[Successful treatment of a patient with a history of pancreatic necrosis and severe multi-organ insufficiency].
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Adult↗
Biomedical subjects
A V Nikolaev
Publications and source records attributed to A V Nikolaev.
An efficient and stereoselective synthesis of beta-D-Arap-(1-->2)-beta-D-Galp-(1-->3)-beta-D-Galp-(1-->4)-alpha-D-Manp, a tetrasaccharide fragment of Leishmania major lipophosphoglycan.
A tetrasaccharide fragment of Leishmania major lipophosphoglycan (which seems to be involved in a biological mechanism for the parasite transmission) has been synthesised using the thioglycoside, trichloroacetimidate and halide-exchange glycosylation procedures and step-wise chain elongation strategy.
Animals↗
[Anatomic resection of spleen in experiment].
The study was carried out in 35 dogs. Basic surgical techniques developed experimentally for organ-saving operations on the spleen are presented. Methods of lobar and segmental resections of the spleen based on detailed study of variants of branching of splenic artery and vein are described. Angiography visualized sharply splenic arteries after lobar and segmental resections, including the stumps of transected arteries. Ultrasonic examination, performed before operation and in different terms after it (3-360 days), specified the size, shape echostructure and anatomic relationship of the spleen with adjacent organs before and after operation.
Anastomosis, Surgical↗
Theory of distinct crystal structures of polymerized fullerides AC60, A = K, Rb, Cs: the specific role of alkalis.
The polymer phases of AC60 form distinct crystal structures characterized by the mutual orientations of the (C( -)(60))(n) chains. We show that the direct electric quadrupole interaction between chains always favors the orthorhombic structure Pmnn with alternating chain orientations. However, the specific quadrupolar polarizability of the alkali metal ions leads to an indirect interchain coupling which favors the monoclinic structure I2/m with equal chain orientations. The competition between direct and indirect interactions explains the structural difference between KC60 and RbC60, CsC60.
Journal Article↗
Characterization of the elongating alpha-D-mannosyl phosphate transferase from three species of Leishmania using synthetic acceptor substrate analogues.
Leishmania express lipophosphoglycans and proteophosphoglycans that contain Galbeta1-4Manalpha1-P phosphosaccharide repeat structures assembled by the sequential addition of Manalpha1-P and betaGal. The synthetic acceptor substrate Galbeta1-4Manalpha1-P-decenyl and a series of analogues were used to probe Leishmania alpha-D-mannosyl phosphate transferase activity. We show that the activity detected with Galbeta1-4Manalpha1-P-decenyl is the elongating alpha-D-mannosyl phosphate transferase associated with lipophosphoglycan biosynthesis (eMPT(LPG)). Differences in the apparent K(m) values for the donor and acceptor substrates were found using L. major, L. mexicana, and L. donovani promastigote membranes, but total activity correlated with the number of lipophosphoglycan repeats. Further comparisons showed that lesion-derived L. mexicana amastigotes, that do not express lipophosphoglycan, lack eMPT(LPG) and that nondividing L. major metacyclic promastigotes contain 5-fold less eMPT(LPG) activity than dividing procyclic promastigotes. The fine specificity of promastigote eMPT(LPG) activity was determined using 24 synthetic analogues of Galbeta1-4Manalpha1-P-decenyl. The three species gave similar results: the negative charge of the phosphodiester and the C-6 hydroxyl of the alphaMan residue are essential for substrate recognition, the latter most likely acting as a hydrogen bond acceptor. The C-6' hydroxyl of the betaGal residue is required for substrate recognition as well as for catalysis. The rate of Manalpha1-P transfer declines with increasing acceptor substrate chain length. The presence of a monosaccharide substituent at the C-3 position of the terminal betaGal residue abrogates Man-P transfer, showing that chain elongation must precede side chain modification during lipophosphoglycan biosynthesis. In contrast, substitution of the penultimate phosphosaccharide repeat does not abrogate transfer but is slightly stimulatory in L. mexicana and inhibitory in L. major.
Amino Acid Sequence↗
C-reactive protein binds to phosphorylated carbohydrates.
