Aspirin treatment of patients with aspirin intolerance, asthma, and nasal polyps.

Patients with the triad of aspirin (ASA) intolerance, asthma, and nasal polyps present a clinical challenge for the allergist because their polyps generally are refractory to traditional treatments and their asthmatic symptoms may become more difficult to control with time. These patients can be desensitized and treated with ASA with subsequent improvement in their nasal and respiratory symptoms. This article describes one such individual and briefly reviews the literature regarding this triad. The diagnosis of ASA intolerance, mechanistic studies, a desensitization protocol, and new therapies are reviewed.

Drug interactions affecting the efficacy of corticosteroid therapy a brief review with an illustrative case.

A drug interaction that seemed to contribute to sudden worsening of corticosteroid-stabilized vasculitis stimulated this review. A large number of drugs share with corticosteroids critical phase I metabolic steps mediated by hepatic cytochrome P450 (CYP) enzymes, particularly the individual enzyme CYP3A4. In their metabolic interaction with CYP3A4 as substrates, a growing number of these drugs have the potential to induce (upregulate) hepatic CYP3A4 levels, resulting in accelerated clearance (and reduced efficacy) of concomitantly administered glucocorticoids, which are also CYP3A4 substrates. Many other drugs can have the opposite effect, that is, they can inhibit CYP3A4 function by tight binding to its active site. This can result in reduced clearance (and augmented efficacy) of concurrently administered glucocorticoids. Current knowledge of this type of drug interaction, the drugs to watch out for, and multiple clinical reports of altered corticosteroid efficacy, are reviewed after presentation of the case illustrating potential relevance to the management of rheumatic diseases.

Tumor-specific cell surface expression of the-KDEL containing, endoplasmic reticular heat shock protein gp96.

Heat shock protein (HSP) gp96/grp94 contains a signal peptide at the amino terminus and a -KDEL sequence at the carboxy terminus and is a major component of the lumen of the mammalian endoplasmic reticulum (ER). We show, by a number of immunolocalization methods using light and electron microscopy, that a significant proportion of intact gp96 molecules is also expressed on the cell surface. Surface gp96 molecules truly represent surface expression and do not result from adventitious deposition of gp96 released by dead cells on to the live cells in culture. Cell surface expression of gp96 is enhanced by heat shock and exposure to reducing agents. Gp96 molecules are not released from plasma membranes by repeated salt washes, and gp96 is not an integral membrane protein. Our observations suggest that gp96 and perhaps other HSPs are anchored to the cell surface as part of larger molecular complexes, which also transport them to the cell surface.

Molecular heterogeneity of tumor rejection antigen/heat shock protein GP96.

Glycoproteins of 96 kDa (gp96) have been shown to mediate tumor-specific immunogenicity of a number of murine sarcomas. The purity of gp96 preparations used in these studies was originally demonstrated by their homogeneity on silver-stained gels and the observation that a single amino acid terminus was detected by micro-sequencing. Results reported here show that gp96 preparations consist of 3-4 closely spaced bands. However, each of the bands is recognized by well-characterized monoclonal or monospecific antibodies to gp96. We have obtained purified preparations of a slowly migrating 110-kDa and a faster migrating 96-kDa band of the gp96 cluster from the Meth A sarcoma and have observed both species to be immunogenic in a dose-restricted manner. In addition to the size-based heterogeneity, purified 96-kDa molecules are found to contain 2 major populations, which share the same amino and carboxy termini but differ in the region recognized by an anti-grp94 monoclonal antibody (MAb). The heterogeneity in gp96 preparations does not result from differences in glycosylation but may result from differential phosphorylation, conformation or the antigenic peptides associated with gp96. It has been suggested that the tumor-specific immunogenicity of gp96 preparations does not derive from gp96 but from a 110-kDa protein which co-purifies with gp96 and is distinct from it. Our observations show instead that the presence of a number of bands in purified gp96 preparations is due to heterogeneity within gp96 molecules rather than to contamination with unrelated proteins.