Biomedical subjects

D Edelstein

Publications and source records attributed to D Edelstein.

At least 37 records · Page 2Linked to original sources

PubMed1995

Cytokeratin expression in human respiratory epithelium of nasal polyps and turbinates.

The cytokertatins in respiratory epithelial cells (REC) of human nasal polyps and turbinates were analyzed by immunohistochemistry. Cytokeratin 19 (CK19) was present in all REC, CK5 and 14 were expressed primarily in basal cells, and CK7, 8, and 18 were found in suprabasal cells. Differences in cytoplasmic locations were also apparent among the individual cytokeratins. CK13 was not detected in any REC of these tissues. The results indicate the profile of cytokeratins in REC of human nasal polyps and turbinates is essentially identical to that of REC in the more distal respiratory tract.

Antibodies, Monoclonal↗

PubMed1994

Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat.

Arterial hypertension has been identified as a major secondary risk factor for diabetic retinopathy. However, the mechanisms by which hypertension worsens retinopathy are unknown. Inhibition of advanced glycation product formation prevents the development of experimental diabetic retinopathy in normotensive diabetic rats. In this study the effect of hypertension on the rate of diabetic retinopathy development and the formation of arteriolar thrombosis was evaluated. We also evaluated the effect of aminoguanidine, an inhibitor of advanced glycation and product formation on retinal pathology of diabetic hypertensive rats. After 26 weeks of diabetes, hypertension accelerated the development of retinopathy despite a lower mean blood glucose level than in the non-hypertensive group (diabetic spontaneous hypertensive rats (SHR) 16.00 +/- 6.83 mmol/l; diabetic normotensive Wistar Kyoto rats (WKY) 34.9 +/- 3.64 mmol/l; p < 0.0001). Diabetic SHR had nearly twice as many acellular capillaries as diabetic WKY (SHR diabetic: 91.9 +/- 7.5 acellular capillaries per mm2 of retinal area vs WKY diabetic: 53.7 +/- 8.5 acellular capillaries per mm2 of retinal area), and a 3.8-fold increase in the number of arteriolar microthromboses (SHR diabetic 23,504 +/- 5523 microns2 vs SHR non-diabetic 6228 +/- 2707 microns2). Aminoguanidine treatment of SHR diabetic rats reduced the number of acellular capillaries by 50%, and completely prevented both arteriolar deposition of PAS-positive material and abnormal microthrombus formation. These data suggest that hypertension-induced deposition of glycated proteins in the retinal vasculature plays a central role in the acceleration of diabetic retinopathy by hypertension.

Aneurysm↗

PubMed1994

Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes.

Intracellular sugars are more reactive glycosylating agents than glucose. In vitro nonezymatic glycosylation of basic fibroblast growth factor (bFGF) by fructose, glucose-6-phosphate (G6P), or glyceraldehyde-3-phosphate (G3P) reduced high affinity heparin-binding activity of recombinant bFGF by 73, 77, and 89%, respectively. Mitogenic activity was reduced 40, 50, and 90%. To investigate the effects of bFGF glycosylation in GM7373 endothelial cells, we first demonstrated that GLUT-1 transporters were not downregulated by increased glucose concentration. In 30 mM glucose, the rate of glucose transport increased 11.6-fold, and the intracellular glucose concentration increased sixfold at 24 h and fivefold at 168 h. The level of total cytosolic protein modified by advanced glycosylation end-products (AGEs) was increased 13.8-fold at 168 h. Under these conditions, mitogenic activity of endothelial cell cytosol was reduced 70%. Anti-bFGF antibody completely neutralized the mitogenic activity at both 5 and 30 nM glucose, demonstrating that all the mitogenic activity was due to bFGF. Immunoblotting and ELISA showed that 30 mM glucose did not decrease detectable bFGF protein, suggesting that the marked decrease in bFGF mitogenic activity resulted from posttranslational modification of bFGF induced by elevated glucose concentration. Cytosolic AGE-bFGF was increased 6.1-fold at 168 h. These data are consistent with the hypothesis that nonenzymatic glycosylation of intracellular protein alters vascular cell function.

Animals↗

PubMed1993

Inhibition of matrix-induced bone differentiation by advanced glycation end-products in rats.

