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S Adler

Publications and source records attributed to S Adler.

At least 19 recordsLinked to original sources
PubMed1992

Specific disruption of renal function and gene transcription by cyclosporin A.

The effects of cyclosporin A (CsA) are cell-specific, ranging from its immunosuppressive action on cells of the immune system to a variety of nonimmunologic toxic side effects. The predominant undesirable side effects of CsA occur in the kidney. Although many toxic renal effects of CsA have been described, the molecular basis of the nephrotoxicity is unknown. Elucidation of the molecular basis for the renal action of CsA may shed light on the function of cyclophilin in nonimmune cell types. The present study demonstrates that CsA selectively reduces the gluconeogenic capacity of rat proximal tubules via a decrease in activity of phosphoenolpyruvate carboxykinase (GTP:oxaloacetate carboxy-lyase (transphosphorylating), E.C. 4.1.1.32; PEPCK). The decrease in renal PEPCK activity occurs within 3 days and reflects a corresponding reduction in renal PEPCK mRNA abundance. This, in turn, is due to a selective inhibition of renal PEPCK gene transcription. Expression of several other renal genes is unaffected by CsA, as is expression of the PEPCK gene in liver. Thus, the effects of CsA are organ-specific and do not represent a general cytotoxic effect on proximal tubule cells. These results suggest that selective inhibition of the activity of a transcription factor(s) required for expression of specific genes in renal tubules may play a role in CsA-induced nephrotoxicity.

Ammonia↗
PubMed1992

Hemagglutinin activation of pathogenic avian influenza viruses of serotype H7 requires the protease recognition motif R-X-K/R-R.

The hemagglutinin of influenza virus A/FPV/Rostock/34 (H7) was altered at its multibasic cleavage site by site-directed mutagenesis and assayed for proteolytic activation after expression in CV-1 cells. The results indicated that the cellular protease responsible for activation recognizes the tetrapeptide motif R-X-K/R-R that must be presented in the correct sequence position. Studies on plaque variants of influenza virus A/fowl/Victoria/75 (H7N7) showed that alteration of the consensus sequence resulted in a loss of pathogenicity for chickens.

Amino Acid Sequence↗
PubMed1992

Integrin receptors in the glomerulus: potential role in glomerular injury.

The extracellular matrix (ECM) exerts important effects on cell function that play a vital role in such diverse processes as embryogenesis, wound healing, cancer metastasis, and inflammation. Interactions between cells and matrix are mediated by a variety of cell surface receptors for different components of the ECM. The integrin family of matrix receptors, the best-studied group thus far, has already been shown to play an important role in cell-matrix and cell-cell interactions in other systems. More recently, the types of integrin receptors present in the glomerulus and on cultured glomerular cells have been defined, and their potential involvement in glomerular injury has been postulated. This review will summarize current knowledge of integrin receptors, their distribution in the kidney, cultured glomerular cell-matrix interactions that might play a role in modulating the glomerular cell response to injury, and the potential role of integrins and other glomerular cell matrix receptors as targets of injury in proteinuric lesions.

Animals↗
PubMed1992

Anti-Fx1A antibody recognizes a beta 1-integrin on glomerular epithelial cells and inhibits adhesion and growth.

Cell-matrix interactions play an important role in regulating cell growth and metabolic activity and potentially in maintaining the integrity of the glomerular filtration barrier. The effect of anti-Fx1A antibody (Ab), the pathogenetic Ab of passive Heymann nephritis, on the interaction of cultured rat glomerular visceral epithelial cells (GEC) with matrix components was examined in an effort to determine whether it affects cell adhesion. Affinity chromatography demonstrated that anti-Fx1A recognizes an alpha 3 beta 1-integrin-type matrix receptor on GEC. Anti-Fx1A inhibited the adhesion of GEC to several substrates (collagen IV approximately equal to collagen I less than laminin approximately equal to fibronectin) in a dose-dependent manner and produced reversible cell detachment and "rounding up" when added to adherent cells. Maximal inhibition of adhesion was similar with anti-Fx1A and anti-beta 1, and competition studies showed no additive effects between anti-Fx1A and anti-beta 1 in inhibiting adhesion, suggesting that the effect of anti-Fx1A on GEC adhesion is attributable to its anti-beta 1 activity. Anti-Fx1A Ab also inhibited the growth of GEC in culture without evidence of cytotoxicity, and cells resumed normal growth on removal of Ab. These studies suggest that anti-Fx1A Ab can bind to matrix receptors on GEC, resulting in inhibition of cell attachment and growth, as well as producing detachment of cells that are already adherent. Interference with GEC-glomerular basement membrane interactions in vivo might have significant effects on glomerular permeability to proteins.