C-reactive protein (CRP) is a major acute phase protein in man. In order to more fully understand the physiological role of this serum protein, we have demonstrated high avidity binding for a defined chemically synthesized carbo-hydrate ligand which represents the repeating disaccharide of lipophosphoglycan, the major surface glycoconjugate of the unicellular parasite Leishmania donovani. Increasing the number of phosphorylated disaccharides in a molecule from one up to seven did not increase the avidity for CRP, however increasing this to 10 potential CRP binding sites did. In order to define the important features of this complex and variable structure for CRP binding we competed CRP binding to whole Leishmania parasites with amino, sulfated, phosphorylated, and unsubstituted monosaccharides, of which only phosphorylated monosaccharides were able to inhibit. Both the carbohydrate and the position of phosphorylation influenced the avidity for CRP. Synthetic oligosaccharides and phospho-oligosaccharides of various lengths and conformations were used to define the structural requirements for CRP recognition. The optimum structure for recognition of a single phosphate group was between two monosaccharide pyranose rings, and within a linear rather than a cyclic molecule. This stresses the importance of the interaction of the CRP binding site with both the carbohydrate and the phosphate group. CRP function may be mediated via the recognition of large arrays of phosphorylated carbohydrates as are characteristic of the surface of microorganisms.
C-Reactive Protein↗
Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase.
Macrophage activation by cytokines or microbial products such as LPS results in the induction and release of several key immune effector molecules including NO and IL-12. These have been shown to play crucial roles in the development of immunity to intracellular pathogens such as Leishmania. The molecular mechanisms underlying the induction of these effector molecules are not fully understood. We now show that the extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases play differential roles in the regulation of LPS-stimulated inducible NO synthase and IL-12 gene expression. In macrophages, LPS stimulates the simultaneous activation of all three classes of MAP kinases, ERK, c-jun N-terminal kinase, and p38, albeit with differential activation kinetics. However, studies using inhibitors selective for ERK (PD98059) and p38 (SB203580) show that while p38 plays an essential role in the induction of inducible NO synthase, ERK MAP kinases play only a minor role in promoting NO generation. In contrast, while p38 promotes induction of IL-12 (p40) mRNA, ERK activation suppresses LPS-mediated IL-12 transcription. The biological relevance of these regulatory signals is demonstrated by our finding that Leishmania lipophosphoglycans, which promote parasite survival, act by stimulating ERK MAP kinase to inhibit macrophage IL-12 production. Thus, as ERK and p38 MAP kinases differentially regulate the induction of the macrophage effector molecules, inducible NO synthase and IL-12, these kinases are potential targets not only for the development of novel strategies to combat intracellular pathogens but also for therapeutic immunomodulation.
Animals↗
Regulation of the miniature plasma membrane Ca(2+) channel I(min) by inositol 1,4,5-trisphosphate receptors.
I(min) is a plasma membrane-located, Ca(2+)-selective channel that is activated by store depletion and regulated by inositol 1,4, 5-trisphosphate (IP(3)). In the present work we examined the coupling between I(min) and IP(3) receptors in excised plasma membrane patches from A431 cells. I(min) was recorded in cell-attached mode and the patches were excised into medium containing IP(3). In about 50% of experiments excision caused the loss of activation of I(min) by IP(3.) In the remaining patches activation of I(min) by IP(3) was lost upon extensive washes of the patch surface. The ability of IP(3) to activate I(min) was restored by treating the patches with rat cerebellar microsomes reach in IP(3) receptors but not by control forebrain microsomes. The re-activated I(min) had the same kinetic properties as I(min) when it is activated by Ca(2+)-mobilizing agonists in intact cells and by IP(3) in excised plasma membrane patches and it was inhibited by the I(crac) inhibitor SKF95365. We propose that I(min) is a form of I(crac) and is gated by IP(3) receptors.
Animals↗
Regulation of macrophage IL-12 synthesis by Leishmania phosphoglycans.
