Function of the dorsal and medial cortex of turtles in learning

The effects of damage to the dorsal and medial cortex of turtles were investigated in two experiments. In the first, damage to the dorsal cortex disrupted acquisition and reversal of a go-no-go discrimination but had no effect on retention of the discrimination if it had been learned preoperatively. Medial cortex damage had no effect. In the second experiment, dorsal cortex damage impaired acquisition, but not extinction or reacquisition, of a discrete-trial keypress. Again, medial cortex damage had no effect. The results suggest that the dorsal cortex is involved in learning in turtles.     

ACCOMMODATIVE DISFACILITY PRESENTING AS INTERMITTENT EXOTROPIA

Abstract Accommodative disfacility and intermittent exotropia are two common clinically-observed ocular abnormalities. However, records of individual system dynamics arc rare and mechanisms for possible interactive effects between the accommodation and the vergence system remain obscure in cases of system dysfunction. We present objective, quantitative, static and dynamic records of accommodation, vergence and related system responses in a symptomatic patient having accommodation disfacility and intermittent exotropia and propose that these two conditions worked in a pathogenic symbiotic manner.     

Intestinal microvascular exchange in the rat during luminal perfusion with formyl-methionyl-leucyl-phenylalanine

Formyl-methionyl-leucyl-phenylalanine (FMLP), a peptide released from bacteria in the gut lumen, is known to both attract and activate neutrophils. The aim of this study was to determine whether luminal perfusion with 1 microM FMLP alters microvascular permeability, blood flow, and neutrophil migration in the small intestine of control rats and rats treated with antineutrophil serum. Microvascular permeability to total plasma proteins was determined from an analysis of lymphatic protein fluxes. Myeloperoxidase activity was used as an index of tissue neutrophil count. Intestinal blood flow was measured using radiolabeled microspheres and the reference blood sample method. In control rats, luminal perfusion with FMLP caused significant increases in blood flow, lymph flow, lymph protein clearance, and microvascular permeability, but it did not alter tissue myeloperoxidase activity. In rats treated with antineutrophil serum, tissue myeloperoxidase levels were reduced by approximately 55%, and the FMLP-induced changes in lymph flow, lymph protein clearance, and microvascular permeability were significantly attenuated. In vitro experiments with isolated rat neutrophils revealed that 1 microM FMLP elicits significant chemotaxis and degranulation yet minimally enhances superoxide production. The results of this study indicate that peptides produced by microorganisms in the gut lumen can increase intestinal microvascular permeability. The FMLP-induced alterations in microvascular exchange appear to be mediated by activated neutrophils.     

Gradation of carcinogen-induced capacity for anchorage-independent growth in cultured rat liver epithelial cells

The effect of epidermal growth factor (EGF) on the capacity for anchorage-independent growth of chemically treated rat hepatic epithelial cells has been investigated. We have performed the studies using 16 clonally derived cell strains which represented single cell-derived subpopulations of a heterogeneous rat hepatic epithelial cell line that had been tumorigenically transformed by 11 repeated treatments with N-methyl-N'-nitro-N-nitrosoguanidine. The results can be summarized as follows. (a) Secondary clonal subpopulations isolated from the colonies formed by these strains in soft agar subsequently and invariably acquired markedly enhanced colony-forming efficiencies as compared to their parental strains. (b) EGF could enhance or induce colony-forming ability in soft agar in all of these cell strains. (c) The magnitudes of enhancement of the colony-forming efficiencies by EGF in soft agar could not be correlated with the absolute EGF-binding capacity of these cell strains. (d) The enhancement or induction of the colony-forming ability by EGF was either reversible or irreversible, partially correlating with the expression of gamma-glutamyl transpeptidase activity by the strains. These findings indicate that the cellular capacity of liver epithelial cells to grow anchorage independently in soft agar medium can be graded according to the pattern of response of EGF induction of colony-forming ability. These grades may reflect the level of neoplastic transformation of these cells. Moreover during the multistep transformation of rat hepatic epithelial cells by a chemical carcinogen, EGF can be used to reveal the presence of altered cells which have acquired partial capacity for the anchor-age-independent growth property. This property may constitute an additional identifiable early step of the neoplastic transformation of these cells.     

Endotoxin induces bacterial translocation and increases xanthine oxidase activity

Previously, we documented that endotoxin induces bacterial translocation from the gut and that inhibition or inactivation of xanthine oxidase activity reduces endotoxin-induced bacterial translocation. Consequently, experiments were performed to correlate endotoxin-induced bacterial translocation with changes in intestinal mucosal structure and xanthine dehydrogenase and oxidase activity. Segments of the jejunum, ileum, cecum, proximal colon, distal colon, and liver were harvested from ICR mice 24 hr after IP administration of E. coli 0111:B4 endotoxin (0.1 mg). Xanthine dehydrogenase and oxidase activities were measured in these samples and correlated with intestinal morphology. Bacteria translocated from the intestines to extraintestinal organs in 70% of the mice receiving endotoxin, while the organs of control mice were sterile (p less than 0.01). Endotoxin injured primarily the ileal and cecal mucosa and increased ileal and hepatic xanthine dehydrogenase and cecal oxidase activities (p less than 0.05). These results suggest that xanthine oxidase-induced mucosal damage plays a role in endotoxin-induced bacterial translocation.     

Scanning electron microscopy of mouse intrahepatic structures.

