Misoprostol and nonsteroidal anti-inflammatory drugs: a tale of effects, outcomes, and costs.
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
J S Levine
Publications and source records attributed to J S Levine.
Aberrant cytokine regulation in macrophages from young autoimmune-prone mice: evidence that the intrinsic defect in MRL macrophage IL-1 expression is transcriptionally controlled.
We have reported that, when compared to macrophages from normal strains, macrophages from the autoimmune-prone MRL and NZB mouse strains demonstrate dramatically reduced IL-1 expression in response to LPS. In MRL mice, this is an intrinsic defect which is unmodified by age, the progression of disease, or the presence of the Ipr gene. Here we report that the key events leading to aberrant IL-1 expression appear to be transcriptional, based on the following three sets of findings. (1) Nuclear run-on analysis demonstrates that the patterns of IL-1 transcription in MRL/+ and BALB/c macrophages are distinct, as the former is clearly more transient. The reduction in MRL/+ IL-1 transcription coincides with a reduction in the levels of nuclear NF-KB and precedes a drop in IL-1 mRNA steady-state levels. (2) Reduced levels of IL-1 transcripts are found in both nuclear and cytosolic fractions of MRL/+ macrophages, arguing against faculty IL-1 mRNA transport into the cytosol as a contributing factor in the establishment of this defect. (3) In the presence of actinomycin D, the rate of RNA degradation is similar in MRL/+ and BALB/c macrophages. Moreover, in vitro RNA decay assays demonstrate that even in the absence of metabolic inhibitors, there is no evidence for an accelerated decay of IL-1 mRNA during exposure to lysates isolated from MRL/+ vs BALB/c macrophages. Taken together, these findings argue that transcription is the predominant level at which this striking example of cytokine dysregulation is controlled.
Animals↗
Interleukin-1 dysregulation is an intrinsic defect in macrophages from MRL autoimmune-prone mice.
Macrophages (M phi) from pre-diseased autoimmune-prone MRL mice (both MRL/+ and MRL/lpr) dramatically underproduce the cytokine interleukin-1 (IL-1) in comparison to M phi from a number of normal strains. In this study we show that IL-1 dysregulation by MRL M phi is fully expressed at birth, and that this defect does not change with time or the development of disease. We also constructed adult irradiation chimeras (consisting of A/J-->MRL and MRL-->A/J mice), and show that M phi isolated from these chimeras display a pattern of IL-1 production indistinguishable from that of the donor strain controls. Moreover, when we constructed a mixed chimera (A/J + MRL-->A/J, the A/J and MRL M phi coexisting within the same animal retained their individual patterns of IL-1 production when isolated by negative selection. Taken together, these results provide the first substantive evidence for an intrinsic defect (IL-1 dysregulation) in M phi from MRL autoimmune-prone mice.
Age Factors↗
Fish oil has protective and therapeutic effects on proteinuria in passive Heymann nephritis.
Passive Heymann nephritis (PHN) is a rat model of membranous nephropathy induced by injecting anti-Fx1A. The onset of proteinuria in PHN is caused by complement-mediated injury to glomerular epithelial cells (GEC) accompanied by enhanced glomerular eicosanoid production. In addition, sublethal injury by complement of rat GECs in culture leads to phospholipase activation, phospholipid hydrolysis and release of arachidonic acid and dienoic prostanoids. Based on these findings, we undertook to determine if substituting arachidonic acid (omega-6) in GEC membrane phospholipids with omega-3 fatty acids derived from fish oil would alter the development and course of proteinuria in PHN. We found that rats fed a diet containing 10% fish oil for four weeks prior to antibody injection developed 50 to 60% less proteinuria between two and six weeks after anti-Fx1A than rats fed an equivalent diet containing 10% safflower oil, and had substantial enrichment of glomerular phospholipids with omega-3 fatty acids and displacement of arachidonic acid. This outcome was associated with a 50% reduction in release of glomerular thromboxane B2 (stable metabolite of thromboxane A2) in the fish oil group. More importantly, when PHN rats with well established proteinuria while on regular chow were randomized to three dietary groups, those fed fish oil had a 25 to 50% decline in proteinuria as compared to those fed lard or safflower oil. This difference was evident within two weeks of randomization and persisted until the end of the study after eight weeks. In neither study could the differences in urine protein excretion be accounted for by protein or calorie deprivation, or by differences in blood pressure, renal function, immune response to sheep IgG, or glomerular deposition of IgG or complement. Thus, our results indicate that dietary fish oil has protective and therapeutic effects with regard to proteinuria in PHN. These benefits may relate to alterations in membrane phospholipid composition in favor of omega-3 fatty acids and release of less reactive trienoic eicosanoids.
