A complementarity-determining region peptide of an anti-desmosome autoantibody may interact with the desmosomal plaque through molecular mimicry with a cytoplasmic desmoglein 1 sequence

The sera of patients with pemphigus, a group of autoimmune blistering skin diseases, contain autoantibodies directed against components of adhering junctions termed desmosomes. F12, a human monoclonal antibody derived from a pemphigus patient, recognizes an unknown polypeptide of the desmosomal and hemidesmosomal plaques. The third complementarity-determining region of the F12 heavy chain (VH-CDR3) was shown to share a four-amino-acid sequence (GSSG) with the intracellular domains of desmoglein 1 and bullous pemphigoid antigen 2 which interact with components of, respectively, the desmosomal and hemidesmosomal plaques. Computer modeling of F12 showed that the GSSG sequence protudes inside the antigen-combining site and thus might be involved in antigen interactions. The GSSG sequence is essential to F12 function, since a peptide containing the VH-CDR3 inhibited its binding to target antigens while VH-CDR3 peptides with specific modifications of the GSSG sequence did not. These data allow us to hypothesize that certain autoantibodies produced during the course of an autoimmune disease can behave as adhesion molecules, through the molecular mimicry of the motif involved in protein/protein adhesion, and to propose a new self-antigen binding mechanism for some autoantibodies.     

Quantification of in-plane motion of the coronary arteries during the cardiac cycle: Implications for acquisition window duration for MR flow quantification

Motion of the coronary arteries during the heart cycle can result in image blurring and inaccurate flow quantification by MR. This condition applies particularly for longer acquisition windows that are typical of breath-hold coronary flow measurements. To determine the sensitivity of the technique to in-plane motion of different coronary arteries, the temporal variation in coronary position was measured in a plane perpendicular to the proximal portion of the vessel. The results indicated the presence of substantial displacement of the coronary arteries within the cardiac cycle, with a magnitude of motion approximately twice as large for the right as for the left coronary arteries. An estimation of the resulting vessel blurring was calculated, showing that the duration of the acquisition window for high spatial resolution coronary flow acquisitions should be less than 25 to 120 msec, depending on the specific coronary artery studied. In addition, these data specify optimal acquisition window placement for high resolution coronary angiography.     

Evaluating the accuracy of using population pharmacokinetic data to predict plasma concentrations of alfentanil

A major reason for quantitating the relationship of drug dose to plasma concentration is to design optimal drug administration schemes (i.e., those that can achieve desired target concentrations of a drug). Recently, the authors completed a population pharmacokinetic analysis of the new opioid alfentanil using the computer program NONMEM. This analysis quantified the effects of age, weight, and sex on disposition of alfentanil in 45 patients, and determined the average pharmacokinetic profile of the drug for the group. Using these population pharmacokinetic parameters, one can predict (estimate) the plasma concentration time course of alfentanil for any given dosage scheme. The present study evaluated the accuracy with which one could use these population data to predict plasma concentrations of alfentanil in a different group of surgical patients given iv boluses and a variable-rate infusion of alfentanil for induction and maintenance of anesthesia for abdominal and superficial surgery. A total of 597 plasma concentrations of alfentanil were measured for 19 patients. For each measured concentration, we used the population pharmacokinetic parameters obtained previously with NONMEM to calculate a predicted concentration. Accuracy and precision of the prediction were assessed by the mean bias of the prediction and by the mean absolute prediction error, respectively. The mean bias (+/- SE) (systematic over- or underprediction) was -7.9 +/- 5.2%. The mean absolute error (+/- SE), a measure of the precision, was 22.3 +/- 2.9%. Therefore, the authors' previously described population pharmacokinetic parameters for alfentanil appear to be "robust," and can be used to design computerized schemes for administration of alfentanil for general surgery.     

Research fellowship in behavioral AIDS research

Announcement

Research fellowship in behavioral AIDS research     

Synergistic action of immunostimulatory DNA and fcgamma receptor IIB-crosslinking on B-cell phenotype and function

CpG DNA functions via the toll-like receptor-9 (TLR-9) receptor, inducing B cell proliferation and promoting immunoglobulin production. B cell responses to CpG DNA-containing immune complexes could be important in chronic autoimmunity and immune responses to bacterial components. Therefore, we investigated the potential synergy of CpG DNA-stimulation with FcgammaR clustering (CFR) on splenic B cell activity. CFR-induced splenocyte proliferation was significantly increased compared to treatment with CpG DNA alone. While the levels of interleukin-10 (IL-10) were increased in CpG DNA-treated splenocyte cultures, particularly following FcgammaRII/III-clustering, CFR treatment reduced IL-6 levels. B-cell maturation in culture was enhanced by CFR. Indeed, the frequency of IgG expressing cells after stimulation with CpG DNA was increased and was even higher after CFR stimulation. Furthermore, the frequency of plasma cell precursors was markedly increased by stimulation with CFR. Late splenic B cell subsets, transitional type 2 (T2) and mature (M) B cells, responded strongly to CpG DNA with proliferation and the response was enhanced by FcgammaR-clustering. Immature transitional type 1 (T1) B cells showed distinctly lower proliferative response to CpG DNA and very small effects of FcgammaR-clustering, despite similar expression of Fcgamma-receptors by all B cell subsets. In conclusion, these data show synergistic impact of CpG DNA and simultaneous FcgammaR-clustering on B cell proliferation and differentiation.