Abnormalities of cell-membrane fluidity in the pathogenesis of disease.
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Abetalipoproteinemia↗
Biomedical subjects
R A Cooper
Publications and source records attributed to R A Cooper.
D-Galactonate utilisation by enteric bacteria. The catabolic pathway in Escherichia coli.
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Adenosine Diphosphate↗
A randomized clinical trial of granulocyte transfusions for infection in acute leukemia.
In a prospective, controlled, randomized study to evaluate the efficacy of filtration-leukapheresis granulocytes in granulocytopenic, febrile patients with leukemia, 19 patients received antibiotics alone, and 12 received antibiotics plus daily granulocyte transfusions from ABO-matched donors. In skin-chamber studies the granulocytes appeared at sites of inflammation for at least six hours after transfusion. Infected subjects survived longer if they received granulocytes. Differences between control and transfused patients were greatest in patients with persistent bone-marrow failure, the 21-day survival being 20 per cent in controls, and 75 per cent in transfused patients. Granulocytes appeared to have no effect on the outcome of febrile episodes in which infection was not documented, the 21-day survival being 79 per cent for controls and 88 per cent for transfused patients. The transfusion of granulocytes thus appears to offer a survival advantage to infected, persistently granulocytopenic patients.
Acute Disease↗
Pyruvate formation during the catabolism of simple hexose sugars by Escherichia coli: studies with pyruvate kinase-negative mutants.
Escherichia coli K-12 mutants lacking the adenosine 5'-monophosphate-activated pyruvate kinase have been isolated accidentally and used to prepare further mutants additionally devoid of the fructose bisphosphate-activated pyruvate kinase. Such double mutants totally devoid of pyruvate kinase activity still grow well under aerobic conditions on sugars that are catabolized by the phosphoenolpyruvate (PEP):sugar phosphotransferase system, but they grow poorly on non-phosphotransferase system sugars. This suggests that although pyruvate kinase plays a major role in the formation of pyruvate from PEP during growth on non-phosphotransferase system sugars, the operation of the PEP:sugar phosphotransferase system can contribute significantly to pyruvate production from PEP. In the absence of pyruvate kinase and an active PEP:sugar phosphotransferase system the methylglyoxal glycolytic bypass may also function to some extent for the formation of pyruvate during the catabolism of simple hexose sugars. No unique physiological role can yet be ascribed to the adenosine 5'-monophosphate-activated pyruvate kinase as a result of these studies.
Escherichia coli↗
Radiography and scintigraphy in tumoral calcinosis.
A case of tumoral calcinosis with tumoral deposits about the knee is reported. Radiographs demonstrate juxta-articular calcific deposits about the right second and fifth distal interphalangeal joints and the left first distal tuft, both hips, both shoulders, first distal phalanx of the left foot and right knee. Radionuclide images clearly demonstrate all areas of tumoral calcinosis.
Calcinosis↗
Decreased fluidity of red cell membrane lipids in abetalipoproteinemia.
Acanthocytic red cells in patients with abetalipoproteinemia are morphologically similar to the red cells in spur cell anemia. Fluidity of membrane lipids is decreased in spur cells due to their excess cholesterol content. Acanthocyte membranes have an increased content of sphingomyelin and a decreased content of lecithin. To assess the effect of this abnormality of acanthocyte membrane lipid composition on membrane fluidity, we studied red cells from five patients with abetalipoproteinemia and four obligate heterozygote family members. Membrane fluidity was measured in terms of microviscosity ( eta) at 37 degrees C, assessed by means of the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. It was increased from 3.2+/-0.1 poise in normals to 4.01-4.14 poise in acanthocytes. This was associated with an increase in the sphingomyelin/lecithin ratio from 0.84+/-0.08 in normals in 1.45-1.61 in acanthocytes. The eta of acanthocyte membranes was not influenced by the degree of vitamin E deficiency. Similar changes in eta were observed in liposomes prepared from red cell lipids. Heterozygotes had normal sphingomyelin/lecithin ratios and normal values for eta. The flow activation energy for viscosity, a measure of the degree of order in the hydrophobic portion of the membrane, was decreased from 8.3 kcal/mole in normal red cells to 7.2 kcal/mole in acanthocytes, indicating that acanthocyte membrane lipids are more ordered. Variations in the sphingomyelin/lecithin mole ratio of liposomes prepared from brain sphingomyelin and egg lecithin with equimolar cholesterol caused similar changes in both eta and activation energy. The deformability of acanthocytes, assessed by means of filtration through 3-mum filters, was decreased. These studies indicate that the increased sphingomyelin/lecithin ratio of acanthocytes is responsible for their decreased membrane fluidity. As in spur cells and in red cells enriched with cholesterol in vitro, this decrease in membrane fluidity occurs coincidentally with an abnormality in cell contour and an impairment in cell deformability.