Animals↗
Production and polarized secretion of basement membrane components by glomerular epithelial cells.
To study the formation of basement membrane by glomerular epithelial cells (GECs), production and secretion of type IV collagen and laminin by rat GECs in culture were evaluated. GECs produced two chains of type IV collagen (180 and 170 kDa) in the ratio of approximately 2 to 1, when immunoprecipitated with antibody to type IV collagen of mouse Engelbreth-Holm-Swarm (EHS) sarcoma. GECs also produced proteins that were precipitated by antibody to EHS laminin, i.e., two bands each in the positions of the A and B chains of mouse laminin. On enzyme-linked immunosorbent assay (ELISA), type IV collagen and laminin were found mainly in the cell-associated fraction and in the subepithelial culture medium. Confluent GECs on membrane filters formed a tight barrier against the flux of macromolecules. Under these conditions, 80% of newly synthesized and secreted matrix proteins were detected in the basolateral medium. Moreover, treatment with ammonium chloride, which is known to affect polarized secretion, caused both type IV collagen and laminin to be secreted via the basolateral and apical surfaces in similar amounts. These results indicate that cultured GECs are polarized and that they produce and secrete basement membrane components via the basolateral side.
Animals↗
Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs.
Inherited selective intestinal malabsorption of cobalamin (Cbl) was observed in a family of giant schnauzer dogs. Family studies and breeding experiments demonstrated simple autosomal recessive inheritance of this disease. Affected puppies exhibited chronic inappetence and failure to thrive beginning between 6 and 12 wk of age. Neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, and megaloblastic changes of the bone marrow were present. Serum Cbl concentrations were low, and methylmalonic aciduria and homocysteinemia were present. Parenteral, but not oral, cyanocobalamin administration rapidly eliminated all signs of Cbl deficiency except for low serum Cbl concentrations. Cbl malabsorption in affected dogs was documented by oral administration of [57Co]cyanocobalamin with or without simultaneous oral administration of intrinsic factor or normal dog gastric juice. Quantitation and function studies of intrinsic factor and transcobalamin-II from affected dogs revealed no abnormality. Other gastrointestinal functions and ileal morphology were normal, indicating a selective defect of Cbl absorption at the level of the ileal enterocyte. Immunoelectron microscopy of ileal biopsies showed that the receptor for intrinsic factor-Cbl complex was absent from the apical brush border microvillus pits of affected dogs. This canine disorder resembles inherited selective intestinal Cbl malabsorption (Imerslund-Gräsbeck syndrome) in humans, and is a spontaneously occurring animal model of early onset Cbl deficiency.
Animals↗
Absence of luminal intrinsic factor after gastric bypass surgery for morbid obesity.
Abnormally low serum cobalamin levels (less than 180 pg/ml) have been observed in 154 of 429 patients (36%) at an average of 22 months (range 3-64 months) after gastric bypass surgery for morbid obesity. Twenty-four patients underwent a Schilling test and retrograde endoscopy of the bypassed gastric segment to determine the presence of intrinsic factor (IF) in gastric aspirates and in mucosal biopsies at 22 +/- 4 months after surgery. Five patients had a normal cobalamin level (405 +/- 44 pg/ml), and gastric juice intrinsic factor was present in three of them (11 +/- 7 ng/ml). Nineteen patients had a low cobalamin level (113 +/- 8 pg/ml), and gastric juice IF was found in only two subjects of this group (10 ng/ml each). Basal gastric juice IF concentration of healthy control subjects was 24 +/- 5 ng/ml. Schilling test results were normal in all five patients of the first group and in only nine patients of the group with cobalamin deficiency after surgery. To assess whether IF was present within the parietal cells of subjects with absent luminal IF, we studied gastric biopsy material of 14 patients using a well-characterized indirect immunoperoxidase method. IF was identified in fundic mucosal biopsy specimens of all 14 patients with absent gastric juice IF. We conclude that cobalamin deficiency occurs in a significant number of patients after gastric bypass and is associated with absence of gastric juice IF. We propose that this abnormality might be caused by inadequate secretion of IF from the bypassed stomach.