Glycation of long-lived proteins is an inevitable consequence of aging that is accelerated in patients with diabetes mellitus. Treatment of demineralized bone matrix particles from 35-week-old normal Long-Evans rats with glycoaldehyde, a precursor of advanced glycation end-products, was used to assess the effects of bone-matrix glycation on the process of bone differentiation. Matrix was incubated in phosphate buffered saline alone, phosphate buffered saline containing glycolaldehyde, glycolaldehyde plus the advanced glycation product-inhibitor aminoguanidine, or glycolaldehyde plus the advanced glycation product-inhibitor sodium cyanoborohydride. Glycolaldehyde increased the matrix advanced glycation product content as measured by specific fluorescence more than two-fold, while inhibiting bone differentiation more than 90% as measured by in vivo 45CaCl2 uptake, alkaline phosphatase levels, and histology. In contrast, simultaneous incubation with the advanced glycation product-inhibitor aminoguanidine or sodium cyanoborohydride not only reduced fluorescence to normal, but also restored bone differentiation. Furthermore, the inhibition of bone differentiation by glycolaldehyde was not reversed by subsequent application of recombinant bone morphogenetic protein-2. These observations suggest that formation of advanced glycation products on bone matrix alters its ability to induce bone formation, and probably involves alterations of binding sites for extractable proteins with direct bone inductive properties such as bone morphogenetic protein-2. Decreased bone formation associated with aging and diabetes may result, in part, from advanced glycation product formation on matrix proteins.

Acetaldehyde↗

PubMed1993

Localized gene transfer into organotypic hippocampal slice cultures and acute hippocampal slices.

Viral vectors derived from herpes simplex virus, type-1 (HSV), can transfer and express genes into fully differentiated, post-mitotic neurons. These vectors also transduce cells effectively in organotypic hippocampal slice cultures. Nanoliter quantities of a virus stock of HSVlac, an HSV vector that directs expression of E. coli beta-galactosidase (beta-gal), were microapplied into stratum pyramidale or stratum granulosum of slice cultures. Twenty-four hours later, a cluster of transduced cells expressing beta-gal was observed at the microapplication site. Gene transfer by microapplication was both effective and rapid. The titer of the HSVlac stocks was determined on NIH3T3 cells. Eighty-three percent of the beta-gal forming units successfully transduced beta-gal after microapplication to slice cultures. beta-Gal expression was detected as rapidly as 4 h after transduction into cultures of fibroblasts or hippocampal slices. The rapid expression of beta-gal by HSVlac allowed efficient transduction of acute hippocampal slices. Many genes have been transduced and expressed using HSV vectors; therefore, this microapplication method can be applied to many neurobiological questions.

Animals↗

PubMed1992

Aminoguanidine ameliorates albuminuria in diabetic hypertensive rats.

We studied the effect of aminoguanidine, an inhibitor of advanced glycation product formation, on albuminuria in chronically diabetic spontaneously hypertensive rats. At the time of killing, there was no statistically significant difference in blood glucose concentration between the treated and untreated diabetic animals (18.2 +/- 0.69 mmol/l), nor was there any difference among the non-diabetic, diabetic untreated, and diabetic treated rats with respect to blood pressure (169 +/- 6.9 mm Hg). However, non-diabetic hypertensive animals had a mean quantitative 24-h urinary albumin excretion of 28 +/- 2 mg albumin/24-h, while untreated diabetic hypertensive animals averaged nearly four times that amount (106 +/- 3 mg albumin/24 h). Without affecting blood pressure, aminoguanidine treatment of diabetic hypertensive animals decreased the diabetic-associated elevation in urinary albumin excretion by 75% (48 +/- 2 mg/24 h). These data suggest than inhibition of advanced glycation product formation ameliorates the glomerular dysfunction caused by chronic hyperglycaemia.

Albuminuria↗

PubMed1992

Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine.

