Publications

Between 1978 and 1980, 359 hepatitis B seronegative homosexual and bisexual men were recruited from the San Francisco municipal sexually transmitted disease clinic for hepatitis B vaccine trials. Of the 359 participants, 320 (89%) consented to have their stored blood samples tested for human immunodeficiency virus antibodies. The prevalence of human immunodeficiency virus infection in these 320 vaccine trial participants rose from 0.3% in 1978 to 50.9% in 1988. The annual incidence of human immunodeficiency virus infection showed that seroconversion peaked in 1980-1982, dropped significantly in 1983, and has remained low. Men less than 30 years old on entry into the study seroconverted earlier in the epidemic and had higher incidence rates than men 30 years or older (p = 0.07). No statistical difference in seroconversion rates was found for other demographic variables. Using a Kaplan-Meier survival curve of the cumulative proportion of men without acquired immunodeficiency syndrome by duration of human immunodeficiency virus infection, an estimated 39% (95% confidence interval 27%-51%) will develop acquired immunodeficiency syndrome within 9.2 years of infection. Cox proportional hazard stepwise analysis showed no correlation between age at seroconversion, race, or year of seroconversion and progression to acquired immunodeficiency syndrome.

Recent changes in the patient population of teaching hospitals, spurred by technologic advances and economic forces, have jeopardized the traditional hospital-based model of residency training. In consequence, there has been increasing attention paid to the need for ambulatory care experience. A primary force in shaping the content of postgraduate medical education is "The Essentials of Accredited Residencies," published in the Directory of Graduate Medical Education Programs. We reviewed recommendations and requirements for ambulatory settings and outpatient experience as specified in the Directory during the years 1961 to 1988 and investigated pending changes in requirements for five major specialties: internal medicine, pediatrics, family practice, general surgery, and obstetrics and gynecology. Increases in the amount of time residents spend in ambulatory care training recently have been mandated in internal medicine and are under consideration in two other specialties, indicating probable major shifts in the locus of postgraduate medical training.

The type 1 human immunodeficiency virus (HIV-1) encodes a 27-kDa protein termed Nef (negative factor). Nef has been reported to down-regulate viral gene transcription directed by the HIV-1 long terminal repeat. To assess the possible role of Nef in the initiation or maintenance of viral latency, we prepared two different nef expression vectors (pNEF from the HXB-3 proviral clone; pNEF-2/3 from HXB-2 and HXB-3) and a control vector containing a frameshift mutation in the HXB-3 nef coding sequence (pNEF-fs). Consistent with prior studies, the Nef proteins produced by pNEF and pNEF-2/3 were approximately 27 kDa in size, posttranslationally modified by myristoylation, and primarily associated with cytoplasmic membrane structures. However, in contrast to previous reports, these Nef proteins failed to inhibit transcriptional activity of the HIV-1 long terminal repeat in any of a variety of cell types, including primary human T lymphocytes, Jurkat or YT-1 leukemic T cells, U-937 promonocytic cells, and nonlymphoid COS cells. Furthermore, HXB-3 proviral clones of HIV-1 containing either a wild-type or mutated version of the nef gene replicated in an indistinguishable manner when transfected into COS cells. Our findings suggest that Nef is neither a transcriptional inhibitor nor a negative viral factor under these assay conditions. Rather, we suggest that the primary biological function of this conserved HIV-1 protein has yet to be defined, perhaps reflecting an intrinsic shortcoming in the in vitro experimental systems presently available for the study of HIV-1.

Asymptomatic myocardial ischemia likely results from an imbalance between myocardial oxygen supply and demand. Although changes in coronary vasomotor tone probably are important in the genesis of asymptomatic ischemia, heart rate increases also play a critical role. Consequently, all three classes of antianginal agents, nitrates, beta-blockers, and calcium entry blockers, have been shown efficacious as monotherapy for silent ischemia. Comparative studies have demonstrated that agents or combination therapies that control heart rate increases during normal activities are superior to regimens that increase average heart rate. Consideration of the side-effect profile of any therapy for asymptomatic patients also is important. The ideal therapy would be with one drug that reduced coronary vasomotor tone and myocardial oxygen demand during normal activities and had no adverse effects. Currently, the calcium entry blockers, diltiazem and verapamil, most closely approximate this ideal. It has yet to be proven, however, that the treatment of asymptomatic myocardial ischemia improves the prognosis of patients with coronary artery disease, and the risk-benefit ratio of pharmacological therapy is not established.