Abetalipoproteinemia↗
Alveolar cell carcinoma in identical twins. Similarity in time of onset, histochemistry, and site of metastasis.
Identical male twins had alveolar cell carcinoma with nearly synchronous onset and similar histopathologic features, both metastatic to the brain. The hypothesis is advanced that there are genes shared by these twins that determine not only the susceptibility of pulmonary cells to malignant transformation but also the character of the resultant neoplasm, including its histologic features and metastatic behavior.
Adenocarcinoma, Bronchiolo-Alveolar↗
Abnormalities of cholesterol-phospholipid composition in platelets and low-density lipoproteins of human hyperbetalipoproteinemia.
Platelets from most patients with type IIa hyperlipoproteinemia (IIa) aggregate in the presence of lower concentrations of epinephrine and adenosine diphosphate (ADP) than are necessary to aggregate normal platelets. We have observed a comparable functional alteration in human platelets made cholesterol-rich in vitro by incubation in a milieu artificially rich in free cholesterol relative to phospholipid. We therefore examined platelet aggregation and lipid composition of platelets and of plasma low-density lipoprotein (LDL) in 19 individuals with IIa (including three homozygotes), seven normolipidemic individuals with symptomatic, angiographically-documented coronary atherosclerosis (atherosclerosis group), and 23 asymptomatic, normolipidemic subjects (control group). More than 99 percent of platelet cholesterol was unesterified. There was a 7 percent increase in the cholesterol content of whole platelets per mole of platelet phospholipid (C/PL) in IIa as compared to normal controls. This resulted from a 22 percent increase in the C/PL of IIa platelet membranes with no change in the C/PL of the soluble or granule fraction. The C/PL of IIa platelets was 6 percent greater than that of platelets from patients with atherosclerosis. As compared to those of normal controls, IIa platelets aggregated in response to a ninefold lower concentration of epinephrine (p less than 0.001) and a twofold lower concentration of ADP (p less than 0.02). The response of atherosclerosis platelets to these agents was comparable to that of controls. In all groups, there was a negative correlation between the log concentration of epinephrine required to produce complete platelet aggregation and the platelet C/PL (r = -0.06; p less than 0.002). The composition of LDL isolated from the plasma of patients with IIa was characterized by a 39 percent increase in the amount of free cholesterol relative to protein and a 35 percent increase in C/PL, as compared with control LDL. These values were increased 23 and 19 percent, respecitvely, when IIa was compared with the atherosclerosis group. In all groups the C/PL of LDL correlated well with the C/PL of platelets (r = =0.61; p less than 0.001). However, a simple cause-and-effect relationship did not appear to exist since (1) erythrocyte membrane C/PL was not affected and (2) normal platelets or erythrocytes underwent no change in C/PL during 18 hours' incubation in IIa plasma. These studies demonstrate that LDL and platelets in IIa contain an increased amount of free cholesterol relative to its principal solubilizer, phospholipid. In platelets this correlates with an increased sensitivity to aggregating agents. Moreover, the similarity between the functional abnormality in IIa platelets and that previously observed in normal platelets made cholesterol-rich in vitro suggests that the lipid composition of platelet membranes may have a direct effect on the function of platelets in man.
Adolescent↗
Effect of cytochalasin B on human monocyte binding and sphering of IgG-coated human erythrocytes.
The ability of human mononuclear phagocytic cells to bind IgG-coated human erythrocytes (EA) and to cause bound EA to become osmotically fragile (sphered) was investigated in the presence of cytochalasin B, a known inhibitor of phagocytosis. Cytochalasin B inhibited the binding of EA to mononuclear cells in a dose-dependent fashion; 80% inhibition of binding was observed at a concentration of 5 mug/ml. This profound effect on EA binding together with presently available data suggested a role for IgG receptor mobility in the macrophage binding of IgG-coated erythrocytes. Cytochalasin B, however, had a minimal effect on the capacity of mononuclear cells to sphere adherent EA, suggesting that the processes involved in macrophage-induced spherocytosis may differ from those operable in phagocytosis.