Aminoguanidine-HCl inhibits the formation of advanced glycosylation end products (AGEs) in vitro and in vivo, but the mechanism by which this occurs has not been determined. Aminoguanidine inhibited glucose-derived AGE formation on RNase A by 67-85% at aminoguanidine-glucose molar ratios of 1:5 to 1:50 without affecting the concentration of Amadori products. Fast-atom-bombardment mass spectrometry of RNase peptides incubated with glucose alone or with glucose plus aminoguanidine showed that aminoguanidine inhibited the formation of AGEs without forming an adduct with glycosylated peptide. These data suggest that the primary mechanism of aminoguanidine action is reaction with Amadori-derived fragmentation products in solution. These findings are relevant to the potential clinical use of aminoguanidine in the prevention of diabetic complications.

Amino Acid Sequence↗

PubMed1991

Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells.

Cross-linking of cell matrix components by nonenzymatic glycosylation may contribute to diabetic glomerulopathy. We examined the effects of modification of matrix by nonenzymatic glycosylation on mesangial cell function. Matrix was generated by growing mesangial cells in tissue culture for 2 wk and removing the cells with a detergent cell-lysis solution. By indirect immunofluorescence and Northern-blot analysis, the remaining matrix contained laminin, fibronectin, and collagens type I and IV. The matrix was modified by incubation for 24 h with 50 mM glycolaldehyde, a highly reactive cross-linking nonenzymatic glycosylation product, or for 2 wk with 200 mM glucose-6-phosphate (G6P). Modification was carried out with or without equimolar aminoguanidine, an inhibitor of cross-link formation. Nonenzymatic glycosylation of the matrix by glycolaldehyde or G6P was confirmed by fluorometry and [14C]G6P incorporation and was prevented by aminoguanidine. [3H]thymidine incorporation for 24 h by mesangial cells plated onto unmodified or modified matrix was then performed. Modification of matrix had no effect on attachment of mesangial cells, determined 4 h after plating. Nonenzymatic glycosylation of matrix by glycolaldehyde or G6P significantly inhibited thymidine incorporation by mesangial cells. This effect was partially reversible by aminoguanidine. Aminoguanidine-modified matrix had no effect on thymidine incorporation. Thymidine-incorporation results were confirmed by direct cell counting. We conclude that modification of matrix by nonenzymatic glycosylation influences growth of mesangial cells, which could contribute to the mesangial abnormalities of diabetic glomerulopathy.

Animals↗

PubMed1990

Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes.

Non-enzymatic glycation of reactive amino groups in model proteins increased the rate of free radical production at physiologic pH by nearly fifty-fold over non-glycated protein. Superoxide generation was confirmed by electron paramagnetic resonance measurements with the spin-trap phenyl-t-butyl-nitrone. Both Schiff base and Amadori glycation products were found to generate free radicals in a ratio of 1:1.5. Free radicals generated by glycated protein increased peroxidation of membranes of linoleic/arachidonic acid vesicles nearly 2-fold over control, suggesting that the increased glycation of proteins in diabetes may accelerate vascular wall lipid oxidative modification.

Arteriosclerosis↗

PubMed1989

Hyperlipoproteinemia in spontaneously diabetic guinea pigs.

A colony of Hartley guinea pigs that exhibit hyperglycemia, glucosuria, and hypertriglyceridemia characteristic of human diabetes mellitus was developed. Initially, a group of guinea pigs that had normal serum glucose concentrations (less than or equal to 200 mg/dL of serum) at 3 to 4 weeks of age was obtained; however, in some of the animals progressively severe hyperglycemia (300 to 500 mg/dL of serum) and glucosuria (greater than 2 g of glucose/24 h) occurred as the animals matured. In addition, the animals exhibiting hyperglycemia and glucosuria had plasma insulin concentrations that were similar to those animals that were not hyperglycemic. The diabetic animals were found to be hypertriglyceridemic, with plasma triglyceride levels of 140 to 290 mg/dL at four months of age. Nondiabetic animals (plasma glucose concentration of less than or equal to 200 mg/dL and no glucosuria) had plasma triglyceride concentrations between 37 and 76 mg/dL. Lipoprotein analysis of plasma from nondiabetic and diabetic animals indicated that the diabetics had a fourfold increase in VLDL triglyceride and protein concentrations. The VLDL had an abnormal apolipoprotein composition and had reduced levels of apoprotein-E. The progeny from the mating of diabetic males and females also exhibited the diabetic trait, suggesting that the origin of the disease is genetic. This colony of guinea pigs is being further investigated as a suitable model for the study of the hyperlipoproteinemia of human noninsulin-dependent diabetes mellitus.