Animals↗
PubMed1992

A variant insulin promoter in non-insulin-dependent diabetes mellitus.

To test the hypothesis that alterations in regulatory regions of the insulin gene occur in a subset of patients with non-insulin-dependent diabetes mellitus (NIDDM), the promoter region was studied by polymerase chain reaction (PCR) amplification directly from genomic DNA, followed by high-resolution polyacrylamide gel electrophoresis under nondenaturing conditions. By using this method a previously identified HincII polymorphism (GTTGAC to GTTGAG at position-56) in American Blacks was readily detected, indicating that single base changes could be observed. In the course of screening the insulin promoter from 40 American Black subjects with NIDDM, an apparent larger allele was found in two individuals. Both patients were shown to have in addition to a normal allele, a larger allele containing an 8-bp repeat, TGGTCTAA from positions -322 to -315 of the insulin promoter. To facilitate rapid screening for the 8-bp repeat, a high-resolution agarose gel electrophoretic analysis was adopted. DNA from American Black NIDDM subjects (n = 100) and nondiabetic subjects (n = 100) was PCR amplified and analyzed. The 8-bp repeat was present in five NIDDM subjects, and one nondiabetic subject. DNA from Mauritius Creoles, also of African ancestry, was analyzed, and the 8-bp repeat was present in 3 of 41 NIDDM subjects, and 0 of 41 nondiabetic subjects. Analysis of glucose metabolism in three presumed normal sibs of an NIDDM patient with an 8-bp repeat revealed that one sib had overt diabetes, and two sibs were glucose intolerant, but there was no consistent segregation of the insulin promoter variant with the diabetes phenotype. The variant promoter was not present in 35 Caucasian NIDDM patients or in 40 Pima Indians. To test the biological consequences of the 8-bp repeat sequence in the insulin promoter, a normal and variant promoter were subcloned into a luciferase plasmid, and reporter gene activity assessed by transient transfection into mouse insulinoma (beta TC1) and hamster insulinoma (HIT) cells. The promoter activity of the variant allele was found to be reduced to 37.9 +/- 10.3% of the activity of the normal promoter in HIT cells (P less than 0.01, n = 4), and 49.1 +/- 6.4% in beta TC1 cells (P less than 0.01, n = 6). These data thus suggest that a naturally occurring variant of the insulin promoter may contribute to the diabetes phenotype in 5-6% of Black NIDDM patients.

Alleles↗
PubMed1992

Characterization of glomerular epithelial cell matrix receptors.

Integrin matrix receptors on glomerular epithelial cells (GEC) may play an important role in adhesion of GEC to the glomerular basement membrane (GBM) and in the maintenance of normal glomerular permeability. Therefore, the author determined the types of matrix receptors present on cultured rat GEC and examined their interactions with several components of the extracellular matrix. Beta 1 integrin matrix receptors were detected on all three glomerular cell types in rat kidney in vivo and at areas of cell-cell contact on cultured GEC. Glomerular epithelial cell adhesion to types I and IV collagen was slightly greater than to laminin and fibronectin. Adhesion to fibronectin was significantly inhibited by a synthetic peptide containing the RGD adhesion sequence. Immunoprecipitation of lysates of surface-iodinated GEC showed the presence of alpha 3 beta 1 integrin. Chromatography of lysates on immobilized collagen showed alpha 3 beta 1 integrin and a 70- to 75-kd protein band as the collagen receptors on GEC. Chromatography on the 120-kd cell-binding fragment of fibronectin disclosed only alpha 3 beta 1 as a specific fibronectin receptor. Antibody to the beta 1 integrin chain inhibited adhesion to laminin and collagen. These studies demonstrate that in vitro, as in vivo, GEC appear to express only alpha 3 beta 1 integrin. Furthermore, this matrix receptor is capable of mediating GEC adhesion to collagen, fibronectin, and laminin, components of the GBM, and presumably plays a similar role in promoting GEC adhesion to GBM in vivo.

Animals↗
PubMed1991

Sustained remission of membranous glomerulonephritis after cyclophosphamide and prednisone.

