Publications

Progressive multifocal leukoencephalopathy (PML), a rare neurological disease, has been sporadically reported in persons infected with human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). From January 1981 through February 1989, in San Francisco, we identified 94 HIV-infected persons with PML, of whom 48 (51%) were pathologically confirmed (as required for AIDS case reporting). These 48 patients were significantly older when diagnosed with AIDS (20% older than 50 years) than patients with AIDS without PML. The remaining 46 (49%) patients, diagnosed clinically and by neuroimaging, did not differ significantly from definitive patients in demographic or survival characteristics after PML diagnosis. We detected antibodies to JC virus, the causative agent of PML, in 9 of 14 (64%) AIDS-related patients with PML, and in 9 of 14 (64%) matched control subjects, suggesting that determination of JC virus antibody status before AIDS diagnosis does not reliably indicate which patients will contract PML. Our study shows that the proportion of patients with AIDS who contracted PML remained stable between 1981 and 1988, but increased in the first 2 months of 1989. Our findings further indicate that PML in HIV-infected patients may be underestimated by as much as 50%.

Kappa B (kappa B) enhancer binding proteins isolated from the nuclei of activated human T cells produce two distinct nucleoprotein complexes when incubated with the kappa B element from the interleukin-2 receptor-alpha (IL-2R alpha) gene. These two DNA-protein complexes are composed of at least four host proteins (p50, p55, p75, p85), each of which shares structural similarity with the v-rel oncogene product. Nuclear expression of these proteins is induced with distinctly biphasic kinetics following phorbol ester activation of T cells (p55/p75 early and p50/p85 late). DNA-protein crosslinking studies have revealed that the more rapidly migrating B2 complex contains both p50 and p55 while the more slowly migrating B1 complex is composed of p50, p55, p75, and p85. Site-directed mutagenesis of the wild-type IL-2R alpha kappa B enhancer (GGGGAATCTCCC) has revealed that the binding of p50 and p55 (B2 complex) is particularly sensitive to alteration of the 5' triplet of deoxyguanosine residues. In contrast, formation of the B1 complex, reflecting the binding of p75 and p85, critically depends upon the more 3' sequences of this enhancer element. DNA binding by all four of these Rel-related factors is blocked by selective chemical modification of lysine and arginine residues, suggesting that both of these basic amino acids are required for binding to the kappa B element. Similarly, covalent modification of free sulfhydryl groups with diamide (reversible) or N-ethylmaleimide (irreversible) results in a complete loss of DNA binding activity. In contrast, mild oxidation with glucose oxidase selectively inhibits p75 and p85 binding while not blocking p50 and p55 interactions. These findings suggest that reduced cysteine thiols play an important role in the DNA binding activity of this family of Rel-related transcription factors.

Although the efficacy of long-term administration of antithrombotic agents in unstable angina has been established, short-term effects on myocardial ischemia are unknown. A retrospective analysis was performed in 47 patients undergoing three-channel continuous ST segment monitoring as part of a multicenter trial using esmolol in unstable angina, in which 20 patients received a continuous heparin infusion during the initial assessment of chest pain. Concomitant medications included calcium channel blockers, beta-adrenergic blockers, nitrates, and aspirin in the majority of patients. Clinical variables between the heparin and no heparin groups were similar, except for fewer males and fewer total artery occlusions in the heparin group. No significant differences in the incidence or duration of ischemia were found in a 36 +/- 16 hour monitoring period. Forty percent of the heparin group had 35 episodes of ischemia with a mean of 11 +/- 10 minutes per episode and a total ischemic time of 48 +/- 39 minutes per patient with ischemia. Forty-four percent of the no heparin group had 47 episodes of ischemia with a mean of 13 +/- 13 minutes per episode and a total ischemic time of 58 +/- 47 minutes per patient with ischemia. Multiple linear regression analysis to adjust for intergroup differences did not alter the results. Eighty-five percent of all episodes were asymptomatic. Clinical events, such as episodes of chest pain, emergency coronary arteriography, or coronary revascularization, were also similar between groups. Thus the short-term administration of heparin did not alter the incidence or duration of ischemia in patients with unstable angina.(ABSTRACT TRUNCATED AT 250 WORDS)