A new role for the p85-phosphatidylinositol 3-kinase regulatory subunit linking FRAP to p70 S6 kinase activation.

The serine/threonine kinase p70 S6 kinase (p70S6K) phosphorylates the 40 S ribosomal protein S6, modulating the translation of an mRNA subset that encodes ribosomal proteins and translation elongation factors. p70S6K is activated in response to mitogenic stimuli and is required for progression through the G(1) phase of the cell cycle and for cell growth. Activation of p70S6K is regulated by phosphorylation of seven different residues distributed throughout the protein, a subset of which depends on the activity of p85/p110 phosphatidylinositol 3-kinase (PI3K); in fact, the phosphorylation status of Thr(229) and Thr(389) is intimately linked to PI3K activity.

[Practice Guidelines of the Spanish Society of Cardiology for the management of cardiac disease in pregnancy].

Maternal adaptation to pregnancy includes reproductive hormone interaction plasma, volume changes with an increase in total body water, vascular alterations with a decrease in systemic resistance and modifications associated with hypercoagulability. These explain, in part, the appearance of signs and symptoms, even in a normal pregnant woman, that are difficult to distinguish from those occurring in heart disease and why some cardiac abnormalities are not well tolerated during pregnancy. Cardiovascular abnormalities are considered the first non-obstetric cause of morbidity and mortality during pregnancy.

[Congenital coronary fistula to right ventricle. Treatment with transcatheter coil embolization].

We report the case of a 3 year old girl with a congenital right coronary artery-right ventricle fistula demonstrated by two dimensional echocardiography with color-flow Doppler and cardiac catheterization and angiography. The treatment was percutaneous transcatheter embolization by two detachable coils (7 mm x 20 cm and 6 mm x 20 cm) with successful complete occlusion. There were no complications.

The identification of phosphatidylinositol 3,5-bisphosphate in T-lymphocytes and its regulation by interleukin-2.

In recent times 3-phosphoinositides have emerged as important regulators of cell metabolism, survival, and proliferation. During the last year, the phospholipid phosphatidylinositol 3, 5-bisphosphate (PtdIns3,5P2) was identified in yeast, fibroblasts, SV40-transformed kidney (COS-7) cells, and platelets. The discovery of this novel phospholipid has increased the complexity of the metabolism relating to the generation of biologically active inositol-containing lipids.

Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase.

p85/p110 phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85-regulatory and a p110-catalytic subunit, which is involved in a variety of cellular responses including cytoskeletal organization, cell survival and proliferation. We describe here the cloning and characterization of p65-PI3K, a mutant of the regulatory subunit of PI3K, which includes the initial 571 residues of the wild type p85alpha-protein linked to a region conserved in the eph tyrosine kinase receptor family. We demonstrate that this mutation, obtained from a transformed cell, unlike previously engineered mutations of the regulatory subunit, induces the constitutive activation of PI3K and contributes to cellular transformation.

Nitric oxide regulates clonal expansion and activation-induced cell death triggered by staphylococcal enterotoxin B.

Increased interest has recently been focused on nitric oxide (NO) due to its several biological roles. Apart from being a potential antimicrobial defense and a mediator of autoimmune diseases, NO also appears to be a strong mediator of T-cell responses. In this report, we have characterized the effect of NO on T-cell function.

Lck is necessary and sufficient for Fas-ligand expression and apoptotic cell death in mature cycling T cells.

Apoptotic cell death is induced in mature cycling T cells upon ligation of the Ag-specific TCR. This process is essential for the maintenance of homeostasis in the immune system, as it is capable of down-regulating ongoing immune responses. The analysis of the mechanism underlying TCR-induced programmed cell death has focused the attention of many scientists recently.

Linomide administration to mice attenuates the induction of nitric oxide synthase elicited by lipopolysaccharide-activated macrophages and prevents nephritis in MRL/Mp-lpr/lpr mice.

Nitric oxide is involved as a messenger molecule in a large number of physiologic and pathologic responses. Local generation of high nitric oxide output through the expression of the calcium-independent, cytokine-inducible form of nitric oxide synthase (iNOS) can result in either protective or damaging effects. The development of drugs that specifically suppress iNOS expression or inhibit its activity may therefore provide an excellent therapeutic tool for treatment of a diverse set of dysfunctions, including asthma, inflammatory processes, and autoimmune disease.

Polyethylene glycol-modified IL-2 abrogates superantigen-induced anergy without affecting peripheral clonal deletion in vivo.

As compared with the native molecule, recombinant human interleukin-2 that is modified by covalently attached polyethylene glycol residues (IL-2-PEG) exhibits a markedly enhanced half-life in vivo, thus facilitating its biological evaluation. We have characterized the effect of IL-2-PEG on the Staphylococcus aureus enterotoxin B (SEB)-induced tolerance of peripheral SEB-reactive (V beta 8+) T cells. Treatment with sublethal doses of IL-2-PEG does not modulate (inhibit or enhance) the SEB-triggered apoptosis and deletion of V beta 8+ T cells.

Differential involvement of Th1 and Th2 cytokines in autoimmune diseases.

By virtue of their functional antagonism, Th1 cells or cells producing the same cytokines as Th1 cells may behave as "suppressor cells' with respect to Th2 cells and vice versa. An excessive Th1- or Th2-like response may favor the development of different autoimmune diseases. As can be expected from their physiological role, Th-1 cytokines participate in autoimmune diseases with a preferential delayed type hypersensitivity component, i.

Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo.

