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

The UP1 single-stranded nucleic acid binding protein from calf thymus (Herrick, G. & Alberts, B.M. (1976) J. Biol. Chem. 251, 2124-2132) has recently been shown to be a proteolytic fragment derived from the A1 heterogeneous nuclear ribonucleoprotein (hnRNP) (Pandolfo et al. (1985) Nucleic Acids Res. 13, 6577-6590). The NH2-terminus of the 22,162 dalton UP1 protein appears to be blocked, which suggests that UP1 represents the NH2-terminal two thirds of this 32,000 dalton hnRNP protein. The complete amino acid sequence for UP1 was derived from automated sequencing of peptides that were purified by HPLC from digests with trypsin, chymotrypsin, Staphylococcus aureus protease, endoproteinase Lys-C, and cyanogen bromide. Trichloroacetic acid precipitation followed by enzymatic digestion in 2 M urea proved to be the best approach for generating UP1 peptides. By carboxymethylating after, rather than before, digestion it was possible to avoid problems associated with the insolubility of the carboxymethylated UP1. All of the resulting peptides in amounts varying from 2 to 15 nmol were coupled to aminopolystyrene prior to solid-phase sequencing. Using these methods, no difficulties were encountered in assigning glutamic acid residues or in completely sequencing peptides that contained up to 25-30 residues. The relative ease with which the UP1 protein was sequenced, requiring only about a year to complete, and the comparatively modest amount of protein required, less than 5 mg, attests to the usefulness of water soluble carbodiimide coupling and solid-phase sequencing for determining the primary structures of proteins. In addition to serving as a basis for determining structural relationships among various mammalian single-stranded nucleic acid binding proteins, the amino acid sequence of UP1 reveals that the A1 hnRNP protein contains a region of internal sequence homology that apparently corresponds to two independent nucleic acid binding sites.
 ...
PMID:Amino acid sequence of UP1, an hnRNP-derived single-stranded nucleic acid binding protein from calf thymus. 303 34

Erythrocytes from 14 patients with homozygous sickle cell anaemia were treated with the calcium ionophore A23187 to induce loss of cellular potassium and water. The dehydrated cells showed a decrease in filterability (loss of deformability) through pores of 5 micron diameter. Oxpentifylline and cetiedil citrate, which preserve erythrocyte cation and water content, had a significant (p less than 0.01) protective effect against loss of deformability at a concentration of 1 mumol/l. Oxpentifylline showed no adverse effect on the rheology, morphology, or haemolysis of sickle cells at concentrations up to 500 mumol/l. Drugs that act on the erythrocyte membrane to maintain cell hydration are of potential rheological benefit in sickle cell anaemia.
 ...
PMID:Oxpentifylline and cetiedil citrate improve deformability of dehydrated sickle cells. 311 75

Renal hemodynamics and solute and water handling were evaluated in 19 sickle cell patients and 8 matched normal subjects during water diuresis, before and after acute oral administration of a nonsteroidal antiinflammatory drug (NSAID). Baseline GFR and RPF were higher in the patients compared to the normals. In contrast to normals, indomethacin and sulindac induced a 16% and 14% decrease in GFR, respectively. Indomethacin resulted in a slight increase in UOsm in normals, but a substantially greater rise in the patients. Following indomethacin a greater fall in FENa, fractional solute delivery to the diluting segment of the nephron [(CH2O + CNa + K)/GFR], fractional solute reabsorption in the diluting segment [CH2O/GFR] and the fraction of distally delivered solute reabsorbed [CH2O/(CH2O + CNa + K)] was observed in the sickle cell patients than in the normal subjects. A similar trend, but of significantly lesser magnitude than that induced by indomethacin, was observed following sulindac in the sickle cell patient. The data imply that the supranormal GFR observed in the sickle cell patients was prostaglandin-mediated. The effects of NSAID's on renal solute and water handling in the sickle cell patients are compatible with a prostaglandin-dependent decreased salt reabsorption in the medullary thick ascending limb of Henle, together with a hyperfunctioning proximal tubule. The data also imply an additional indomethacin-sensitive antinatriuretic effect in the diluting segment in these patients. Moreover, the results suggest that in sickle cell anemia sulindac may not have a "renal sparing" advantage over other NSAID's.
 ...
PMID:Effects of nonsteroidal antiinflammatory drugs on renal function in sickle cell anemia. 319 68

