Antigen presenting cell function in HIV-1 infected patients

Antigen presenting cell (APC) function is central to the activation of anti-viral cytotoxic T-cells and antibody production. In previous studies we have evaluated APC function in HIV-1 infected patients as the capacity to present peptide to a well defined panel of CD4 T-cell clones. We found that APC from HIV-1 infected patients were defective in the capacity to present peptide to CD4 T-cell clones. The APC defect uncovered by this method was present early in infection and worsened with increasing viral load, suggesting that it was an important determinant of progression and anti-viral efficacy. The CD4 T-cell clones were, however, found to vary in their susceptibility to the APC defect. CD4 T-cell clones that failed to respond to peptide presented by HIV + APC were 1000-fold more readily inhibited by anti-CD4 antibody than T-cell clones which consistently responded to APC from patients infected with HIV-1 (HIV + APC). An intermediate group of T-cell clones were also identified that only responded to peptide and HIV + APC from asymptomatic patients. These results suggested that the underlying mechanism for the APC defect was binding of T-cell CD4 by APC-associated gp120. In this paper we discuss the evidence to support this hypothesis.     

Mammographic Screening Downstages Breast Carcinomas at Time of Diagnosis: A Community-Based Experience

Abstract: To determine the effectiveness of screening mammography in a community medical setting, data from a population-based, retrospective study was analyzed. Medical records of 827 patients with newly diagnosed breast cancer in California between October 1994 and March 1996 were reviewed. The primary care physician's record was abstracted for clinical history, including recommendation of screening mammography. The facility records where final diagnosis was made were abstracted for stage and treatment data. Among the patients who did not have previous screening mammography, 65.7% were diagnosed with "advanced" breast cancer (stages II, III, IV), while only 39.9% who had previous screening mammography were diagnosed with advanced breast cancer (p < 0.001). This study has reaffirmed that screening mammography of adult females generates downstaging at the time of diagnosis of breast cancer. Despite possession of a health insurance program and receiving educational materials, only 65% of patients over 50 years of age had screening mammography. As opposed to the once-a-year mailing of general reminders to all women 40 years old and older, developing a longitudinal electronic medical record in the managed care setting will support a more coordinated and individualized intervention based on age, date of last mammogram, and relative risk, among other factors. Continuing education efforts must also be directed to referring physicians, who may not yet recognize the value of screening mammography.     

Ventromedial prefrontal cortex mediates guessing

Guessing is an important component of everyday cognition. The present study examined the neural substrates of guessing using a simple card-playing task in conjunction with functional magnetic resonance imaging (fMRI). Subjects were scanned under four conditions. In two, they were shown images of the back of a playing card and had to guess either the colour or the suit of the card. In the other two they were shown the face of a card and had to report either the colour or the suit. Guessing compared to reporting was associated with significant activations in lateral prefrontal cortex (right more than left), right orbitofrontal cortex, anterior cingulate, bilateral inferior parietal cortex and right thalamus. Increasing the guessing demands by manipulating the number of alternative outcomes was associated with activation of the left lateral and medial orbitofrontal cortex. These data suggest that while simple two choice guessing depends on an extensive neural system including regions of the right lateral prefrontal cortex, activation of orbitofrontal cortex increases as the probabilistic contingencies become more complex. Guessing thus involves not only systems implicated in working memory processes but also depends upon orbitofrontal cortex. This region is not typically activated in working memory tasks and its activation may reflect additional requirements of dealing with uncertainty.     

Anti-inflammatory activity of c(ILDV-NH(CH2)5CO), a novel, selective, cyclic peptide inhibitor of VLA-4-mediated cell adhesion.

1. Small, N- to C-terminal cyclized peptides containing the leucyl-aspartyl-valine (LDV) motif from fibronectin connecting segment-1 (CS-1) have been investigated for their effects on the adhesion of human T-lymphoblastic leukaemia cells (MOLT-4) to human plasma fibronectin in vitro mediated by the integrin Very Late Antigen (VLA)-4 (alpha4beta1, CD49d/CD29). 2. Cyclo(-isoleucyl-leucyl-aspartyl-valyl-aminohexanoyl-) (c(ILDV-NH(CH2)5CO)) was approximately 5 fold more potent (IC50 3.6+/-0.44 microM) than the 25-amino acid linear CS-1 peptide. Cyclic peptides containing two more or one less methylene groups had similar potency to c(ILDV-NH(CH2)5CO) while a compound containing three less methylene groups, c(ILDV-NH(CH2)2CO), was inactive at 100 microM. 3. c(ILDV-NH(CH2)5CO) had little effect on cell adhesion mediated by two other integrins, VLA-5 (alpha5,beta1, CD49e/CD29) (K562 cell adhesion to fibronectin) or Leukocyte Function Associated molecule-1 (LFA-1, alphabeta2, CD11a/CD18) (U937 cell adhesion to Chinese hamster ovary cells transfected with intercellular adhesion molecule-1) at concentrations up to 300 microM. 4. c(ILDV-NH(CH2)5CO) inhibited ovalbumin delayed-type hypersensitivity or oxazolone contact hypersensitivity in Balb/c mice when dosed continuously from subcutaneous osmotic mini-pumps (0.1-10 mg kg(-1) day(-1)). Maximum inhibition (approximately 40%) was similar to that caused by the monoclonal antibody PS/2 (7.5 mg kg(-1) i.v.) directed against the alpha4 integrin subunit. 5. c(ILDV-NH(CH2)5CO) also inhibited oxazolone contact hypersensitivity when dosed intravenously 20 h after oxazolone challenge (1-10 mg kg(-1)). Ear swelling was reduced at 3 h and 4 h but not at 1 h and 2 h post-dose (10 mg kg(-1)). 6. Small molecule VLA-4 inhibitors derived from c(ILDV-NH(CH2)5CO) may be useful as anti-inflammatory agents.     

Chimaeric G alpha proteins: their potential use in drug discovery

Approaches that allow ligand occupancy of a wide range of G protein-coupled receptors to be converted into robust assays amenable to relatively high-throughput analysis are ideal for screening for novel ligands at this class of receptor. Many attempts have been made to design universal ligand-screening systems such that any GPCR can be screened using a common assay end-point. Manipulation of the G protein within the assay system offers the possibility of achieving this. To better understand the domains involved in the interactions between G protein-coupled receptors, G proteins and effector polypeptides and the fine details of these contacts, a wide range of chimaeric G protein alpha subunits have been produced. Graeme Milligan and Stephen Rees discuss the information generated by such studies and the ways in which such chimaeric G proteins can be integrated into assay systems for drug discovery.