It is now generally accepted that IFN-gamma, secreted by Th1 cells, is the most potent cytokine leading to macrophage activation and host resistance against infection with the intracellular protozoan parasite Leishmania. It is also established that IL-12 is a critical cytokine involved in the differentiation and expansion of Th1 cells. Therefore, the ability of Leishmania parasites to actively suppress IL-12 production by host macrophages may be an important strategy for parasite survival. Here we report that a major parasite cell surface molecule, phosphoglycan (PG), of Leishmania could selectively inhibit the synthesis of IL-12(p40, p70) by activated murine macrophages. Furthermore, synthetic PG (sPG) was able to inhibit IL-12 release in a dose-dependent manner. Inhibition was dependent on the galactose(beta1-4)mannose(alpha1)-PO4 repeating units and not the glycophosphoinositol lipid anchor of lipophosphoglycan. At the concentration used, sPG had no effect on the release of TNF-alpha or IL-6 in activated macrophages. The inhibition of IL-12(p40) production was at the transcriptional level, but was not mediated through NF kappaB inhibition. These data demonstrate that PG may be an important molecule for the establishment and survival of the parasite in permissive hosts.
Animals↗
The preparation of neoglycoconjugates containing inter-saccharide phosphodiester linkages as potential anti-Leishmania vaccines.
The Leishmania express complex glycoconjugates containing phosphosaccharide repeat units at all stages of their life-cycle. One of these molecules, lipophosphoglycan (LPG) has been suggested to be a vaccine candidate. To assess the immunological properties of Leishmania phosphosaccharides, we have prepared neoglycoproteins and neoglycolipids containing synthetic Leishmania phosphosaccharide repeats. The coupling procedure uses the dec-9-enyl spacer of previously synthesised phosphosaccharides for linkage to protein and phospholipid. This alkene moiety is converted by ozonolysis to an aldehyde which is then attached to protein and phospholipid amino groups by reductive amination. The procedure produces neoglycoconjugates in good yield and without compromising the labile phosphodiester linkages within the phosphosaccharide chains.
Animals↗
[Preoperative thermoradiotherapy in the combined treatment of rectal tumors is the inferior ampullar segmentŏ].
Data on the examination of 260 radically-treated patients with rectal tumors in the inferior ampullar segment are presented. 107 patients received surgery alone, another 75--preoperative radiotherapy, while still another 78--preoperative thermoradiotherapy. Combined treatment of stage III tumors significantly reduced recurrence incidence and was followed by significant increase in recurrence-free survival rates. In cases of tumor disseminated to the regional lymph nodes, recurrence-free survival was observed after preoperative thermoradiation only.
Adult↗
[K+]out accelerates inactivation of Shal-channels responsible for A-current in rat CA1 neurons.
Somato-dendritic subthreshold transient potassium current [I(SA)] was measured in acutely isolated rat hippocampal CA1 pyramidal neurons. The inactivation of this current was insensitive to externally applied H2O2 (20 mM) which causes cysteine oxidation. This result suggests that Shal-channels not Shaker Kv1.4 channels underlie the somato-dendritic I(SA) in rat CA1 pyramidal neurons. The kinetics of the I(SA) inactivation was measured at various [K+]out. Increase in [K+]out leads to acceleration of Shal-channel inactivation. Thus, the shift in [K+]out from 1 to 50 mM results in decreased inactivation time constant from 37 to 19 ms. This effect of [K+]out on the I(SA) is opposite to the previously described action of [K+]out on the inactivation of Shaker K+ channels.
Animals↗
[Growth of stable clones of mouse fibroblast cell line C3H10T1/2 expressing the human retinoblastoma gene product].
Phosphorylation and dephosphorylation of the retinoblastoma gene product (pRB) are recognized as necessary events in the cell cycle progression. To study the role of pRB in regulation of cell proliferation, the stable cell lines with constitutive expression of the exogenous RB gene can be employed. In order to obtain such cell lines in this work C3H10T1/2 mouse fibroblasts were infected with defective retrovirus encompassing the RB and Neo gene conferring resistance to geniticine (G418). The pRB production and its phosphorylation pattern were analyzed by immunoblotting in cell lysates considering well known data on correlation between pRB phosphorylation pattern and its electrophoretic mobility. Cell lines subjected to G418 selection with the following cloning procedure were identical to the control cells expressing beta-galactosidase, when compared for pRB production and phosphorylation in the cell cycle stages characterized by hyperphosphorylated pRB. However, cells of the experimental cell lines hypophosphorylated pRB much faster and accumulated much more underphosphorylated protein compared to the control cell lines. The doubling time of the cells was not affected either by changes in the pRB phosphorylation pattern or by its overproduction during separate cell cycle stages. These results suggest that maintaining of the physiological level of pRB phosphorylation in cycling cells is strictly controlled and is considered to be a more important condition of the cell cycle progression than pRB dephosphorylation.