Cell Adhesion↗
High ectopic kidney presenting as an abnormal liver-lung scan: case report.
An unusual cause for a positive liver-lung scan is presented. A cold area between the base of the right lung and the liver in a 78-year-old woman was reported as being due to a subphrenic abscess. This defect was subsequently found to be a right subphrenic kidney.
Aged↗
Concanavalin A-mediated binding and sphering of human red blood cells by homologous monocytes.
Human red blood cells sensitized with concanavalin A became bound to homologous peripheral blood monocytes. Binding occured at a concentration of 10(5) molecules of tetrameric Con A per red blood cell (RBC) and increased with additional Con A. RBC binding began within 5 min and was maximal at 90 min. Phagocytosis of sensitized RBCs was minimal. RBC attachment was prevented by 0.01 M alpha-methyl-D-mannopyranoside, and, once the RBC-monocyte rosette was established, bound RBCs were largely removed with this specific saccharide inhibitor of Con A. RBCs attached to monocytes became spherocytic and osmotically fragile. The recognition of concanavalin A (Con A)-coated RBCs was not mediated through the monocyte IgG-Fc receptor. These studies demonstrate that, like IgG and C3b, Con A is capable of mediating the binding of human RBCs to human monocytes. Red cells so bound are damaged at the monocyte surface.
Binding Sites↗
Membrane microviscosity and human platelet function.
An increased sensitivity to epinephrine-induced aggregation has been observed both in platelets obtained from patients with type IIa hyperlipoproteinemia and in normal platelets following incubation with cholesterol-rich lecithin dispersions. We have reported previously that the membrane fraction of platelets is enriched with cholesterol relative to phospholipid under each of these conditions. To further explore the effect of cholesterol on platelet membranes, we have examined the fluidity (microviscosity) of whole platelets and platelet subcellular fractions using a hydrophobic fluorescent probe, 1,6-diphenyl-1,3,5-hexatriene (DPH), under conditions in which the cholesterol-to-phospholipid mole ratio (C/PL) of platelets was varied by incubation with various cholesterol-lecithin sonicated dispersions. The C/PL of platelets directly influenced the rotational diffusion of DPH, as indicated by changes in fluorescence polarization. This was reflected in an increase in microviscosity at 37 degrees C (ETA37) from 2.84 P in normal platelets to 4.06 P in platelets with a 118% increase in C/PL. Conversely, platelets with a 43% decrease in C/PL had a 13% decrease in eta37. A strong correlation (r = 0.94) existed between C/PL and eta37 throughout this entire range. However, C/PL had no effect on the excited-state fluorescence lifetime of DPH. Both C/PL and eta37 were lower in isolated platelet membranes than in the platelet granule fraction. When platelets were incubated for 20 h with cholesterol-rich dispersions, there was an increase in C/PL and eta37 in both the membrane and granule fractions. However, this occurred more rapidly in membranes so that, at 5 h (a time when an increased sensitivity of whole platelets to epinephrine is evident), membrane C/PL had increased 55% and eta37 had increased 42%, whereas granule C/PL and eta37 had changed minimally. Cholesterol-rich platelets and subcellular fractions had a lower fusion (or flow) activation energy for viscosity (deltaE), reflecting a higher degree of order, and the converse was true in cholesterol-poor platelets. Moreover, a strong negative correlation existed between the percent change in deltaE and the percent change in eta37 induced either by cholesterol incorporation or depletion. These data demonstrate that cholesterol influences the fluidity and the degree of order within the hydrophobic core of platelet membranes. Changes induced in these physical properties by an excess of cholesterol relative to phospholipid may underlie the abnormal reception or transmission of the aggregation stimulus in cholesterol-rich platelets.
Binding Sites↗
Carcinoma of the small bowel. A complication of regional enteritis.
The 35th and 36th cases of adenocarcinoma arising in small bowel affected with regional enteritis are presented. The pathology of all reported cases is reviewed. An association between regional enteritis and carcinoma of the small bowel is suggested.
Adenocarcinoma↗
Estrogen receptors and hormone dependency in human breast cancer.