The sickling process causes secondary changes in cell shape, size, cation and water content, and membrane structure that contribute to the impairment of intrinsic cell deformability (Figure 2). This rheological defect is partially compensated by a low haematocrit, which moderates the rise in whole-blood viscosity, and by a rise in cardiac output which increases capillary flow velocity (Berger and King, 1982). A delicate balance exists between these mechanisms and any local disturbance of this balance by pathological changes in factors extrinsic to the sickle cell (Figure 2) can precipitate vaso-occlusion. There is still considerable controversy over the site (arteriolar, capillary, or venular) of vaso-occlusion, the type of sickle cell (reversibly sickled or irreversibly sickled) that is primarily involved, and the relative importance of extra-erythrocytic precipitating factors such as stasis, hypoxia, hyperosmolality, acidosis, alteration in temperature, acute-phase rise in plasma proteins and leukocytes, prothrombotic changes in coagulation factors and platelets, and adhesion of blood cells to vascular endothelium (Figure 2). A low-grade hypercoagulable state has been described in patients with SS (Leichtman and Brewer, 1978; Richardson et al, 1979) which may be related to the procoagulant effect of the shift of phosphatidyl serine to the outer lipid bilayer of the sickle cell (Chiu et al, 1981; Franck et al, 1985). Platelets appear to accumulate at sites of vaso-occlusion (Siegel et al, 1985) and their migration to the vessel wall may be enhanced by the presence of poorly deformable erythrocytes (Aarts et al, 1984). Endothelial cell damage in the arterial or venous circulation may also contribute (Klug et al, 1982). Thus vaso-occlusion appears to result from a complex interaction between blood cells, plasma proteins and endothelium and any one of several precipitating factors may disturb the fragile steady state and cause a painful crisis. The study of sickle cells by rheological methods has considerable potential for investigating the pathophysiology of vaso-occlusive episodes in the SCD and for monitoring, both in vitro and ex vivo, the efficacy of antisickling compounds. Because of the multiple intrinsic and extrinsic factors that contribute to the rheological defect, it is not yet known which of these should be the primary target for an antisickling agent. In-vitro rheological studies in which different metabolic stresses can be applied to intact sickle cells in the presence of a putative antisickling drug should help to answer this question.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Rheology of the sickle cell disorders. 332 64

The pathophysiological events in sickle cell disease are critically dependent on the intracellular concentration of hemoglobin S, which varies inversely with cell cation and water content. Erythrocytes of SS homozygotes exposed to oxygen or carbon monoxide decrease their potassium and water content through a pathway for potassium transport that is activated by both cell swelling and decrease in internal pH. This pathway is not inhibited by ouabain either with or without bumetanide. When SS erythrocytes were separated according to density, the pH- and volume-dependent potassium transport was greatest in the least dense fraction and was reduced in the densest cells. This pathway, which does not depend on polymerization of sickle hemoglobin, may be important in regulating the cation and water content of SS erythrocytes.
 ...
PMID:Regulation of erythrocyte cation and water content in sickle cell anemia. 396 86

Free water reabsorption (T(c) (H2O)) measured during 10% mannitol diuresis and subsequently during 3% saline diuresis was compared in patients with sickle cell anemia and in normal subjects. During mannitol infusion, T(c) (H2O) progressively rose with increasing osmolar clearance (C(osm)) and reached a maximal level in both groups studied. During hypertonic saline diuresis, T(c) (H2O) progressively rose in the normal subjects and exceeded the maximal levels attained during mannitol diuresis, with no evidence of a maximal T(c) (H2O) level appearing. In contrast, none of the saline curves significantly exceeded the mannitol curves in the sickle cell patients but tended to parallel the mannitol curves at comparable rates of solute clearance. Since T(c) (H2O) is an index of both solute (sodium) transport from the loop of Henle and solute accumulation in the hypertonic medullary interstitium, tubular sodium handling was examined in both sickle cell patients and control subjects alike. No difference in the tubular transport of sodium could be demonstrated either under conditions of sodium loading or under conditions in which the tubular sodium load was low (water diuresis). These data support the conclusion that the defect in urinary concentration in sickle cell patients is caused by a limitation in maintaining a high concentration of solute in the medullary interstitium, thus limiting the rate of T(c) (H2O) from the collecting duct.
 ...
PMID:Nature of the renal concentrating defect in sickle cell disease. 602 70

A multiple-pulse nuclear magnetic resonance technique has been used to measure the order parameter, SFF, at 40 MHz for dimyristoylphosphatidylcholine labeled with a difluoromethylene group at the 4-, 8-, or 12-position of the sn-2-acyl chain dispersed in water in the liquid-crystalline phase. The Carr-Purcell-Meiboom-Gill multiple-pulse sequence can resolve the homonuclear dipolar coupling between the two fluorine nuclei, thus making a direct determination of the order parameter, SFF, for the F-F internuclear vector possible. Other interactions, such as the 19F chemical shift anisotropy, heteronuclear dipolar couplings, and field inhomogeneity, which normally obscure the dipolar splitting, are effectively canceled. The order parameters obtained in this work compare well with those obtained by 19F nuclear magnetic resonance line-shape analysis of the 19F-labeled phospholipids reported in the following paper [Dowd, S. R., Simplaceanu, V., & Ho, C. (1984) Biochemistry (following paper in this issue)] as well as comparable SCD order parameters, determined for the deuterium-carbon internuclear vector of deuterium-labeled phospholipids [Oldfield, E., Meadows, M., Rice, D., & Jacobs, R. (1978) Biochemistry 17, 2727-2740]. The present results clearly show the usefulness of using nuclear magnetic resonance spectroscopy to investigate lipid-lipid and protein-lipid interactions, especially for those systems containing a difluoromethylene group in the acyl chain of a phospholipid molecule.
 ...
PMID:Fluorine-19 nuclear magnetic resonance investigation of fluorine-19-labeled phospholipids. 1. A multiple-pulse study. 652 52