Livers of normal mice were prepared for scanning electron microscopic (SEM) study by fracturing or slicing lobes fixed in situ by perfusion with paraformaldehyde. Fracturing fixed liver exposes surfaces of hepatocytes and sinusoidal endothelial cells, whereas slicing the tissue reveals the internal structures of portal tracts. Earlier studies have delineated the major surface characteristics of hepatocytes and sinusoidal endothelial cells of rats. Surfaces of hepatocytes in the mouse differ from those in the rat by having larger and more numerous peg and hole complexes on the flat intercellular surface and less dense populations of perisinusoidal microvilli. Sinusoidal endothelial cells in the mouse have fewer large fenestrations than do similar cells in the rat; clusters of small fenestrations appear similarly distributed in both species. The surfaces of capsular mesothelial cells, Kupffer cells, bile duct epithelial cells, and endothelial cells of major vessels are similar in rat and mouse.The methods described for preparing liver for SEM examination are simple, rapid, and reproducible. The SEM is a useful tool with which to study intrahepatic surface structures, and its use may allow further correlations to be made between hepatic structure and function in both health and disease.     

Abagovomab: an anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancer

Ovarian cancer remains the leading cause of death due to gynecologic malignancies. Most patients present with advanced disease at the time of diagnosis. Although many have a good initial response to surgical debulking and platinum-based chemotherapy, relapse is common, with the eventual development of chemotherapy resistance. Innovative treatments are needed in the remission setting to prolong the disease-free interval or prevent recurrence. Abagovomab is a murine monoclonal anti-idiotypic antibody (molecular weight: 165-175 kDa) that functionally imitates the tumor-associated antigen, CA-125. It has been shown to be well tolerated and to induce a sustained immune response in initial Phase I and II clinical trials. An ongoing, double-blind, placebo-controlled, multicenter, Phase III trial (MIMOSA) completed its double-blind period in December 2010 and will compare abagovomab maintenance therapy to placebo, which will definitively determine the efficacy of this immunotherapeutic approach in patients with ovarian cancer.     

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0–0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.This work was supported by DK 43785 (to M.B.G., Project 6), DK 33720 (to R.D.S.), and DK 40249 (to R.B.S.).     

Effects of Reactive Oxygen and Nitrogen Metabolites on RANTES- and IL-5-Induced Eosinophil Chemotactic Activity in Vitro

Eosinophils and increased production of nitric oxide (NO) and superoxide, components of peroxynitrite, have been implicated in the pathogenesis of a number of allergic disorders including asthma. Peroxynitrite induced protein nitration may compromise enzyme and protein function. We hypothesized that peroxynitrite may modulate eosinophil migration by modulating chemotactic cytokines. To test this hypothesis, the eosinophil chemotactic responses of regulated on activation, normal T cell expressed and secreted (RANTES) and interleukin (IL)-5 incubated with and without peroxynitrite were evaluated. Peroxynitrite-attenuated RANTES and IL-5 induced eosinophil chemotactic activity (ECA) in a dose-dependent manner (P < 0.05) but did not attenuate leukotriene B4 or complement-activated serum ECA. The reducing agents deferoxamine and dithiothreitol reversed the ECA inhibition by peroxynitrite, and exogenous L-tyrosine abrogated the inhibition by peroxynitrite. PAPA-NONOate, a NO donor, or superoxide generated by lumazine or xanthine and xanthine oxidase, did not show an inhibitory effect on ECA. The peroxynitrite generator, 3-morpholinosydnonimine, caused a concentration-dependent inhibition of ECA. Peroxynitrite reduced RANTES and IL-5 binding to eosinophils and resulted in nitrotyrosine formation. These findings are consistent with nitration of tyrosine by peroxynitrite with subsequent inhibition of RANTES and IL-5 binding to eosinophils and suggest that peroxynitrite may play a role in regulation of eosinophil chemotaxis.     

Localization of a putative liver tumor suppressor locus to a 950-kb region of human 11p11.2-p12 using rat liver tumor microcell hybrid cell lines

We previously demonstrated that a locus (or loci) linked to the D11S436 marker, which is within the approximately 6-Mb cen-p12 region of human chromosome 11, suppresses the tumorigenic potential of some rat liver epithelial tumor microcell hybrid (MCH) cell lines. To more precisely map this putative liver tumor suppressor locus, we examined 25 loci from human chromosome 11 in suppressed MCH cell lines. Detailed analysis of these markers revealed a minimal area of overlap among the suppressed MCH cell lines corresponding to the chromosomal region bounded by (but not including) microsatellite markers D11S1319 and D11S1958E and containing microsatellite markers D11S436, D11S554, and D11S1344. Direct examination of the kang ai 1 (KAI1) prostatic adenocarcinoma metastasis suppressor gene (which is closely linked to D11S1344) produced evidence suggesting that this locus was not responsible for tumor suppression in this model system. In addition, our data strongly suggested that the putative liver tumor suppressor locus was distinct from other known 11p tumor suppressor loci, including the multiple exotoses 2 locus (at 11p11.2-p12), Wilms' tumor 1 locus (at 11p13), and Wilms' tumor 2 locus (at 11p15.5). The results of this study significantly narrowed the chromosomal location of the putative liver tumor suppressor locus to a region of human 11p11.2-p12 that is approximately 950 kb. This advance forms the basis for positional cloning of candidate genes from this region and, in addition, identified a number of chromosomal markers that will be useful for determining the involvement of this locus in the pathogenesis of human liver cancer. Mol. Carcinog. 19:267–272, 1997. © 1997 Wiley-Liss, Inc.