A model for decision support in signal triage.

Spontaneous reporting of suspected adverse drug reactions (ADRs) has long been a cornerstone of pharmacovigilance. With the increasingly large volume of ADRs, regulatory agencies, scientific/academic organizations and marketing authorization holders have applied statistical tools to assist in signal detection by identifying disproportionate reporting relationships in spontaneous reporting databases. These tools have generated large numbers of signals defined as drug-ADR reporting associations that meet specified statistical criteria.

Transcriptional activation of Alzheimer's beta-amyloid precursor protein gene by stress.

A neuropathological hallmark of Alzheimer's disease (AD) is the neuritic plaque, composed of an extracellular cluster of degenerating nerve terminals with a central core that is in part composed of deposits of a 4 kDa beta-amyloid peptide. Over-expression of the amyloid precursor protein (beta-APP) gene could be a contributing factor in the aberrant processing of the precursor protein, possibly leading to the formation of beta-amyloid. In AD the brain exhibits several features which indicate that neurons affected by AD exist under conditions of stress.

A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene.

Overexpression of the beta-amyloid precursor protein gene (beta-APP) may contribute to the abnormal generation of beta-amyloid protein in Alzheimer's disease. We demonstrate using a human glial cell line (1321N1) that activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) increases beta-APP mRNA levels, induces known components of the transcription factor activator protein-1 (AP-1), and increases protein-DNA binding activity to AP-1 sequences within the beta-APP promoter. A beta-APP promoter-luciferase reporter gene is transcriptionally activated by PMA, as well as by expression of constitutively activated PKC or by expression of c-Jun.

Cyclophilin-40, a protein with homology to the P59 component of the steroid receptor complex. Cloning of the cDNA and further characterization.

We have reported previously the isolation and preliminary characterization of a 40-kDa cyclosporin A (CsA)-binding protein, cyclophilin-40 (CyP-40). To determine the sequence of this protein, degenerate oligonucleotide primers based on bovine brain CyP-40 tryptic peptides were used to generate a polymerase chain reaction fragment of CyP-40 cDNA. This was used to isolate the complete cDNA from a human pancreatic islet cell library.