detailed understanding of the processes accompanying ATP depletion and/or Ca accumulation that limit cell deformability, we have used a viscodiffractometric method to identify the cellular factors contributing to reduced whole cell deformability. Analysis of the influence of the suspending medium osmolality on deformability showed the presence of two independent processes. One was a Ca-independent reduction in cell surface area/volume ratio, resulting from the spheroechinocyte formation that follows total ATP consumption. The other was a Ca-dependent increase in intracellular viscosity resulting from a Ca-induced loss of intracellular potassium and water. This deformability loss due to increased intracellular viscosity was found for cells depleted of ATP in the presence of Ca and in cells treated with Ca and A23187 without prior depletion. Ionophore-treated cells at high Ca concentration (>500 muM) formed spheroechinocytes with reduced surface area and a further loss of whole cell deformability. The rate of deformability loss associated with Ca-induced spheroechinocytosis was much more rapid than that associated with ATP-depletion-induced spheroechinocytosis, suggesting different mechanisms for the morphologic changes. No major effects of altered membrane elasticity on the reduced deformability of either ATP-depleted or Ca-loaded cells were observed.

Adenosine Triphosphate↗
PubMed1981

Deficiency of skeletal membrane protein band 4.1 in homozygous hereditary elliptocytosis. Implications for erythrocyte membrane stability.

Erythrocytes from three patients with severe hemolytic anemia, marked erythrocyte fragmentation, and elliptocytic poikilocytosis, were studied in terms of both their membrane protein composition and their mechanical characteristics. Erythrocytes from the patients' parents and one minimally affected and one normal sibling were also studied. Morphologic observations implied that the severely affected patients suffered from homozygous hereditary elliptocytosis because erythrocytes of both parents and the one minimally affected sibling showed moderate elliptocytosis on smear, whereas those of an unaffected sibling had normal morphology. The parallel findings of markedly reduced levels of band 4.1 in the erythrocyte membrane proteins of the patients and an intermediate reduction in the cells of the parents and the putative heterozygous sibling, suggest that the elliptocytic shape of the cells was related to the reduced levels of band 4.1. Additional studies showed marked abnormalities in cellular deformability and membrane fragility in the erythrocytes from the homozygous patients. Importantly, these changes were also closely proportional to the reduced levels of band 4.1, suggesting a central role for this protein in the maintenance of normal membrane stability and normal cell shape. It seems likely that this role for band 4.1 is intimately related to its known biochemical connection to the "membrane skeleton" through its linkage with spectrin and actin.

Actins↗
PubMed1981

Possible roles for the membrane cytoskeleton in regulating red cell stability and deformability.

Several observations suggest the presence of a membrane cytoskeleton in the red cell. Some of these imply possible roles for that cytoskeleton in regulating red cell shape and deformability. One of the most striking examples of this role is that of the spectrin-free spherocyte mouse. In this condition, spectrin is virtually absent from the membranes of erythrocyte cells and osmotic fragility and survival is markedly affected. The mice are afflicted with an extreme haemolytic anaemia which is barely compatible with life. An unequivocal role for the cytoskeleton in being responsible for this disorder has been shown through experiments in which the cytoskeleton has been reconstituted by specific rebinding of normal mouse spectrin to these defective cell membranes. Marked improvement in membrane fragmentation, membrane, membrane fusion, and osmotic stability following reconstitution indicated that these functions are partially regulated through the membrane cytoskeleton, and its predominant protein, spectrin.

Anemia, Hemolytic↗
PubMed1981

Factors that limit whole cell deformability in erythrocytes after calcium loading and ATP depletion.

Whole cell deformability of ATP-depleted and Ca-loaded red cells has been measured at various osmolalities to determine those cellular factors responsible for the reduce deformability of these cells. For cells depleted of ATP in Ca-free medium, a progressive loss of hypotonic deformability identified membrane loss with reduced surface area-to-volume ratio as the dominant mechanism of deformability loss. For cells treated with Ca and the ionophore A23187 without prior depletion, a rapid loss of isotonic deformability, reversible in hypotonic medium, identified dehydration with increased internal viscosity as the dominant mechanism of deformability loss. In contrast to previously held concepts, increased membrane rigidity was not found to have a major influence.

Adenosine Triphosphate↗
PubMed1981

A new method for studying the deformability of isolated erythrocyte membranes.

The development of a new system for measuring the deformability of isolated erythrocyte membranes is described. This system, which uses ektacytometry of resealed erythrocyte membranes, enables one to directly measure membrane properties in the absence of internal viscosity effects. Preliminary observations have indicated that cross-linking membrane proteins gave rise to reduced membrane deformability.

Cell-Free System↗