OBJECTIVE: To determine the effect of cyclophosphamide and prednisone on progressive renal failure and on nephrotic features in patients with membranous glomerulonephritis. DESIGN: Prospective, nonrandomized time series. SETTING: Outpatient clinic at a university medical center. PATIENTS: Eleven consecutive patients with biopsy-proven membranous glomerulonephritis and rising plasma creatinine levels over at least 6 months. INTERVENTION: Cyclophosphamide and prednisone in ten patients and cyclophosphamide alone in one patient. MEASUREMENTS AND MAIN RESULTS: In ten patients treated with both agents, the median plasma creatinine rose 53 mumol/L (0.6 mg/dL) over the months before treatment from 141 to 194 mumol/L (1.6 to 2.2 mg/dL) (95% CI, 27 to 141 mumol/L; P = 0.002). After combined therapy for 6 months, the median plasma creatinine fell to 133 mumol/L (1.5 mg/dL) for a median decline of 62 mumol/L (0.7 mg/dL) (CI, 44 to 150 mumol/L; P = 0.006). Pretreatment plasma creatinine levels, which ranged from 159 to 371 mumol/L (1.8 to 4.2 mg/dL), decreased in the ten patients by 6 months and remained stable in seven of the eight patients followed 24 to 54 months after therapy was completed. The median urine protein excretion decreased by 9.6 g/d with 12 months of therapy in the ten patients from 11.9 to 2.3 g/d (CI, 6.0 to 15.1 g/d; P less than 0.001). The median plasma albumin rose by 14 g/L from 24 to 38 g/L (CI, 11 to 19 g/L; P less than 0.001). The median plasma cholesterol fell by 3.26 mumol/L (140 mg/dL) from 10.45 to 6.52 mumol/L (405 to 252 mg/dL) (CI, 1.42 to 7.16 mumol/L; P = 0.01). One patient who had a relapse 30 months after completing therapy responded to re-treatment with renal function and nephrotic variables returning toward normal. The eleventh patient received cyclophosphamide alone and had a course similar to that of the combined therapy group. CONCLUSION: Cyclophosphamide plus prednisone can promote prolonged remissions in membranous glomerulonephritis even when renal function is already declining.

Adult↗
PubMed1991

Hyperthermia in eccentrically located pelvic tumors: excessive heating of the perineal fat and normal tissue temperatures.

Regional hyperthermia in deep-seated tumors can be limited by excessive heating of normal tissues, usually associated with pain or local discomfort. In this report, 57 hyperthermia treatments in 8 patients with locally advanced presacral recurrences of colorectal cancer were analyzed with respect to normal tissue temperatures, especially with respect to the perineal fat temperature. In 27 treatments, 1 to 2 catheters had been inserted from the perineal region through a large part of the perirectal and presacral fat into the tumor, so that temperature profiles of the perineal fat could be obtained. The mean maximum temperature (+/- SD) of the vagina, rectum, bladder, muscle tissue, and perineal fat was 40.8 +/- 1.2 degrees C, 40.9 +/- 1.6 degrees C, 40.5 +/- 1.6 degrees C, 39.8 +/- 0.7 degrees C, and 42.6 +/- 1.1 degrees C, respectively. The mean maximum systemic temperature (+/- SD) was 37.7 +/- 0.7 degrees C. In 42% of the treatments, the temperature in the perineal fat ranged between 43 and 46 degrees C and was treatment-limiting. In conclusion, overheating of the perineal fat is a problem in the treatment of eccentrically located tumors of the presacral region when relatively high temperatures in the tumor will be maintained for longer time periods.

Adipose Tissue↗
PubMed1991

Heparin alters epidermal growth factor metabolism in cultured rat glomerular epithelial cells.

Extracellular matrix plays an important role in regulating cell growth. The authors have previously shown that heparin and heparan sulfate inhibit glomerular visceral epithelial cell (GEC) growth and that epidermal growth factor (EGF) can partially reverse the effect of heparin. The authors studied EGF processing by GEC in an attempt to clarify the mechanism by which heparin inhibits GEC growth. Control and heparin-treated GEC rapidly internalized 125I-EGF (within 15 minutes). In heparin-treated cells, 125I-EGF reappeared on the cell surface during the course of a 1-hour incubation and the percent internalized dropped significantly to 59.0% +/- 8.6%, suggesting recycling of 125I-EGF-occupied receptors. After incubation with 125I-EGF, heparin-treated cells also released significantly more cpm of 125I into EGF-free medium (2526 +/- 68 cpm-H; 903 +/- 32-C). Analysis of the released 125I by gel filtration chromatography showed more totally degraded 125I-EGF in media from heparin-treated cells (30.8% +/- 1.6% in heparin-treated versus 17.8% +/- 3.2 in control; P less than 0.05). Analysis of EGF-induced dimerization of receptors showed no effect of heparin on this ratio. These studies suggest that heparin decreases GEC response to EGF by accelerating its uptake and degradation. Matrix alterations in disease states may thus play a role in altering cell responsiveness to growth factors.