Animals↗

PubMed1988

Surgical treatment of blindness secondary to intraorbital hemorrhage.

Rapid progression to blindness due to intraorbital hemorrhage following various forms of trauma requires immediate, aggressive intervention, with the potential to restore vision. Orbital decompression via either an external ethmoidectomy or transantral approach is described. The diagnosis, anatomy, and pathogenetic mechanisms relevant to these cases are reviewed.

Aged↗

PubMed1987

The abnormally large frontal sinus. I. A practical method for its determination based upon an analysis of 100 normal patients.

One hundred normal Caldwell view radiographs were examined on patients who had no signs or symptoms referable to the frontal sinuses. Magnification factors were determined for Caldwell views obtained on a dedicated head unit and as part of a skull series. The areas of the frontal sinuses were actually measured with a Zeiss Videoplan 2 computer and corrected for magnification. The area variation in this normal population was determined. Four linear measurements were individually correlated with these areas. Two of these lines had excellent correlation with the sinus area and if either of these lines exceeds a calculated value, the sinus area exceeds the 99th percentile of the normal population and can be considered abnormally enlarged. This technique provides a rapid, easy, and reliable method for assessing abnormally enlarged frontal sinus areas.

Frontal Sinus↗

PubMed1987

Abnormally large frontal sinus. II. Nomenclature, pathology, and symptoms.

Based on a review of the literature and analysis of six new cases, three categories of enlarged, aerated sinuses are defined, namely: hypersinus, pneumosinus dilatans, and pneumocele. The information gained by our study of the area variation of the frontal sinuses in a normal population (part I of this paper) was utilized to define the term hypersinus. In this condition there is generalized enlargement of the sinus beyond the upper limit of normal in an asymptomatic patient. The principal difference between pneumosinus dilatans and a pneumocele is the presence of bony thinning or erosion in the latter entity. The clinical findings and the possible etiologies of these conditions are discussed.

Adult↗

PubMed1986

Clonidine and the hormonal responses to graded exercise in healthy subjects.

The aim of this study was to assess the acute effects of clonidine, an alpha 2-adrenergic agonist, on hormonal responses to graded exercise in 8 healthy young men. After fasting overnight, each subject was tested on 2 mornings, 1 week apart. On one occasion he was given 200 micrograms clonidine orally and on the other identical placebo tablets, the order being randomized in a double-blind fashion over the 2 days. Thereafter each subject performed 2 successive treadmill runs, equivalent to 60 and 100%, respectively, of maximal aerobic power. Clonidine pretreatment blunted the maximal increase in plasma catecholamines by more than 60% of the control response (p less than 0.01), without significantly altering the rise of plasma cortisol or ACTH. Furthermore, clonidine significantly reduced the exercise-induced maximal rise in plasma glucose, without modifying the slight decline in mean plasma insulin or increase in pancreatic glucagon levels. The drug did not affect the maximal increments in plasma growth hormone or prolactin occurring after exercise. It was concluded that a single dose of clonidine suppressed peripheral sympathetic responses, without altering central (pituitary) alpha-adrenergic-mediated hormonal responses, to short-term exercise in healthy men.

Adrenocorticotropic Hormone↗

PubMed1980

Serum lipoproteins of diabetic rats fed a high cholesterol diet.

Feeding a diet containing 2% cholesterol and 1% cholic acid (wt/wt) to rats made diabetic by administration of streptozotocin (45 mg/kg) produced marked hypercholesterolemia characterized by high concentrations of very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) and a reduction in concentration of high density lipoproteins (HDL). The VLDL was unique in that it contained apo A-I and apo A-IV in addition to its usual complement of apoproteins: apo B, apo E, and the C apoproteins. IDL had a similar apoprotein composition. The HDL from these rats was deficient in apo E. Nondiabetic rats fed the same diet exhibited similar qualitative changes in lipoprotein concentration and composition but with lesser increases in VLDL and IDL concentrations. The altered apoprotein composition suggested that the hyperlipoproteinemia associated with cholesterol feeding in the rat is due to an inadequate rate of removal of lipoproteins of intestinal origin, and that this is greatly exacerbated by diabetes.

