Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, including inflammatory epithelial cells. NO has been detected in the exhaled air of normal human subjects, and its concentration is raised in asthmatic patients. To study whether exhaled NO arises from the respiratory tract, we administered a NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), by inhalation (490 mg) in a double-blind randomized manner in nine normal and six asthmatic subjects. Because exhaled NO may arise from an inducible isoform of NO synthase that may be inhibited by glucocorticosteroids, we also studied the effects of oral prednisolone (30 mg orally for 3 d) in seven normal and six asthmatic subjects in a separate double-blind crossover study with matched placebo. After nebulized L-NMMA, there was a significant fall in peak exhaled NO compared with saline control values, with a mean fall of 43.6 +/- 5.6% in normal subjects (p < 0.01) and of 39.7 +/- 6.5% (p < 0.01) in asthmatic subjects, which persisted for 4 h. There were no effects of L-NMMA inhalation on heart rate, blood pressure, or FEV1 in either normal or asthmatic patients. Administration of oral prednisolone (30 mg) resulted in a fall in exhaled NO concentrations in asthmatic subjects by 21.6 +/- 5.0% at 48 h (p < 0.01) but no significant change in normal subjects. These data suggest that NOS inhibitors may be safely given in normal and asthmatic patients and that the increased exhaled NO seen in asthmatic patients is likely to be caused by induction of inducible NOS.     

The mammalian Y chromosome: a new perspective

If pityriasis lichenoides et varioliformis acuta (PLAVA) exists in the vagina or cervical os of the uterus, it may cause premature labor and premature rupture of the membranes.     

Flow cytometric assay of modulation of P-glycoprotein function in whole blood by the multidrug resistance inhibitor GG918

Galactose-1-phosphate uridyl transferase (GALT) deficiency causes classical galactosemia in humans. Mice deficient in this enzyme were created by gene targeting. GALT-deficient mice develop biochemical features similar to those seen in humans with GALT deficiency, but fail to develop the pattern of acute toxicity seen in newborns with classical galactosemia. This study suggests that alternative routes of galactose metabolism are important in the pathogenesis of galactosemia.     

CTLA4Ig inhibits alloantibody responses to repeated blood transfusions

Allosensitization is a fundamental problem that limits the effectiveness of blood transfusions. Patients who receive multiple transfusions of blood or blood components frequently develop alloantibodies against donor alloantigens. Allosensitized patients are refractory to further transfusion and difficult to transplant successfully. CTLA4Ig fusion protein, which blocks the CD28-B7 costimulatory pathway in T-lymphocyte activation, was tested for its capacity to inhibit allosensitization to blood transfusions. Groups of LEW (RT1') rats were transfused with ACI blood (RT1a) together with L6 (a human immunoglobulin G1 [IgG1] antibody as isotype control) or CTLA4Ig in different doses (0.004, 0.02, 0.1, and 0.5 mg). Rats were retransfused with ACI blood after 28 and 84 days without any additional CTLA4Ig therapy. Weekly sera samples were tested for alloantibody against donor leukocytes using flow cytometry. CTLA4Ig caused a dose-dependent decrease in the IgM alloantibody response against donor major histocompatibility complex (MHC) class I antigens. In addition, 0.02-, 0.1-, and 0.50-mg doses of CTLA4Ig totally inhibited the IgG responses to the first transfusion, and this immunosuppressive effect persisted for the second and third transfusions. To study the capacity of CTLA4Ig to prevent a secondary immune response, three groups of LEW rats were transfused with ACI blood with no accompanying treatment. Animals were retransfused 28 days later with ACI blood together with L6 control antibody or 0.5 or 2.5 mg CTLA4Ig. CTLA4Ig, but not L6, prevented an increase in IgG alloantibody response despite repeated transfusions. The effects of CTLA4Ig treatment on helper T-lymphocyte proliferation was tested by limiting dilution analysis (LDA). Peripheral blood cells taken 30 days after blood transfusion and CTLA4Ig treatment contained significantly decreased donor-specific T-lymphocyte precursors compared with L6-treated rats. These data support the idea that blocking the B7/CD28 signal of T-lymphocyte activation by CTLA4Ig treatment at the time of transfusion may be an important therapeutic tool to inhibit alloantibody responses to blood transfusions.