Peptic ulcer perforation associated with steroid use

A ten-year (1974 to 1984) retrospective chart review was conducted to find all patients with peptic ulcer perforation associated with steroid treatment. During this period, 151 peptic ulcer perforations occurred, 25 (17%) associated with steroid use. Twenty patients had the diagnosis confirmed at operation, five at autopsy. The most common operative procedure was oversewing of the perforation with an omental patch (ten cases). Postoperative complications occurred in 16 patients and were multiple in 11. Underlying malignant neoplasms were the most common concurrent disease (11 patients), five patients having brain metastasis. Of 25 patients, 15 died--five preoperatively and ten postoperatively. Patients older than age 50 years had an overall mortality of 85%; those younger than age 50 years, 17%. A recurring pattern in 21 patients was perforation occurring after a major increase in steroid dose (pulse). Ulcer perforations associated with steroid use constitute a significant portion of all ulcer perforations, are lethal in most patients older than age 50 years, and are often associated with a steroid pulse before perforation.     

Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine.

The immunosuppressive drug, mizoribine, has been used to prevent rejection of organ allografts in humans and in animal models. Based on studies in cell lines, mizoribine has been postulated to be an inhibitor of inosine monophosphate (IMP) dehydrogenase (EC1.2.1.14), a pivotal enzyme in the formation of guanine ribonucleotides from IMP. To further characterize the mechanism of action of this drug, we studied the effect of mizoribine on human peripheral blood T cells stimulated with alloantigen, anti-CD3 MAb, or pharmacologic mitogens. Mizoribine (1-50 micrograms/ml) was able to inhibit T cell proliferation by 10-100% in a dose-dependent fashion to all stimuli tested. Measurements of purine ribonucleotide pools by HPLC showed that mizoribine led to a decrease in intracellular GTP levels, and that repletion of GTP reversed its antiproliferative effects. We also examined sequential events occurring after T cell stimulation. Early events in T cell activation, as assessed by steady-state mRNA levels of c-myc, IL-2, c-myb, histone, and cdc2 kinase, as well as surface IL-2 receptor expression, were unaffected. However, cell cycle analysis revealed decreased numbers of cells in S, G2, and M phases, and showed that the G1/S block was reversed with GTP repletion. These data indicate that mizoribine has an effect on T cell proliferation by a mechanism distinct from that of cyclosporine or corticosteroids, and therefore may be useful in combination immunosuppressive regimens.     

Role of immune interferon in the monocytic differentiation of human promyelocytic cell lines induced by leukocyte conditioned medium

Conditioned medium (CM) from lectin-stimulated human leukocytes contains factors that induce human promyelocytic cell lines to differentiate along the monocytic pathway. In this report, we show that human promyelocytic cell lines are also induced to differentiate along this pathway by immune interferon (IFN gamma). Various preparations of IFN alpha tested did not induce this differentiation. In cultures containing IFN gamma, the cells are induced to coordinately express monocyte markers and functions such as monocyte-specific surface antigens, HLA-DR antigens, nonspecific esterase, receptors for the Fc fragment of IgG, and the ability to mediate antibody-dependent cell- mediated cytotoxicity. Our data indicate that differentiation induced by IFN gamma is not secondary to an arrest of growth of promyelocytic cell lines, but rather that a proportion of cells is induced along a programmed pathway of terminal differentiation similar to that of normal monocytes. CM contains IFN gamma, but its ability to induce differentiation is greater than expected on the basis of its content of IFN gamma. Treatments at 56 degrees C or at pH 2.0, which abolish IFN gamma activity, abrogate the differentiation ability of CM. The antiviral activity and the differentiation activity contained in the CM are coeluted from gel filtration and reverse-phase columns. Monoclonal antibodies anti-IFN gamma, which completely abrogate the differentiation ability of IFN gamma and the antiviral activity in the CM, completely suppress the induction of some monocyte markers by CM, but only reduce the expression of others. When IFN gamma is added to CM, promyelocytic cell lines are induced to differentiate to a much greater extent than that induced by either IFN gamma or IFN gamma- depleted CM alone. These results show that the differentiation activity of leukocyte CM is due to the synergistic effect of IFN gamma and other factors not yet identified.     

