Biomedical subjects
Publications and source records attributed to K L Schmidt.
Increased levels of OC can be detected in late RA with high disease activity, whereas no major bone impairment is detectable in early and advanced stages of RA suggesting a more serious bone involvement in this form of the disease. OC appears to be a good marker to identify osteopenia in late onset active RA.
Fluoresceinated lectins were employed to qualitatively evaluate cell surface carbohydrates, with and without ethanol exposure, in rat stomach mucosae. Rats received 1 ml of saline, or 50% or 100% ethanol orally. After 30 min, tissue samples of the glandular stomach were retrieved, cryosectioned, and incubated with one of a panel of lectins. Another set of sections was preincubated with neuraminidase to remove sialic acid residues. Qualitative evaluation of lectin binding showed that although several different sites stained, concanavalin A was the only lectin to stain the extracellular matrix, and soybean agglutinin the only lectin to stain chief cells. Neuraminidase preincubation enhanced lectin binding to both stained and previously unstained sites. Ethanol, both 50% and 100%, produced changes in both neuraminidase-treated and untreated tissues, increasing the specific binding of concanavalin A, Ulex europaeus agglutinin I, and wheat germ agglutinin, while decreasing Helix pomatia agglutinin and soybean agglutinin. These results suggest that ethanol can, through unknown mechanisms, alter carbohydrate binding affinity.
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A 75-year-old woman with untreated primary hypothyroidism was found with peripheral neuropathy (including carpal tunnel syndrome), severe myopathy (high levels of creatine phosphokinase) and destructive arthropathy, affecting fingers, toes and the left knee. Radiographs of her knee showed destructive lesions of the tibial plateau similar to a pathologic compression fracture, while the joints of the fingers and toes showed all signs of severe erosive osteoarthritis (OA), radiographically documented over a period of 7 years. It is suggested that hypothyroidism is causally related to the development of erosive OA.
We studied secretory activity of the adrenal gland by determining cortisol blood levels throughout a 24-h cycle at 2-h intervals in 26 patients with rheumatoid arthritis (RA), not previously treated with glucocorticosteroids or disease modifying drugs. In patients with low erythrocyte sedimentation rates [(ESR) up to 40 mm/h] and medium disease activity (ESR between 40 and 80 mm/h), cortisol maxima and minima shifted to earlier times of the day whereas in patients with high activity (ESR higher than 80 mm/h) the circadian rhythm was lost or markedly reduced. The inflammatory activity of the RA significantly correlated with the adrenal cortisol secretion (linear regression analysis between ESR and the arithmetic mean value of cortisol throughout a 24-h cycle with a coefficient of regression r = 0.63, n = 26, p less than 0.001). The influence of mediators of inflammation, such as interleukin 1, on hypothalamic centers, stimulating the hypothalamus-pituitary-adrenal axis, is discussed.
Flow cytometric analysis was done on exfoliated urothelial cells from 11 control patients and 31 patients with transitional cell carcinoma: 9 grade I, 11 grade II, and 11 grade III. The determination of aneuploidy by DNA analysis did not provide identification of low-grade tumor cells. Other flow cytometric parameters of cellular change such as cell size, nuclear size, nuclear/cytoplasmic ratio, or cell refractivity may provide better identification of low-grade lesions.
This study compared the ability of topical 16,16-dimethyl prostaglandin E2 in a dose range of 0.3-3.0 micrograms/ml to prevent aspirin-induced injury in the canine stomach under both in vivo and in vitro conditions. For in vitro studies, isolated strips of oxyntic mucosa were exposed to 10 or 20 mM aspirin (ASA) at pH 1-4, with and without treatment with 16,16-dimethyl prostaglandin E2. For in vivo experiments, a portion of the oxyntic stomach was mounted between the rings of a Lucite chamber, with splenic vessels intact, such that the mucosa was divided into halves. Both sides were exposed to 20 mM ASA at pH 1 or 2, and one side also received concomitant treatment with 16,16-dimethyl prostaglandin E2. After ASA exposure, tissue samples were prepared for quantitative microscopic analysis of the degree of injury. Under both experimental conditions, the magnitude of gastric injury by ASA was pH-related, being most pronounced at pH 1; this damage was worse under in vitro conditions, and both concentrations of ASA were equally damaging in this setting. 16,16-Dimethyl prostaglandin E2 failed to prevent ASA injury in vitro at any pH and ASA concentration tested, but markedly reduced the magnitude of injury in vivo. The most effective protective dose of 16,16-dimethyl prostaglandin E2 under in vivo conditions was 1.0 micrograms/ml. The diminished tolerance to ASA damage in vitro when compared with in vivo, and the inability of 16,16-dimethyl prostaglandin E2 to prevent these damaging effects in vitro, underscores the probable crucial role for blood flow, and possibly neural innervation, in mediating the protective effects of prostaglandins.