Animals↗
PubMed1991

In vivo and in vitro rat model for cyclosporine-induced proximal tubular toxicity.

Cyclosporine is used widely to prevent transplant rejection. Unfortunately, this drug causes both renal glomerular and tubular damage. To develop a stable reproducible noncatabolic animal model of cyclosporine nephrotoxicity, rats were fed a special liquid diet and daily administered 7.5 mg/kg of cyclosporine intramuscularly. Twenty-one days after this regimen was started, the body weight of cyclosporine-treated rats had increased 15%, a value only 38% less than the increase in pair-fed controls. After 21 days, glomerular filtration rate fell 34% in cyclosporine-treated rats (p less than 0.001) compared with the pair-fed controls. Simultaneously, citrate and N-acetylglucosaminidase excretion increased significantly. When isolated proximal tubules obtained after 21 days from the cyclosporine and pair-fed rats were incubated by using 1.0 mmol/L glutamine and 1.0 mmol/L citrate substrates, ammonia production was reduced 40% and glucose production reduced 20% (p less than 0.001) in the cyclosporine-treated rats. Discontinuing cyclosporine for 7 days partially reversed all these changes. The glomerular filtration rate in cyclosporine-treated rats now was only 15% below that in controls (p less than 0.05), N-acetylglucosaminidase excretion was the same in both groups, and urinary citrate excretion in the cyclosporine-treated rats fell from 122% to 62% above that in controls. In vitro differences in tubular ammonia and glucose production also narrowed. In summary, these experiments describe a stable reproducible noncatabolic and at least partially reversible rat model for studying cyclosporine nephrotoxicity.

Acetylglucosaminidase↗
PubMed1990

Control of rat glomerular epithelial cell growth in vitro.

The interaction of cultured rat GEC1 with several growth factors was explored in order to obtain a better understanding of in vivo factors which might stimulate GEC proliferation. GEC proliferated in response to EGF but not IGF-1, MSA or PDGF. Specific, saturable receptors for EGF were detected in saturation and competition binding studies utilizing 125I-EGF with an approximate Kd of 1.7 nM and 86,000 binding sites per cell. TGF-beta inhibited GEC growth in a time and dose dependent manner with a brief early exposure resulting in prolonged growth inhibition which was not reversible by EGF. Exposure to TGF-beta sufficient to maximally inhibit growth had no effect on EGF binding to GEC. More prolonged exposure to TGF-beta, however, did result in an increase in the apparent number of EGF receptors on GEC but no change in Kd. These studies suggest that EGF and TGF-beta released by inflammatory cells or platelets during the course of glomerular injury may play a role in modulating glomerular cell proliferation.

Animals↗
PubMed1990

The C'-terminal interaction domain of the thyroid hormone receptor confers the ability of the DNA site to dictate positive or negative transcriptional activity.

To investigate mechanisms responsible for positive and negative transcriptional control, we have utilized two types of promoters that are differentially regulated by thyroid hormone (T3) receptors. Promoters containing the palindromic T3 response element TCAGGTCA TGACCTGA are positively regulated by the T3 receptor after the administration of T3, whereas otherwise identical promoters containing the estrogen response element TCAGGTCA CTG TGACCTGA can be regulated negatively; converse effects are observed with the estrogen receptor. We describe evidence that the transcriptional inhibitory effects of the T3 or estrogen receptors on the estrogen or T3 response elements, respectively, are imposed by amino acid sequences in the C'-terminal region that colocalize with dimerization and hormone-binding domains and that these sequences can transfer inhibitory functions to other classes of transcription factors. Removal of the C'-terminal dimerization and hormone-binding domains of either the alpha T3 or estrogen receptors permits each receptor to act constitutively to enhance transcription on both T3 and estrogen response elements. It is, therefore, suggested that protein-protein interactions between receptor C' termini limit the subset of DNA binding sites on which transcriptional activation occurs.

Animals↗
PubMed1990

Chronic animal testing of new cardiac pacing electrodes.