3T3 Cells↗
[Adjuvant radiotherapy in the combined treatment of rectal cancer].
Radiotherapy was given postoperatively to 37 out of 81 patients with metastases into the regional lymph nodes (stage C after Dukes) to prevent relapse. All the patients had undergone radical surgery. No significant decrease in relapse incidence could be achieved unless an absorbed dose of 40 Gy was received postoperatively. However, combined treatment failed to produce a significant rise in five-year survival due to deaths from distant metastases.
Combined Modality Therapy↗
Synthetic phospho-oligosaccharide fragments of lipophosphoglycan as acceptors for Leishmania major alpha-D-mannosylphosphate transferase.
Protozoan parasites of the genus Leishmania synthesise lipophosphoglycans, phosphoglycans and proteophosphoglycans that contain phosphosaccharide-repeat units of [-6Gal beta 1-4Man alpha 1-P-]. In this study, a GDP-Man-dependent alpha-mannosylphosphate-transferase activity was detected in washed Leishmania major membranes using synthetic phospho-oligosaccharide fragments of lipophosphoglycan as acceptor substrates. The divalent-cation-dependent alpha-mannosylphosphate-transferase activity had an apparent K(m) for GDP-Man of about 15-20 microM and a pH optimum of 7.0. The activity showed a requirement for a non-reducing terminal beta Gal residue and for one or more phosphodiester units preceding the acceptor site. Based on these results, the activity may be defined as a GDP-Man: Gal beta 1-4Man alpha 1-P-R alpha-mannosylphosphate-transferase. This acceptor specificity is consistent with a role for the alpha-mannosylphosphate transferase in the elongation of phosphosaccharide-repeat domains of Leishmania glycoconjugates rather than in the priming of these domains. An identical or similar activity must exist in the amastigote forms of the Leishmania that produce and secrete proteophosphoglycan material and the activity therefore represents a feasible target for the development of chemotherapeutics.
Animals↗
Regulation of the expression of nitric oxide synthase and leishmanicidal activity by glycoconjugates of Leishmania lipophosphoglycan in murine macrophages.
Lipophosphoglycan (LPG) glycoconjugates from promastigotes of Leishmania were not able to induce the expression of the cytokine-inducible nitric oxide synthase (iNOS) by the murine macrophage cell line, J774. However, they synergize with interferon gamma to stimulate the macrophages to express high levels of iNOS. This synergistic effect was critically time-dependent. Preincubation of J774 cells with the LPG glycans 4-18 h before stimulation with interferon gamma resulted in a significant reduction in the expression of iNOS mRNA and of NO synthesis, compared with cells preincubated with culture medium alone. The regulatory effect on the induction of iNOS by LPG is located in the LPG phosphoglycan disaccharide backbone. Synthetic fragments of this backbone had a similar regulatory effect on NO synthesis. Further, the production of NO by activated macrophages in the present system was correlated directly with the leishmanicidal capacity of the cells. These data therefore demonstrate that LPG glycoconjugates have a profound effect on the survival of Leishmania parasites through their ability to regulate the expression of iNOS by macrophages.
Animals↗
[Repair of the wounded and resected kidney surface by the flap of musculus obliques externus abdominus (experimental study)].
The experimental studies in 15 human cadavers and 15 animals (dogs) have been performed to test the use of the flap musculus obliques externus abdominis in plastic repair of wound and resected kidney surface. The vascular and nervous bundle of the muscle has been detected. It is easy to mobilise the muscle, that has good hemostatic, fixing, and plastic properties. Morphological tests of the flap demonstrated no signs of necrosis. There were no changes in kidney parenchyma either.
Abdominal Muscles↗
The chemical synthesis of Leishmania donovani phosphoglycan via polycondensation of a glycobiosyl hydrogenphosphonate monomer.
A polycondensation of 2,3,6-tri-O-benzoyl-4-O-(2,3,4-tri-O-benzoyl-beta-D-galactopyranosyl)-al pha-D-mannopyranosyl hydrogenphosphonate in the presence of trimethylacetyl chloride has been used to synthesize a linear poly[beta-D-galactopyranosyl-(1-->4)-alpha-D-mannopyranosyl phosphate] representing the phosphoglycan part of the lipophosphoglycan from Leishmania donovani.
Animals↗