Chlorpromazine (CPZ) has potent immunomodulatory effects in vivo; it induces humoral autoimmunity in up to 50% of patients, inhibits delayed-type hypersensitivity reactions, and suppresses lethal immune hyperactivation in animal models of septic shock. Here, we show that in an in vivo model of acute superantigen-driven immune activation, CPZ independently down-regulates the production of various T cell-derived lymphokines (IL-2, IFN-gamma, IL-4, TNF, and GM-CSF) and up-regulates the secretion of IL-10. Whereas only low, if any, serum IL-10 levels are detectable by ELISA after injection of CPZ, bacterial LPS, or staphylococcal enterotoxin B (SEB) alone, simultaneous administration of CPZ + LPS or CPZ + SEB causes a significant increase in IL-10 production in vivo.

Pertussis toxin interferes with superantigen-induced deletion of peripheral T cells without affecting T cell activation in vivo. Inhibition of deletion and associated programmed cell death depends on ADP-ribosyltransferase activity.

Intravenous injection of a bacterial superantigen such as Staphylococcus aureus enterotoxin B (SEB) causes transient activation and expansion of SEB-reactive V beta 8+ T cells, as well as specific down-regulation of the immune response, through partial deletion of superantigen-reactive T cells. Here we demonstrate that co-administration of pertussis toxin (PTX) and SEB reduces the SEB-induced deletion of V beta 8+ T cells, although it does not affect T cell activation and proliferation. PTX abrogates the SEB-driven deletion of V beta 8+CD4+ (not V beta 8+CD8+) splenocytes that is observed early (12-24 h) after SEB injection.

Differential in vivo effects of a superantigen and an antibody targeted to the same T cell receptor. Activation-induced cell death vs passive macrophage-dependent deletion.

Superantigens have multiple pleiotropic effects in vivo, causing the activation, proliferation, and deletion of specific T cells. In our study, we analyzed the effects of the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) on peripheral T cells in vivo. As an internal control we took advantage of a IgG2a mAb, F23.

Linomide inhibits programmed cell death of peripheral T cells in vivo.

Programmed cell death (PCD) is involved in the physiological regulation of lymphocyte turnover, as well in the antigen-driven selection of T and B cells. Here it is shown that the immunomodulator linomide (quinoline-3-carboxamide) inhibits the apoptotic decay of peripheral T lymphocytes in response to three different stimuli. First, linomide reduces the superantigen-mediated apoptosis and deletion of specific T lymphocytes of both the CD4+ and the CD8+ subsets without affecting other superantigen-triggered phenomena such as T cell expansion and anergy.

Linomide, a novel immunomodulator that prevents death in four models of septic shock.

Intravenous injections of 50 micrograms Staphylococcus aureus enterotoxin B (SEB) or bacterial lipopolysaccharide (LPS) are lethal, provided that mice are simultaneously sensitized with either N-galactosamine (GalN) or the anti-glucocorticoid RU-38486. Similar to the synthetic glucocorticoid (GC) receptor agonist dexamethasone, pharmacological doses of the immunomodulator linomide (quinoline-3-carboxamide) prevent death in all four models of lethal septic shock (LPS + GalN, LPS + RU-38486, SEB + GalN, and SEB + RU-38486) and inhibit the secretion of tumor necrosis factor, one of the major intermediate effector molecules of SEB and LPS toxicity. In this system, cyclosporine A (CsA), although effective in suppressing SEB toxicity, fails to counteract the lethal effect of LPS.

Glucocorticoid-mediated control of the activation and clonal deletion of peripheral T cells in vivo.

Poly- and oligoclonal T cell stimuli like anti-CD3 epsilon monoclonal antibody or Staphylococcus aureus enterotoxin B (SEB), injected at doses that per se are not lethal, provoke acute death within less than 24 h, provided that endogenous glucocorticoids (GC) are depleted by adrenalectomy or by injection of saturating amounts of the GC receptor antagonist RU-38486 (mifepristone). Pharmacological doses of the GC agonist dexamethasone (DEX) alter the in vivo response of splenic V beta 8+ T cells to SEB, thus impeding the expansion of such cells and causing their rapid (3 d) clonal deletion. In contrast, coadministration of RU-38486 counteracts a SEB-induced early (12 h) reduction of V beta 8+CD4+ and V beta 8+CD8+ spleen cells.

[Mucinous carcinoma of the breast. An analysis of 12 cases].

From 1975 to 1985 we review 12 cases of mucinous carcinoma of the breast in the "Hospital Civil de Guadalajara" and we found: one in the male sex and 11 in female. The mean age was 53 years 4 (36.3%) were nulliparas, the period between the star of symptomatology and the treatment was of 3 months to 6 years, 50% were in the upperexternal quadrant, the size was of 2 to 20 cm; 5 were pure mucinous and 7 mixed (with ductal invasive carcinoma), metastasis were presenting 9 patients and the treatment utilized in the majority of the cases was the radical mastectomy.

[Miniplates in the treatment of mandibular fractures].

We present in this paper the treatment of mandibule fractures with miniplates of titanium. The miniplates have provided stable fixation and compared with other techniques improved in all concepts. The complication rates have been very low: there were not infections.

Hemodynamic effect of dextran, dobutamine, and pericardiocentesis in cardiac tamponade secondary to subacute heart rupture.

Seventeen patients with acute myocardial infarction and tamponade after subacute ventricular free-wall rupture were treated with dextran, dobutamine, and pericardiocentesis before definitive surgical repair. In all of the patients the diagnosis was confirmed anatomically. Dextran (200 to 900 ml), administered to 10 patients, induced a significant increase in systolic blood pressure, cardiac index, stroke index, right atrial pressure, and pulmonary capillary pressure.