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The effects of 16,16 dimethyl prostaglandin E2 (dmPGE2) on the gastric mucosa of rats subjected to 1, 2, and 24 hours of water immersion stress were examined histologically. Results indicated a time-related increase in the total percentage length of glandular mucosa injured in normal saline (NS) pretreated rats that was significantly attenuated by subcutaneous dmPGE2 pretreatment (5 micrograms/kg) after 1 hour (46.0 +/- 12.9 vs. 16.8 +/- 2.3; p less than 0.005), 2 hours (45.4 +/- 1.0 vs. 13.8 +/- 2.2; p less than 0.001), and 24 hours (93.1 +/- 2.6 vs. 65.1 +/- 7.0; p less than 0.005) of water immersion stress. Moreover, dmPGE2 essentially prevented the occurrence of deep, glandular injury that, in NS controls, involved approximately 13% and 26% of the mucosal surface after 2 and 24 hours of immersion stress, respectively. Additionally, tissue levels of glutathione (mumole/g weight of wet tissue) were measured to determine its role under such conditions. After 1 hour of stress, there were no differences in glutathione levels between NS or dmPGE2 pretreated animals and fasted controls. After 2 and 24 hours of stress, there were likewise no differences in glutathione levels between NS and dmPGE2 pretreated groups, although levels in both groups were significantly decreased from fasted controls by approximately 30% at 2 hours and 37-47% after 24 hours. These histologic and biochemical data indicate that dmPGE2 attenuates both the extent and depth of glandular mucosal injury and does so in a manner unrelated to alterations in glutathione levels in gastric epithelium.
The present study histologically investigated the efficacy of pretreating rat gastric mucosa with the mild irritants, 10% and 25% ethanol (EtOH), against the known damaging effects of 100% EtOH. Fasted rats received 1 ml of either water, 10% EtOH, or 25% EtOH by orogastric intubation. Fifteen minutes later, a portion of these animals was sacrificed and tissue samples of the oxyntic region of the stomach were excised and processed for quantitative histologic analysis. Remaining animals received a 1 ml oral bolus of the necrotizing agent, 100% EtOH. Five minutes later, these animals were sacrificed and tissues were prepared in a like manner. In a separate series of experiments, the aforementioned protocols were repeated, except that all animals received the prostaglandin synthetase inhibitor, indomethacin (5.0 mg/kg intraperitoneally), 30 min before administration of the mild irritant. Microscopically, the administration of water or 10% EtOH alone caused a small and comparable amount of superficial injury to the gastric mucosa. Moreover, both substances failed to induce protection in stomachs subsequently exposed to 100% EtOH. Indomethacin pretreatment did not significantly alter any of these findings. In marked contrast, 25% EtOH alone elicited a substantial degree of superficial damage to the gastric mucosa. Nevertheless it significantly reduced the depth of injury in animals subsequently challenged by 100% EtOH. Indomethacin failed to aggravate the effects of 25% EtOH alone, but partially inhibited the protective effect of this mild irritant against 100% EtOH induced damage. Our findings indicate that adaptive cytoprotection is a real phenomenon that can be demonstrated microscopically. Such protection is limited primarily to the deep mucosal layers (i.e. gastric glands), appears in part to be prostaglandin mediated and seems to require the generation of moderate surface cell damage (as occurred with 25% EtOH, but not 10% EtOH) to induce its initiation.
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The effects of absolute ethanol (EtOH) and 16,16-dimethyl-prostaglandin E2 (PGE2) on the ultrastructure of rat gastric mucosa were assessed using standard electron microscopic techniques. Fasted rats were injected subcutaneously with 10 micrograms/kg body weight of PGE2 or saline. After 30 min, animals received orally 100% EtOH or an equal volume of saline. Gastric mucosa was sampled at 5 min and 1, 2, 8, and 24 h post-EtOH and tissues procured for scanning and transmission electron microscopy. Both mucosal epithelial and connective tissue compartments were assessed. At 5 min after EtOH, in saline-pretreated animals, tissues showed extensive destruction of epithelium and connective tissue; major breaks in the basal laminae were coincident with hemorrhage. Deep-lying epithelial cells and most of the basal lamina were spared in tissues exposed to PGE2 prior to EtOH, permitting nearly complete repair within 24 h. Restitution proceeded over small breaks or pleats of basal lamina but failed in regions of total destruction of this structure. These data indicate that PGE2 protects not only deep-lying epithelial cells from EtOH damage but associated connective tissue as well and that sparing of both compartments leads to orderly and rapid epithelial restitution.