Circadian rhythm in gastric mucosal blood flow in fasting rat stomach

Circadian rhythms are present in several gastric functions including acid secretion and emptying rates. We hypothesize that aggressive and defensive factors in the gastric mucosa follow similar circadian rhythms. The purpose of this study was to determine if gastric mucosal blood flow, a known defensive factor, manifests a circadian rhythm in fasting rats. Ninety-six male Sprague-Dawley rats were light-adapted in isolation chambers for 3 weeks prior to the study. Half the rats experienced light from 6:00 AM to 6:00 PM, the other half from 6:00 PM to 6:00 AM. After an 18-hr fast, 12 rats were studied at each of eight sampling times: 0100, 0400, 0700, 1000, 1300, 1600, 1900, and 2200 hr after lights on (HALO). After anesthesia and laparotomy, the stomachs were opened along the anterior surface, gently stretched with mucosal surface upmost, and trapped between two lucite rings, with blood supply intact. Mucosal blood flow (ml/min/100 g) was measured in the forestomach, corpus, and antrum with a laser Doppler flowmeter (TSI Laserflo BPM 403). Cosinor analysis showed a significant (P less than 0.01) circadian rhythm in gastric mucosal blood flow within the corpus and antrum, but not in the forestomach. Peak time for corpus blood flow was 21:45 +/- 0:56 HALO (3:45 AM). In the antrum it was 0:51 +/- 1:08 HALO (6:51 AM). These results support the hypothesis that circadian rhythms in mucosal defensive functions are an integral part of normal gastric physiology.     

Isolation from porcine cardiac muscle of a Ca2+-activated protease that partially degrades myofibrils

A protein fraction displaying Ca²⁺-activated proteolytic activity has been isolated from porcine cardiac muscle. The crude enzyme was purified approximately 2000 fold by isoelectric precipitation followed by gel permeation chromatography and by ion exchange chromatography. The partially purified enzyme exhibited optimal activity against either cardiac myofibril or casein substrates between pH 7.5 and 8.0, and in the presence of 1 mm Ca²⁺ and at least 2 mm 2-mercaptoethanol. The enzyme removes Z-discs from skeletal and cardiac myofibrils and also removes the density from intercalated discs of cardiac myofibrils. The enzyme hydrolyzes troponin-T and troponin-I of both cardiac and skeletal muscle myofibrils in vitro. In its proteolytic effect on either cardiac or skeletal myofibrils and in all other properties examined, the Ca²⁺-activated, cardiac protease is similar to a Ca²⁺-activated protease (CAF) recently purified from porcine skeletal muscle (Dayton, W. R., Reville, W. J., Goll, D. E. and Stromer, M. H. (1976) Biochemistry15, 2159–2167). It is possible that the Ca²⁺-activated, cardiac protease plays a role in degradation of myofibrils in injured myocardial cells.     

Myocardial bethanidine kinetics after single-dose intravenous infusion: correlation with plasma kinetics in closed-chest dogs

Myocardial and plasma bethanidine kinetics were determined in five dogs after an intravenous dose of 6 mg/kg/10 min. Serial myocardial drug concentrations were determined from endomyocardial samples obtained by transvenous biopsies between 15 min and 72 h. Tissue and plasma samples were assayed by gas-liquid chromatography. Bethanidine was rapidly concentrated in myocardium within 15 min. Tissue/plasma drug ratios averaged 131 +/- 35 between 15 min and 2 h and 53 +/- 10 between 6 and 48 h. Parallel biexponential decay then occurred for both tissue and plasma compartments; the terminal half-life approximated 16 h. Based on differences in rates of myocardial drug kinetics, the cardiac antifibrillatory effects of bethanidine may occur more rapidly than those of bretylium.