Clinical and Local Effects of Antacids and Physical Therapy as Shown Gastroscopically

All physicians should be alert to indications of suicidal intent on the part of depressed or mentally ill patients. Hospital personnel generally should also know the importance of immediately reporting unusual behavior on the part of patients. Patients who seem likely to attempt suicide should be hospitalized and carefully supervised. Treatment should not be undertaken at home. Some of the newer antidepressant drugs are effective in treating potentially suicidal patients.     

TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved

The newly identified tripartite motif (TRIM) family of proteins mediate innate immunity and other critical cellular functions. Here we show that TRIM21, which mediates the autoimmune diseases rheumatoid arthritis, systemic lupus erythematosus, and Sjögren''s syndrome, is a previously undescribed IgG receptor with a binding mechanism unlike known mammalian Fcγ receptors. TRIM21 simultaneously targets conserved hot-spot residues on both Ig domains of the Fc fragment using a PRYSPRY domain with a preformed multisite interface. The binding sites on both TRIM21 and Fc are highly conserved to the extent that the proteins are functionally interchangeable through murine, canine, primate, and human species. Pre-steady-state analysis exposes mechanistic conservation at the level of individual residues, which make the same energetic and kinetic contributions to binding despite varying in sequence. Together, our results reveal that TRIM21 is a previously undescribed type of IgG receptor based on a non-Ig scaffold whose interaction at the fundamental level—structural, thermodynamic, and kinetic—is evolutionarily conserved.     

INTERACTION OF THE CARBOHYDRATE-BINDING PROTEIN CONCANAVALIN A WITH NORMAL AND TRANSFORMED CELLS

It has been shown that the carbohydrate-binding protein concanavalin A (ConA) can agglutinate leukemic cells and cells transformed by polyoma virus, simian virus 40, chemical carcinogens, and X-irradiation. This protein did not agglutinate normal cells under the same conditions. The agglutination was reversed by competition with α-methyl-D-glucopyranoside (α-MG), a carbohydrate that strongly binds to ConA, but not by the carbohydrates α-methyl-L-fucopyranoside or N-acetylglucosamine, with no binding or weak binding to ConA. Destruction of the α-MG binding sites of the native protein by removal of bivalent metal ions abolished the agglutination produced by the native protein. The treatment of cells with trypsin resulted in the agglutination of normal cells by ConA and a decrease of agglutinability of transformed cells. When nonagglutinating untransformed 3T3 cells were infected with simian virus 40 and normal rat cells were infected with polyoma virus, the infected cells became agglutinable several days after virus infection. The percentage of cells agglutinated, about 50 per cent, was much higher than the percentage of cells hereditarily transformed. The results indicate that the surface membrane of transformed cells contains sites that interact with the α-MG binding sites of ConA, that such sites can be found on the surface membrane of normal cells after treatment with trypsin, and that the change in the surface structure from normal to transformed occurs in cells that are abortively transformed.     

Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes

BACKGROUND/AIMS: Liver failure is a life threatening condition currently treated by palliative measures and, when applicable, organ transplantation. The use of a bioartificial organ capable of fulfilling the main functions of the liver would represent an attractive alternative. However, the shortage of suitable donor cells, and their limited growth ability have impeded the development of this strategy. We investigated whether lentiviral vectors allow for conditional immortalization of human hepatocytes and whether these immortalized hepatocytes could reverse lethal acute liver failure. METHODS: We exposed primary human hepatocytes to Cre-excisable lentiviral vectors coding for SV40T Antigen, telomerase, and/or Bmi-1 and tested the functionality of the resulting cell lines. Therapeutic potential of immortalized hepatocytes were tested in a murine model of acetaminophen-induced hepatic injury. RESULTS: The immortalized hepatocytes grew continuously yet were non-tumorigenic, stopped proliferating when exposed to Cre recombinase, and conserved defining properties of primary hepatocytes, including the ability to secrete liver-specific proteins and to detoxify drugs. The implantation of encapsulated immortalized human hepatocytes rescued mice from lethal doses of acetaminophen. CONCLUSIONS: Lentiviral vectors represent tools of choice for immortalization of non-dividing primary cells, and lentivirally immortalized human hepatocytes are promising reagents for cell-based therapy of acute liver failure.     

Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma

OBJECTIVE: To study the expression of Toll-like receptor 2 (TLR-2) and TLR-4 and its association with proinflammatory cytokines in synovial tissue from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and healthy individuals. METHODS: Synovial tissue specimens from 29 RA patients were stained for TLR-2, TLR-4, and proinflammatory cytokines (interleukin-1beta [IL-1beta], IL-12, IL-17, IL-18, and tumor necrosis factor alpha [TNFalpha]). The expression of TLR-2, TLR-4, and cytokines as well as the degree of inflammation in synovial tissue were compared between patients with RA, patients with OA (n = 5), and healthy individuals (n = 3). Peripheral blood mononuclear cells (PBMCs) were incubated with IL-12 and IL-18, and TLR expression was assessed using fluorescence-activated cell sorter analysis. Production of TNFalpha and IL-6 was measured using Luminex bead array technology. RESULTS: In RA synovial tissue, the expression of TLR-2 was slightly higher than that of TLR-4. Interestingly, both TLR-2 and TLR-4 were expressed at higher levels in moderately inflamed synovium, as compared with synovial tissue with no or severe inflammation. TLR expression in both the lining and the sublining was associated with the presence of IL-12 and IL-18, but no other cytokines, in the lining. The expression of both TLRs was low in synovial tissue from OA patients and healthy donors. Stimulation of PBMCs with IL-12 and IL-18 resulted in increased expression of both TLR-2 and TLR-4; this could be blocked with anti-interferon-gamma (anti-IFNgamma) antibodies, suggesting a role for IFNgamma. Lipopolysaccharide- or lipoteichoic acid-mediated triggering of PBMCs incubated with IL-12/IL-18 or IFNgamma led to an increased production of both TNFalpha and IL-6, indicating the functionality of TLR-2 and TLR-4. CONCLUSION: TLR-2 and TLR-4 are expressed in synovial tissue of patients with clinically active disease and are associated with the levels of both IL-12 and IL-18. The synergistic effect of IL-12 and IL-18 on T cell IFNgamma production seems to regulate expression of TLR-2 and TLR-4 in the synovial tissue of RA patients.