Adult↗
Purification, properties, and immunochemical localization of a receptor for intrinsic factor-cobalamin complex in the rat kidney.
High levels of receptor for intrinsic factor-cobalamin (vitamin B12) were detected in human, canine, and rat kidneys. The ratio of specific activity (picomoles/mg of protein) for kidney relative to intestine was 116, 20, and 797, respectively, in these species. The receptor was purified about 3000-fold from 200 g of rat kidney with a recovery of 16% and exhibited a single band on nondenaturing gel electrophoresis. Quantitative amino acid analysis of the receptor gave a value of 457,310 g of amino acid/mol of intrinsic factor-cobalamin binding activity. The pure receptor revealed an Mr of 430,000, as assessed by filtration with Bio-Gel A-5m. Treatment with papain resulted in the production of active monomers of Mr to about 205,000-210,000. Electrophoresis in the presence of sodium dodecyl sulfate confirmed the monomer Mr to be 230,000. The monomer receptor did not reveal the presence of any further subunits upon reductive alkylation. Following cyanogen bromide cleavage the kidney receptor revealed three peptides of Mr 115,000, 60,000, and 54,000. The pI of these peptides was 5.17, 6.17, and 6.17, respectively. Western blot analysis using antiserum raised to the receptor demonstrated a protein with an Mr of 175,000 and 230,000 for intestinal and kidney membrane receptors, respectively. Immunologically, the rat kidney receptor was identical to the rat ileal receptor but was distinct from the canine ileal receptor. Ultrastructural localization revealed the presence of the receptor in the apical surface membrane of proximal tubular cells of the kidney and absorptive cells of the ileum. The kidney is the best source for obtaining this receptor in reasonable quantities.
Amino Acids↗
The origin and evolution of atmospheric oxygen.
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Atmosphere↗
Interleukin 3-dependent mouse mast cells express the cholera toxin-binding acidic glycosphingolipid, ganglioside GM1, and increase their histamine content in response to toxin.
The acidic glycosphingolipid, ganglioside GM1, which is the binding site for cholera toxin on many cell types, was identified by chemical and by flow cytometric analyses of mouse interleukin 3-dependent, bone marrow culture-derived mast cells (BMMC). Ganglioside GM1 and other acidic glycosphingolipids were isolated from BMMC by chloroform/methanol extraction and chromatography on DEAE-Sephadex and were analyzed by thin layer chromatography. The presence of ganglioside GM1 in the BMMC extract was demonstrated by its co-migration with ganglioside GM1 standard in thin layer chromatography and by the binding of peroxidase-labeled cholera toxin B subunit to both molecules. As assessed by fluorescence flow cytometric analysis of the binding of fluorescein-conjugated cholera toxin B subunit, the majority of BMMC expressed ganglioside GM1 on their surface, and the total presentation per cell increased as cells progressed from the G1 to S to G2 + M phases of the cell cycle. The addition of increasing amounts of cholera toxin starting with 0.08 microgram/ml to BMMC cultured in 50% WEHI 3-conditioned medium containing IL 3 for 48 hr caused the adhesion of BMMC to the tissue culture flasks to increase in a dose-related manner, from less than 1% adherent cells in cultures without toxin to a plateau value of approximately 17% adherent in the presence of 1.25 micrograms/ml of toxin. The histamine content of BMMC increased from 26.7 +/- 3.59 ng/10(6) cells (mean +/- SD, n = 4) for control cultures to 201 +/- 17.4 ng/10(6) cells (mean +/- SD, n = 4) for nonadherent cells and to 588 +/- 89.4 ng/10(6) cells (mean +/- SD, n = 4) for adherent cells after 48 hr of culture in 0.31 microgram/ml cholera toxin, which was the optimal dose for nonadherent and adherent populations. The content of another preformed intragranular mediator, beta-hexosaminidase, did not increase appreciably in the presence of cholera toxin (n = 3). The increase in the histamine content of BMMC after the addition of 0.31 microgram/ml cholera toxin was detectable at 4 hr, plateaued by 24 to 48 hr, and gradually declined over the next 6 days. Cholera toxin also augmented the histamine content of BMMC in the presence of purified synthetic IL 3. Preincubation of whole cholera toxin with purified ganglioside GM1 inhibited the histamine-augmenting effects of cholera toxin on BMMC, indicating that the effect was not due to a contaminant, and neither the A nor B subunit of cholera toxin alone increased the histamine content of BMMC.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Cocaine-induced hepatotoxicity in humans.
