Effective use of ribonucleotide reductase inhibitors (Didox and Trimidox) alone or in combination with didanosine (ddI) to suppress disease progression and increase survival in murine acquired immunodeficiency syndrome (MAIDS)

Ribonucleotide reductase inhibitors (RRIs) have been recently shown to inhibit retroviral replication. We examined a new series of RRIs, 3,4-dihydroxybenzohydroxamic acid (Didox) and 3,4,5-trihydroxybenzohydroxamidoxime (Trimidox) for their ability to alter disease progression in murine acquired immunodeficiency syndrome (MAIDS), both alone and in combination with 2',3'-dideoxyinosine (ddI). MAIDS disease was induced by inoculation of female C57BL/6 mice with the LP-BM5 murine leukemia virus (MuLV) and disease progression characterized by extensive peripheral lymphadenopathy and splenomegaly. Efficacy of treatment with these drugs was based upon their ability to influence survival and disease pathophysiology by monitoring the development of splenomegaly. Toxicity was determined by changes in body weight, total peripheral white blood cell count and hematocrit. Didox or trimidox monotherapy was associated with increased survival and decreased disease pathophysiology, with no apparent toxicity. Combined with ddI, their ability to reduce development of viral induced splenomegaly was enhanced compared to trimidox, didox or ddI alone. These results demonstrate RRIs have potent activity in reversing the disease manifestations characteristic of MAIDS. Further studies are warranted to determine human clinical efficacy.     

Effects of midazolam on the differentiation of murine myeloid leukemia cells

The effects of midazolam (MID) on the in vitro growth and differentiation of two murine myeloid leukemia WEHI 3B (JCS) and M1 cells were studied. MID inhibits the proliferation of both M1 and JCS cells in a dose-dependent manner. At the concentration of 10 micrograms/ml, MID was found to induce both monocytic and granulocytic differentiation of the JCS but not M1 cells. Induction of morphological differentiation of the JCS cells was also associated with the enhanced expression of the differentiation antigens Mac-1, F4/80, and Gr-1 for the cells. Results from mRNA phenotyping experiments also indicated that the expression of tumor necrosis factor (TNF-alpha) and neutrophil-specific J11d differentiation marker was significantly upregulated in MID-treated JCS cells. In addition, the phagocytic activity of MID-treated JCS cells was increased towards opsonized yeast cells. Results from this investigation suggested that MID may be used as an inducer for further study on the mechanisms of differentiation in these myeloid leukemia cells.     

The characteristics of the causative agents of suppurative-inflammatory complications in hemophiliacs

Morphological-cultural and physiological-biochemical properties of 24 strains of microorganisms agents of pyo-inflammatory complications of different localization in patients with hemophilia have been studied. Microorganisms strains presented by the following species: Staphylococcus aureus, S. epidermidis, S. saprophyticus, Proteus vulgaris, P. morganii, Hafnia alvei, Serratia marcescens, have been identified. It was found out that in monoculture staphylococci prove to be the leading etiological agent (60.9%), gram-negative enterobacteria (52.2%) and bacterial associations (8.7%) occur more rarely. Special attention was paid to the study of resistance of antibiotics, circulation and pathogenicity factors that had a direct effect on the main disease severity. It was ascertained that high activity of enzymes and presence of pathogenicity factors were the peculiarities of microorganisms isolated from pyo-septic sites in patients with hemophilia. All the strains possessed multiple resistance to antibiotics.     

POEMS syndrome: an unusual cause of bilateral optic disk swelling

Four cases of acute ileal diverticulitis are presented wherein early diagnosis helped avoid emergent surgery. All patients did well initially with conservative medical management. Acute ileal diverticulitis, although uncommon, should be suspected when the clinical presentation indicates an inflammatory condition of the lower right abdomen. Surgery, when required for recurrent disease, can be reserved for the interval between acute episodes.     

Non-anticoagulant heparin increases endothelial nitric oxide synthase activity: role of inhibitory guanine nucleotide proteins

Heparin, which is widely used clinically, has recently been shown to have specific properties affecting the vascular endothelium. We hypothesized that heparin stimulates endothelial nitric oxide synthase (eNOS) activity by a mechanism independent of its anticoagulant properties and dependent on an inhibitory guanine nucleotide regulatory protein (Gi). We determined the effect of both heparin and N-acetyl heparin (Non-Hep), a heparin derivative without anticoagulant properties, on eNOS activity in cultured bovine aortic endothelial cells and on endothelium-dependent relaxation in isolated vascular rings. The eNOS activity was determined by measuring both citrulline and nitric oxide (NO) metabolite formation. Heparin and Non-Hep dose-dependently increased basal eNOS activity (ED50 1.0 microgram/ml or 0.15 U/ml), an effect that was significantly inhibited by pertussis toxin (100 ng/ml), a Gi-protein inhibitor. Agonist-stimulated (acetylcholine, 10 microM) eNOS activity was potentiated following pre-treatment with both heparin and Non-Hep and reversed by pertussis toxin. Heparin and Non-Hep induced a dose-dependent relaxation in preconstricted thoracic aortic rings, an effect that was significantly inhibited by pertussis toxin, endothelial inactivation (following treatment with sodium deoxycholate) and NG-nitro-L-arginine-methyl ester (L-NAME). We conclude that heparin and non-anticoagulant heparin induce endothelium-dependent relaxation following activation of eNOS by a mechanism involving a Gi-protein. Administration of heparin derivatives without anticoagulant properties may have therapeutic implications for the preservation of eNOS in conditions characterized by endothelial dysfunction.