The term "cytoprotection" originally described the ability of prostaglandins, independent of their known antisecretory activity, to prevent macroscopic evidence of gastric injury induced in different animal models under various experimental conditions. Several recent reports have challenged this concept because the apparent macroscopic protection could not be confirmed microscopically. To determine whether prostaglandins do indeed possess cytoprotective properties, and if such effects are dependent on the dose and the route of prostaglandin administration, studies were performed using 16,16 dimethyl prostaglandin E2 (PGE2) and the known gastric damaging agent, ethanol. Fasted rats received either oral or subcutaneous PGE2 in doses of 10 or 20 micrograms/kg or equal volumes of saline. Thirty minutes later, animals were given a 1-ml oral bolus of 50% or 100% ethanol or an equal volume of saline. At 5 minutes to 24 hours following ethanol, animals were sacrificed, and tissues from the glandular portion of the stomach were removed for histologic quantification of injury. At 5 minutes following ethanol, PGE2 reduced the depth of injury, but had no protective effects against surface cell damage when compared with control animals. By 24 hours after ethanol, most of the PGE2-treated mucosa was repaired. Oral administration of 10 micrograms/kg PGE2 was more cytoprotective at 5 minutes after ethanol than when administered by subcutaneous injection. This relationship was not true for the 20 micrograms/kg dose. We conclude that cytoprotection can be confirmed histologically, but is limited primarily to the deep mucosa. The ability of PGE2 to enhance healing is probably related to the prevention of deep mucosal injury, which thereby allows epithelial reconstitution to occur. Lastly, the effectiveness of PGE2 as a cytoprotective agent is dose- and route-dependent.
The effect of 16,16 dimethyl prostaglandin E2 (PG) upon tight junctions (TJs) of adjacent surface mucous cells (SMCs) as a possible mechanism by which PGs mediate their protective effects was studied using transmission electron microscopy (TEM) and freeze fracture (FF) techniques. Fasted rats were subcutaneously injected with 10 micrograms/kg of PG or an equal volume of saline, followed 30 min later by 1 ml of oral 100% ethanol or saline. Ten or sixty minutes later, animals were sacrificed and stomach blocks were prepared for TEM or FF using standard techniques. Electron micrographs (X60,000) were obtained and the distance between SMC inner membrane leaflets was measured with a micrometer and expressed as TJ width. Stomach blocks for FF were stored at 4 degrees C, cryoprotected, freeze fractured, and photographed by TEM (X30,000). At 0.5-micron intervals, measurements of TJ strand number and depth were made. No statistical differences were found in TJ width or strand number of SMCs among the various experimental groups when compared with controls at each sacrifice time. At the 60 but not 10 min sacrifice time, TJ depth was greatly increased in cells treated with 10 micrograms/kg PG prior to ethanol exposure (P less than 0.025) in contrast to control mucosae. We conclude that 16,16-dimethyl PGE2 induces no changes in the structural composition of TJs as a possible explanation for its protective properties. The increase in TJ depth observed in ethanol exposed mucosa following PG pretreatment at the 60 min sacrifice time is most likely related to the architectural restructuring that occurs during reconstitution of damaged surface epithelium.
The tissue localization of multilamellar vesicles (MLV) (size 0.5-5.0 microns) composed of dimyristoylphosphatidyl choline (DMPC) and dimyristoylphosphatidyl glycerol (DMPG) (molar ratio 7:3) containing a lipophilic cisplatin analogue (NDDP) was studied in mice by freeze fracture (FF) and transmission electron microscopy (TEM). Liposomes were observed within cytoplasmic vacuoles of hepatocytes and Kupffer cells in normal mice as early as 5 minutes after intravenous (iv) administration of MLV-NDDP. Liposomes within hepatocytes were more numerous but smaller in diameter (0.5-2.0 microns) than those within Kupffer cells (2.0-4.0 microns). In normal lung examined by FF or TEM at 5 minutes after MLV-NDDP administration, liposomes were only observed in the intravascular space. Liposomes could not be identified within Type I or II pneumocytes nor within the alveolar space. Two hours after iv administration, the distribution within the liver showed an increased number of liposomes in the hepatocytes with some evidence of liposome decomposition. The distribution in the lung was virtually identical to that observed at 5 minutes. The pattern of tissue localization within lung and liver of empty MLV 5 minutes and 2 hours after iv administration was identical to that of MLV-NDDP. In mice bearing gross liver metastases of M5076 reticulosarcoma, liposomes were present in the cytoplasm of tumor cells as well as normal cells 5 minutes and 2 hours after the iv administration of MLV-NDDP. These studies suggest that MLV composed of DMPC and DMPG containing NDDP are able to cross the liver sinusoidal capillaries and gain access to both hepatocytes from normal liver and malignant cells of M5076 reticulosarcoma from liver metastases.