A patient with hepatonecrosis associated with cocaine use is presented. Postmortem examination of the liver showed marked periportal inflammation and necrosis, and mild diffuse fatty infiltration. These pathologic findings are identical to those previously reported in a mouse model of cocaine hepatotoxicity.
Adult↗
Negative appendix with suspected appendicitis: an update.
We report a retrospective study of 282 consecutive patients who had appendectomy for suspected acute appendicitis at the University of Miami/Jackson Memorial Medical Center during a 15-month period. The overall incidence of negative explorations of 7.4% was significantly lower than that reported in the literature, and occurred without a significant increase in the incidence of perforation (22%). Since no sophisticated diagnostic tests were used, we suggest that a decrease in the presently accepted negative exploration rate of 15% to 20% can be achieved on the basis of a careful history, detailed physical examination, and basic laboratory and x-ray studies.
Acute Disease↗
Paget disease of the spine: CT with clinical correlation.
Thirty-six patients with pagetic involvement of the spine were evaluated clinically and by computed tomography (CT). Pagetic phase, modeling expansion, degree and site of spinal stenosis, and pagetic facet joint arthropathy were recorded for each involved vertebral segment. CT demonstrated spinal stenosis in 20 patients, 11 of whom exhibited spinal stenosis on plain films. Twenty-one patients had symptoms of neck or back pain, with associated neurologic dysfunction in 13. Spinal stenosis was present in 81% of the symptomatic patients and 20% of the asymptomatic patients. Severe pagetic facet arthropathy was present in 17 of the symptomatic patients. We conclude that spinal stenosis is an important cause of vertebral pain and neurologic dysfunction.
Aged↗
Intrinsic factor within parietal cells of patients with juvenile pernicious anemia. A retrospective immunohistochemical study.
One of the diverse group of disorders that cause pernicious anemia in childhood, juvenile pernicious anemia, has been characterized by normal acid secretion, normal gastric mucosal histology, adequate intestinal absorption of cobalamin in the presence of exogenous gastric intrinsic factor (IF), but the inadequate "production" of IF from birth. Inadequate production has been inferred from the absence of measured IF in stimulated gastric secretions. To assess whether immunogenic IF was commonly present within the parietal cells of subjects with juvenile pernicious anemia, we studied paraffin-embedded biopsy material from the largest reported series of childhood pernicious anemia, using a well-characterized indirect immunoperoxidase method. Preliminary studies were able to identify IF in fundic mucosal biopsy specimens that had been stored for as long as 27 yr. In a blinded evaluation, six of the nine fundic biopsy specimens from children with juvenile pernicious anemia demonstrated immunogenic IF. Two sets of siblings were concordant for the presence or absence of intracellular IF, and six gastric biopsy specimens from patients with Imerslund's syndrome were all positive for IF. These findings indicate that juvenile pernicious anemia is a heterogeneous group of disorders whose similar clinical expression might be caused by (a) inadequate synthesis of IF, (b) a block in IF secretion, (c) the secretion of an abnormal IF that does not bind to cobalamin, or (d) the secretion of other abnormal IFs that could contain a number of other functional defects.
Anemia, Pernicious↗
Cobalamin malabsorption in three siblings due to an abnormal intrinsic factor that is markedly susceptible to acid and proteolysis.
