, 5 and the LJP 394-90-09 Investigator ConsortiumObjective. To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-doublestranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare.Methods. We conducted a randomized, placebocontrolled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat ( Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced >50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P ‫؍‬ 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated.Conclusion. Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.There is a substantial body of evidence implicating anti-double-stranded DNA (anti-dsDNA) antibodies in the pathogenesis of lupus nephritis. Anti-dsDNA antibodies are rarely found in individuals without SLE (1-4), and their presence is diagnostic for SLE and prognostic for development of lupus nephritis. The presence of anti-dsDNA antibodies often correlates with active renal disease (5-8). Anti-dsDNA antibodies are concentrated in the kidneys of SLE patients and often have a much higher avidity for dsDNA than do antibodies in the circulation (9,10). Well-controlled studies have demonstrated a strong correlation between rises in anti-dsDNA antibody levels and subsequent exacerbations of . Similarly, reductions in antiClinicalTrials.gov identifier: NCT00035308.

To determine whether complement turnover in synovial fluids of patients with rheumatoid arthritis (RA) reflects activation by the classical or alternative pathway, we used novel immunoassays to measure products of complement activation (the membrane attack complex SCSb-9 and the cleavage fragments Bb and C4d). Mean synovial fluid levels of SC5b-9 were more than 8 times higher in RA than in crystal-induced arthritis (gout and pseudogout) and over 16 times higher than in degenerative joint disease (D JD). Similarly, Bb levels were more than 3 times higher in RA synovial fluids than in crystal-induced arthritis and over 7 times higher than in DJD. Levels of C4d did not differ among the groups. SC5b-9 levels correlated with synovial fluid C3 anaphylatoxin (C3a), Bb, and C4d levels (r = 0.81, 0.62, and 0.51, respectively). In patients with RA, synovial fluid SC5b-9 levels correlated with C3a and Bb (r = 0.6 and 0.56, respectively) but not with C4d.Therefore, novel assays for complement activation indicate that both classical and alternative pathways are involved in complement turnover and that the alternative pathway contributes more to complement activation in RA than in DJD or crystal-induced arthritis.Proteolytic cleavage of the third component of complement (C3) links the two different paths of

Cefoperazone was compared with penicillin against Streptococcus pneumoniae, gentamicin against Escherichia coli, and ampicillin and chloramphenicol against Haemophilus influenzae in the therapy of experimental meningitis in rabbits. Meningitis was produced by intracistemal inoculation into cerebrospinal fluid, and all antibiotics were administered intravenously over 8 h in dosages that would achieve serum levels comparable to those found in humans. The mean percent penetration into purulent cerebrospinal fluid, expressed as (cerebrospinal fluid concentration/serum concentration) x 100%o, was 2.6% for penicillin, 22.0% for gentamicin, 12.1% for ampicillin, 23.8% for chloramphenicol, and 6.4% for cefoperazone. The mean cerebrospinal fluid antibiotic concentrations exceeded the minimum bactericidal concentration for the test strain in each experimental model, except for ampicillin in experimental meningitis due to the P-lactamaseproducing H. influenzae. Cefoperazone produced a significantly faster bactericidal effect after 4 h of treatment when compared with penicillin (P = 0.037) and ampicillin (P = 0.01) in meningitis caused by S. pneumoniae and H. influenzae (ampicillin susceptible), respectively. In meningitis caused by E. coli, cefoperazone was significantly (P = 0.006) more rapidly bactericidal after 8 h of treatment when compared to gentamicin. In addition, cefoperazone was significantly more rapidly bactericidal than either ampicillin or chloramphenicol in experimental meningitis due to P-lactamase-producing H. influenzae. Cefoperazone deserves further evaluation in the therapy of bacterial meningitis in humans.

The influence of methylprednisolone on the passage of ampicillin and gentamicin into and activity within cerebrospinal fluid was examined in two models of experimental meningitis. Steroid pretreatment reduced the concentrations of these drugs in purulent cerebrospinal fluid of rabbits with experimental pneumococcal and Escherichia coli meningitis (P < 0.05). However, the resultant mean concentrations of these antibiotics in cerebrospinal fluid still exceeded the minimal bactericidal concentrations of the infecting organisms. The rate of bactericidal effect in vivo was unaffected by steroid therapy in each model. Methylprednisolone did not have deleterious effects on the course of treated experimental meningitis under these short-term (24-h) experiments.

The influence of preformed antibody on the induction of experimental Candida albicans endocarditis was investigated by both in vitro and in vivo techniques. Preincubation of C. albicans with immune serum (raised in rabbits by intravenous injection of Formalin-killed yeast cells) decreased adhesion to the constituents of nonbacterial thrombotic endocarditis, e.g., fibrin plus platelets, in vitro. Two different methods, with radiolabeled or viable yeast cells, were confirmatory and demonstrated decreased adhesion of immune serum-treated C. albicans cells to 0 to 7.8% of control values (P < 0.001). These results correlated with protection from the development of C. albicans endocarditis in the immunized rabbits. The mean (± standard deviation) infectious dose for 50% of the animals was 105.29 + 100.07 in 48 control animals versus 107.11 + 100.22 in 37 immunized rabbits (P < 0.001). These studies suggest that humoral antibody may protect against C. albicans endocarditis, perhaps through inhibition of adhesion, a crucial early step in the pathogenesis of endocarditis. Bacterial adhesion to fibrin and platelets, the forms were observed adherent to the traumaticonstitutents of nonbacterial thrombotic endo-cally induced aortic valve vegetations (comcarditis, is an important step in the pathogenesis posed of fibrin and platelets) within 30 min of of infective endocarditis. The relative frequency intravenous inoculation (2, 7). Various Candida of bacterial isolates in endocarditis cases correspecies differ in their ability to adhere to fibrinlates directly with the ability of these species to platelet surfaces in vitro; adherence correlates adhere to heart valves in vitro. Production of directly with the production of endocarditis in extracellular dextran by viridans streptococci experimental animals (34). These observations promotes adhesion to artificial fibrin-platelet suggest that differences in yeast adhesion to matrices (35) or damaged canine cardiac valve fibrin-platelet deposits may explain the relative tissue in vitro. In addition, anti-whole cell anti-frequency of isolation of Candida species in serum to Streptococcus sanguis decreases adhe-endocarditis cases. However, the role of antision to fibrin-platelet surfaces in vitro, which body in this interaction is unknown. Preliminary correlates directly with protection from endo-observations suggested that anti-yeast cell wall carditis development due to this organism in antibody decreases adhesion of C. albicans to preimmunized rabbits in vivo (36). fibrin-platelet surfaces (21, 22), similar to results Fungal endocarditis is increasing in frequency obtained with S. sanguis (36). These issues were and usually appears in three clinical settings: addressed further in the present experiments. after prosthetic valvular insertion, in intrave-The purpose of this study was to determine the nous drug abusers, and as a complication of influence of preformed anti-whole cell antibody prolonged intravenous antibiotic administration on yeast adhesion to the constitutents of nono...