Animals↗

PubMed1979

Apoproteins of high density lipoproteins in the urine of normal subjects.

Apoproteins of high density lipoproteins were detected in the urine of normal subjects after the urinary proteins were highly concentrated. By immunoelectrophoresis, all of the urinary apoproteins gave precipitin lines with similar electrophoretic mobility. This suggests that the various apoproteins are present in the same particle. The apoproteins were present only in the ultracentrifugal fraction of density greater than 1.24 g/ml. Neither apoprotein B nor apoprotein E were detected in the urine, suggesting that very low density and low density lipoproteins are not excreted in the urine of normal subjects.

Apolipoproteins↗

PubMed1977

Reversal of orotic acid-induced fatty liver in rats by clofibrate.

The addition of 1 per cent orotic acid to a sucrose-enriched semipurified diet results in markedly fatty liver when fed to rats for 7 to 22 days. Light microscopy reveals lipid droplets, mostly small, distributed throughout the cytoplasm of all hepatocytes. Electron microscopy shows that all the endoplasmic reticulum (ER) is broken into vesicles. Within the interior (cisterna) of each vesicle one or more lipid droplets are present. Morphologic signs of normal lipid transport (ER to Golgi apparatus to space of Disse) disappear: the Golgi elements are flattened and lack very low density lipoproteins particles; the Golgi-derived secretory vacuoles are not present. Biochemical analyses show an increase in hepatic triacylglycerol levels, to approximately 8 times the levels of sucrose-fed controls by the 7th day, 18 times by the 15th day, and 25 times by the 22nd day. Hepatic cholesterol levels increase, 2- to 4-fold. Serum triacylglycerol levels fall markedly; serum cholesterol levels are reduced. Immunoelectrophoretic determinations show that the apoprotein B component of plasma lipoproteins is practically absent at 7 days and increases slightly at 22 days. Reversal of an orotic acid-induced fatty liver is achieved by adding ethyl chlorophenoxyisobutyrate (clofibrate or CPIB) to the diet. By 8 to 16 days the ER of the hepatocytes returns to its usual parallel configuration and lipid droplets are not seen within its cisternae. Morphologic features of normal lipid transport reappear. GERL becomes prominent, distended with small particles, interpreted as lipid undergoing degradation. Lipid-containing residual bodies are common. Peroxisomes are more numerous than in hepatocytes of control rats. Liver triacylglycerol levels approach sucrose-fed control levels, and serum triacylglycerol levels return to chow-fed control levels. Hepatic cholesterol levels are similar to those of sucrose-fed and chow-fed controls, whereas serum cholesterol levels are lower. Serum apoprotein B levels return to chow-fed control levels. A sequence of events terminating in the removal of lipid from the hepatocytes is suggested by observation of morphologic changes following chlorophenoxyisobutyrate administration. This appears to involve transport of lipid into the cytosol where it accumulates as large spheres. Extensive accumulations of smooth ER appear. The cytosol lipid then disappears as the rough ER develops. Peroxisomes and mitochondria are prominent during the reversal process.

Animals↗

PubMed1976

Apolipoproteins in rat serum and renal lymph.

The concentration of apolipoproteins was measured by quantitative immunoelectrophoresis in rat serum, in the lipoprotein-free ultracentrifugal fraction (density greater than 1.21) of serum, and in renal lymph. The A-IV and arginine-rich apolipoproteins were present in high concentrations (greater than 18.5% of serum concentration) both in the fraction of density greater than 1.21 and in renal lymph, whereas the other apolipoproteins were found in low concentrations ( less than 7% of serum concentration). The major apolipoproteins of renal lymph were similar to those found in the fraction of density greater than 1.21; however, the apolipoproteins composition of the renal lymph was very different from the apolipoprotein composition of serum lipoproteins. The presence of certain apolipoproteins in the fraction of density greater than 1.21 and in renal lymph suggests that these apolipoproteins might be present in the circulation as "free" apolipoproteins. The possible physiological importance of these specific apolipoproteins is postulated.

Animals↗