We used light microscopy, transmission electron microscopy, and stereological point-counting methods to investigate the response of rat gastric chief cells to corticosterone and thyroxine during postnatal development. Administration of corticosterone or thyroxine to normal animals in the first two postnatal weeks increased relative numbers of chief cells in the fundic mucosa but did not change the absolute number of total cells in each gland. The chief cells displayed more rough endoplasmic reticulum, zymogen granules, and Golgi saccules in corticosterone- or thyroxine-injected rats than in normal control rats. When rats were either adrenalectomized or made hypothyroid using propylthiouracil, the number of chief cells dramatically decreased. Ultrastructural studies of chief cells from adrenalectomized or hypothyroid rats showed retarded differentiation as indicated by increased free ribosomes, less rough endoplasmic reticulum, fewer zymogen granules, and poorly developed Golgi apparatuses. In adrenalectomized animals, thyroxine replacement alone failed to induce the histological maturation of chief cells, but addition of corticosterone stimulated chief cell differentiation. In hypothyroid animals, either thyroxine or corticosterone replacement restored the differentiation of chief cells to normal levels. Our data indicate that 1) corticosterone is necessary for gastric chief cell maturation during postnatal development, 2) a decrease or loss in either corticosterone and/or thyroxine results in retarded chief cell differentiation and functional activity, and 3) the effect of thyroxine on chief cell development is secondary to an accompanying increase in serum corticosterone.
The effect of corticosterone and thyroxine on the development of parietal cells was studied in 20-day-old rats. Either corticosterone or thyroxine injection significantly increased the amount of mitochondria, tubulovesicles, and intracellular canaliculi in normal rat pup parietal cells. However, the ultrastructure of parietal cells did not change when rats were adrenalectomized or made hypothyroid by propylthiouracil (PTU) during the first week of life. Corticosterone had the same effect in hypothyroid rats as in normal rats, increasing the volume fraction of mitochondria and the surface density of tubulovesicles and intracellular canaliculi in the parietal cell. However, thyroxine failed to do so in adrenalectomized animals. When 20-day-old adrenalectomized or hypothyroid rats were challenged with secretagogues, there was no increase in maximal acid output over the basal secretory rate, while normal rats showed a 40-50% increase. We conclude that 1) normal parietal cells respond to additional thyroxine or corticosterone with increases in volume fraction of mitochondria and surface density of tubulovesicles and intracellular canaliculi; 2) the dramatic decreases in acid secretion observed in adrenalectomized or PTU-treated rats are not explained by the morphology of parietal cells that remains normal; 3) the effect of thyroxine on the development of acid secretion is mediated by corticosterone; and 4) unlike chief cells the morphological development of parietal cells does not appear to depend on corticosterone or thyroxine after postnatal day 7.
Failure to absorb bile acids by the ileum leads to fluid secretion by the colon and diarrhea in adults. The infant ileum, however, does not actively transport bile acids. Therefore, we investigated the effect of taurodeoxycholic acid (TDCA) on ion transport in the colon of rabbits 7-10 days old. We mounted distal colon from infant and adult rabbits in modified Ussing chambers and exposed the mucosal or serosal surfaces to TDCA. In the adult, 50 microM TDCA produced an increase in short-circuit current (delta Isc = 1.0 +/- 0.3 mu eq . h-1 . cm-2, P less than 0.05) and Cl secretion. In the infant, the effect was different, Isc was reduced (delta Isc = -1.1 +/- 0.2 mu eq . h-1 . cm-2, P less than 0.01) and ion flux was not altered. Microscopy demonstrated that the infant epithelium was not significantly damaged by exposure to TDCA at these concentrations. The infant colon was, however, capable of a secretory response to a variety of agonists including theophylline, carbachol, bradykinin, serotonin, and 12,13-dibutyryl phorbol ester. The infant rabbit distal colon lacks a secretory response to TDCA during that period when the ileum cannot transport bile acids.