To evaluate the electrical performance of new electrode technologies, 24 leads containing either carbon coated porous titanium (BIOPORE, (Intermedics, Inc., Freeport, TX], iridium oxide (IROX), or iridium oxide coated with polyethylene glycol (IROX-PEG) electrodes (eight of each) were implanted into the ventricles of 12 canines. Stimulation threshold data was measured at regular intervals for 24 weeks. Low acute values were observed for all leads (0.32 +/- .13 V at 0.6 msec pulse width), but the IROX-PEG electrode demonstrated lower subchronic, peak, and chronic values. Compared to implant, the IROX-PEG electrodes' stimulation thresholds rose only 0.23 V when chronic conditions occurred. There were no significant differences between the electrodes in pacing impedance or R wave amplitude measurements. We conclude that both IROX and IROX-PEG technologies represent a promising approach to the design of more efficient cardiac pacing leads.

Animals↗
PubMed1990

Brain pH in acute isocapnic metabolic acidosis and hypoxia: a 31P-nuclear magnetic resonance study.

It is well known that brain pH changes rapidly in acute hypercapnia or hypocapnia. The effect of acute isocapnic metabolic acid-base change on brain pH is less certain. To study this problem, acute isocapnic metabolic acidosis was induced by HCl or lactic acid infusions in rats, and recovery from acidosis was accomplished by NaHCO3 infusion. Brain pH was measured by 31P-nuclear magnetic resonance. Despite decreases in blood pH of 0.34 and 0.36 units, respectively, in less than 1 h of acid infusion and rapid recovery during bicarbonate infusion, brain pH was unaffected (ranging between 7.08 and 7.11) and was uncorrelated with blood pH. The blood pH minus brain pH gradient was eliminated by the acidosis. By contrast, hypoxia-induced endogenous lactic acidosis lowered blood and brain pH equivalently, but the fall in brain pH preceded that in blood. During normoxic recovery, brain pH overshot and became alkaline when blood pH was still significantly reduced and blood lactate levels were markedly elevated. Presumably, this is due to stimulated active H+ transport. The results demonstrate that brain pH is affected differently in metabolic, respiratory, and endogenous acid-base disturbances. Thus brain pH cannot be predicted solely from blood pH values.

Acid-Base Imbalance↗
PubMed1990

Effect of acid-base changes on urinary hydrolases in Fabry's disease after renal transplantation.

Fabry's disease, which is characterized by alpha-galactosidase A (AG) deficiency, causes early renal failure. Kidney transplants do not reliably supply the deficient enzyme. To assess both urinary excretion of AG by the transplant and the relationship between urine and serum hydrolase activity, acute and chronic acid-base studies were performed in normal control subjects and in the patient with Fabry's disease who had undergone renal transplantation. For the acute studies, alkalosis was induced by intravenous infusion of sodium bicarbonate and acidosis was induced by ingestion of ammonium chloride. The chronic study involved long-term ingestion of NH4Cl by only the patient with Fabry's disease. The results show that AG is secreted by the renal graft. Urinary hydrolase excretion was increased by acute alkalinization and decreased by acute acidification. Acute, but not chronic, acidification increased the patient's serum AG activity, indicating that long-term acidification is not useful for treating Fabry's disease after transplantation. The large changes in hydrolyase excretion induced by acute and chronic acid-base changes show the difficulty of using lysosomal enzymuria as a diagnostic marker for renal disorders without knowledge of acid-base conditions.

Adult↗
PubMed1990

Reversal of inhibition of rat glomerular epithelial cell growth by growth factors.

The ability of several growth factors to reverse heparin-induced inhibition of rat glomerular epithelial cell (GEC) growth and the mechanism of growth inhibition were explored in vitro. Insulin-like growth factor-1, rat multiplication-stimulating activity, and platelet-derived growth factor had no effect on proliferation of cultured GEC exposed to heparin (100 micrograms/ml). Epidermal growth factor (EGF) partially reversed heparin-induced growth inhibition in a dose-dependent fashion with a maximum effect seen at 1 ng/ml. No additive effect was seen with combinations of EGF and the other growth factors assayed. A decrease in EGF-stimulated incorporation of 3H-thymidine by GEC was seen with as little as 2 hours of heparin exposure and persisted for up to 48 hours. Heparin consistently increased binding of 125I-EGF to GEC with a significant increase apparent after 2 hours of exposure and a further increase with a 24-hour exposure. Increased EGF binding to heparin-treated cells was due to a significant increase in the association constant of EGF and its receptor with no effect on receptor number. Interactions between GEC and heparinlike glycosaminoglycans in the glomerular basement membrane may play a role in the regulation of GEC proliferation in normal and diseased states.

Animals↗