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Adenocarcinoma, Mucinous↗
Cellular cholesterol ester accumulation induced by free cholesterol-rich lipid dispersions.
The influence of lipoprotein composition on free cholesterol (RC) esterification and accumulation of esterified cholesterol (EC) was studied in cells of Fu5AH rat hepatoma exposed to culture media supplemented with (FC/P) ranging from 0.6 to 2.8. In the presence of normal human serum, FC-lecithin dispersions witb a FC/P greater than one stimulated both the esterification of FC and the accumulation of cellular EC. Conversely, dispersions with FC/P values of approximately one had no effect on either FC esterification or the accumulation of EC when compared to cells grown in the absence of lipid dispersions. No stimulation of cellular response was obtained when FC-rich dispersions were added to cells in the absence of serum; however, stimulation was observed when cells were exposed to isolated human serum lipoproteins (very low density, low density, and high density). With each lipoprotein, FC-lecithin dispersions with FC/P values less than one inhibited cholesteryl ester accumulation, FC-rich dispersions stimulated, and dispersions with FC/P values of approximately one had an effect equivalent to that of isolated lipproteins alone. These studies extablish that cellular FC esterification and EC content are not influenced solely by the FC concentration of medium, but rather respond to the ratio of FC to phospholipidl These studies also suggest that serum lipoproteins participate in the transfer of FC carried by FC-rich lecithin dispersions to cells.
Blood↗
Overview of cancer pathology.
A brief review of cancer pathology is presented for physical therapists interested in cancer treatment programs. The relationship of cancer pathology to diagnosis and treatment is illustrated. Cancer biology definitions, cancer classification, grading and staging, and the multidisciplinary approach to treatment are discussed.
Humans↗
Halofenate: a potent inhibitor of normal and hypersensitive platelets.
Platelet hypersensitivity has been documented in diabetes and angina pectoris and can be partially reversed in hyperbetalipoproteinemia by clofibrate. We therefore examined the effects of incubating another lipid-lowering agent, halofenate, with both normal platelets and platelets made hypersensitive in vitro by incorporation of 55 per cent excess cholesterol into their membranes. At therapeutic concentrations, halofenate caused a time- and dose-dependent inhibition of the aggregation of normal platelets by epinephrine. After 30 minutes' incubation at 37 degrees C., halofenate significantly inhibited the extent of aggregation by 88 per cent (p less than 0.01), whereas clofibrate inhibited aggregation by 44 per cent (p less than 0.01). Halofenate was a more potent inhibitor of platelets than clofibrate (p less than 0.01). The mean threshold concentration of epinephrine necessary for aggregation of normal platelets (4.2 muM) was not significatnly increased with clofibrate (10 muM) but was markedly elevated with halofenate (245 muM; p less than 0.001). Significant but less dramatic increases in threshold concentration of ADP and collagen were found with halofenate but no clofibrate. Cholesterol-rich platelets were 114-fold more sensitive to epinephrine and twofold more sensitive to ADP than normal platelets but after incubation with halofenate became even less sensitive than normal. Clofibrate inhibited the extent of aggregation of hypersensitive platelets but did not alter the threshold concentration of epinephrine necessary for aggregation. Thus, halofenate is more potent than clofibrate in reducing the sensitivity of normal platelets to aggregating agents in vitro and can completely reverse experimentally produced platelet hypersensitivity. These data suggest that halofenate might be useful in reversing increased platelet sensitivity in cardiovascular diseases.
Adenosine Diphosphate↗
Inhibition of cation cotransport by cholesterol enrichment of human red cell membranes.
1. Human red cells were enriched with cholesterol by incubation with lipid dispersions having a high cholesterol: phospholipid mol ratio and the kinetics of the furosemide-sensitive cotransport for Na+ and K+ were measured. 2. Influxes of both K+ and Na+ through this system were inhibited by 70 and 76% in cholesterol-rich cells (cholesterol: phospholipid mol ratio 1.80) and the Km of the furosemide-sensitive flux components for both K+ and Na+ decreased. 3. Effluxes of both K+ and Na+ are inhibited by furosemide and the magnitudes of these furosemide-sensitive components are markedly decreased in cholesterol-rich cells. 4. The inhibitory effect of cholesterol enrichment on this carrier-mediated transport of cations suggests that cholesterol may either alter the position of the carrier or retard its movement within a more viscous membrane micro-environment.
Biological Transport, Active↗