Three siblings presented in their second year of life with megaloblastic anemia that responded to parenteral cobalamin (Cbl). Schilling tests were less than 1%, correcting to 5 to 15% after addition of hog intrinsic factor (IF). Gastric acid analysis and gastric biopsies were normal by light and electron microscopy. Gastric juice contained less than 3 pmol/ml of Cbl-binding ability due to IF (normal, 10-34 pmol/ml) and less than 2 pmol/ml of IF when measured with a radioimmunoassay (RIA) using normal human IF-[57Co]Cbl and rabbit anti-human IF serum (normal, 17-66 pmol/ml). However, RIA employing rabbit anti-hog IF serum gave values of 4-13 pmol/ml of IF (normal, 11-33 pmol/ml). This material had an apparent molecular weight of 40,000 (normal IF = 70,000). The IF from gastric biopsies appeared normal in terms of Cbl-binding ability, ileal binding, molecular weight, and both RIAs. This IF differed from normal mucosal IF, in that it lost its Cbl-binding ability when incubated at 37 degrees C at acid pH or in the presence of pepsin or trypsin. This loss was retarded when [57Co]Cbl was bound to the IF before these incubations. The stabilizing effects of neutralization and Cbl were also demonstrated in vivo. Schilling tests for the siblings of 0.4, 0.5, and 1.0% increased to 2.7, 5.7, and 4.3% (P less than 0.05), respectively, when the Schilling tests were repeated with the addition of NaHCO3 and cobinamide (which allows Cbl to bind immediately to IF). We conclude that Cbl malabsorption in these children is due to an abnormal IF that is markedly susceptible to acid and proteolytic enzymes which cause a decrease in its molecular weight and Cbl-binding ability and a loss of antigenic determinants that are recognized by the anti-human IF serum.
Anemia, Megaloblastic↗
Blue-sensitive cones in the primate retina: microspectrophotometry of the visual pigment.
Direct absorbance and bleaching absorbance-difference spectra were obtained using a photon-counting microspectrophotometer from the outer segments of ten blue-sensitive cones of macaque monkeys. The peak wavelength (lambda max) of the direct measurements was 426 +/- 3.4 nm, whereas the lambda max of the bleaching difference was 434 +/- 6.6 nm. We consider these values to be upper and lower bounds since both measurements may be shifted in opposite directions by wavelength-dependent effects. Therefore, the true peak sensitivity must be close to 430 nm.
Animals↗
Immunocytochemical localization of the intrinsic factor-cobalamin receptor in dog-ileum: distribution of intracellular receptor during cell maturation.
Absorption of cobalamin is facilitated by the binding of the intrinsic factor-cobalamin complex (IF-cbl) to specific receptors in the ileum. The physical and biochemical characteristics of this ligand-receptor binding reaction have been extensively studied, but little is known about the cellular mechanisms or receptor synthesis, intracellular transport, and expression on the microvillus surface membrane. We attempted to delineate these mechanisms by using ultrastructural immunocytochemistry to localize the IF-cbl receptor in the crypt, mid-villus, and villus tip regions of mucosal biopsies obtained from the ileum of anesthetized dogs. Prior to initiating the ileal localization studies, the antisera to purified canine IF-cbl receptor that was employed in our studies was shown to have specificity for site (e.g., ileal enterocytes vs. other cells within the gastrointestinal tract) and immunohistochemical specificity. Receptor synthesis in endoplasmic reticulum begins in crypt enterocytes, but continues in cells throughout the villus. In the mid-villus region synthesized receptor translocates vectorially to the microvillus surface associated with membranous vesicles and then inserts into the microvillus pit. Receptor remains fixed to the microvillus pit and does not distribute uniformly over the brush border membrane. All villus tip enterocytes contained IF-cbl receptor in microvillus pits, vesicles, and endoplasmic reticulum, but in addition extensive perinuclear membrane staining was evident as well as re-internalized receptor associated with multivesicular bodies. Basolateral membranes contained no receptor at any level of the villus. These observations suggest that the IF-cbl receptor (a) translocates to the apical cell surface at the mid-villus region by transport in vesicles, (b) directly inserts into and then remains fixed in microvillus pits, (c) is elaborated on the luminal surface most extensively in villus tip cells, and (d) although reinternalized, does not move IF and/or cbl to the basolateral cell surface.
Animals↗
Aphthous ulceration in diversion colitis. Clinical implications.
Two cases of aphthous ulceration apparently due to diversion colitis are described. There was no evidence of Crohn's disease initially or at follow-up. Aphthous ulceration of the colon and diversion colitis are reviewed, and the nonspecificity of aphthae for Crohn's disease is stressed. The presence of aphthous ulcers in a diverted colon should not preclude colostomy closure.
Adult↗