Fluorine-19 nuclear magnetic resonance spectra at 282.4 MHz of dimyristoylphosphatidylcholine specifically labeled with a difluoromethylene group at the 4-, 8-, or 12-position of the sn-2-acyl chain and dispersed in excess water show the characteristic powder-pattern line shapes associated with an anisotropic axially symmetric chemical shift tensor, altered by the presence of the homonuclear dipolar interaction of the fluorine nuclei and of heteronuclear dipolar interactions between fluorine and nearby protons. Values for the anisotropy of the fluorine-19 chemical shift and for the fluorine-fluorine internuclear vector order parameter, SFF, as a function of temperature have been determined for the phospholipid dispersions with and without cholesterol. An increased mobility is evidenced in both cases as the temperature is raised. For the phospholipid dispersions in water, the values of SFF parallel quite well the behavior of the carbon-deuterium internuclear vector order parameter, SCD, as determined by deuterium nuclear magnetic resonance spectroscopy for the same labeled position. The effect of adding cholesterol is seen as a restriction of the chain mobility and the eventual disappearance of the phase transition. These new experiments provide a value of 166 ppm for the anisotropy of the axially symmetric chemical shift tensor of a difluoromethylene group in a phospholipid acyl chain. They also demonstrate the feasibility as well as the advantages of using a difluoromethylene group as a probe for molecular motions in the phospholipid bilayers.
 ...
PMID:Fluorine-19 nuclear magnetic resonance investigation of fluorine-19-labeled phospholipids. 2. A line-shape analysis. 652 53

Morbidity and mortality patterns were examined among 968 pediatric patients on the island of Dominica. These children, whose ages ranged from newborn to 13 years, were seen by the consulting pediatrician at Princess Margaret Hospital during a 9-month period in 1978-79; 852 children were seen as inpatients. A total of 477 cases of infectious disease were diagnosed among inpatients alone. Stool examination in a subsample of these children revealed parasites (mostly Trichuris) in roughly half. Also found was a relatively high prevalence of chronic health problems, especially rheumatic heart disease (34 cases), mental retardation (28 cases), epilepsy (31 cases), and sickle cell anemia (21 cases). Examination of the hospital records of 100 of the inpatients ages 6 months-5 years demonstrated that 34% were low weight-for-age according to the World Health Organization classification. There were 34 deaths (9 pediatric patients and 255 newborns). The high neonatal mortality is attributed to an unusually high incidence of immaturity and prematurity, irregular and insufficient hospital oxygen supply, and a septicemia epidemic. Although these findings reflect patterns of the more serious diseases, they could be useful in planning preventive health measures. The high prevalence of malnutrition points to a need for nutrition education, promotion of breastfeeding, promotion of vegetable growing, and the introduction of a home-based growth chart. The high incidence of diarrhea, typhoid fever, and helminthiases highlights problems with general hygiene, latrines, and water supply. There is also a need for follow-up facilities for children with rheumatic heart disease, epilepsy, and sickle cell anemia. It is suggested that hospital care could be improved by dividing pediatric and neonatology wards into 5 units: isolation ward, malnutrition ward, semi-intensive care unit, general pediatrics, and pediatric surgery.
 ...
PMID:Morbidity and mortality patterns among pediatric patients in Dominica (West Indies). 662 10

To assess the possibility that the membrane lesion seen in sickle cells involves oxidant damage, we investigated the relationship between irreversibly sickled cells and glutathione levels and Heinz body production. We found that the mean level of red cell glutathione, whether expressed as micromoles per gram of hemoglobin or micromoles per milliliter of cell water, was significantly decreased in 39 patients with sickle cell anemia. A weak but significant negative correlation between glutathione levels and irreversibly sickled cell counts in the patients was observed. Stractan density gradient studies were performed to determine glutathione differences in normal- and abnormal-appearing sickle cells. The percent of abnormal cells in each of the five stractan gradient fractions was negatively correlated with both the micromole per gram of hemoglobin and micromole per milliliter of cell water levels of glutathione. Another indicator of susceptibility to oxidant stress, Heinz body formation, was increased in patients with sickle cell anemia vs controls in response to oxidant stress. Surprisingly, we found that the majority of Heinz bodies were in the non-ISC fraction of cells, rather than in the irreversibly sickled cells.
 ...
PMID:Relationship of glutathione levels and Heinz body formation to irreversibly sickled cells in sickle cell anemia. 669 74


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>