Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis.

An all oral treatment for cryptococcal meningitis is attractive, particularly where amphotericin B use is impractical. Both fluconazole and flucytosine are available in oral formulations and have activity against Cryptococcus neoformans. We conducted a prospective phase II dose escalation study employing doses of fluconazole ranging from 800 to 2000 mg daily for 10 weeks used alone or combined with flucytosine at 100 mg/kg per day for the first 4 weeks. We found that increasing doses of fluconazole were associated with an increase in survival and a decrease in the time to conversion of the cerebrospinal fluid from culture positive to culture negative. Addition of flucytosine to fluconazole improved outcomes in each dosing cohort. High doses of fluconazole alone or combined with flucytosine were well tolerated.

Milk of nonhuman origin and infectious diseases in humans.

Milk and milk products from domestic animals, which are potential infectious hazards, are made more so by modern milk production, because milk from thousands of animals is often pooled prior to bottling or before manufacturing derivative products. Thus, contaminated milk from 1 animal can result in a widespread problem. Pasteurization largely eliminates this hazard. Most disease transmission caused by contamination of the milk supply has been eliminated by hygienic production measures and pasteurization. However, contamination may occur after pasteurization, and no process works perfectly all of the time. Despite scientific opinion that pasteurized products are safer than raw ones--and are equally nutritious--segments of the population regard raw milk products as more nutritious and better tasting than pasteurized milk products. Thus, low levels of raw milk consumption persist in the United States and other developed nations. Occasional milk-associated disease outbreaks caused by raw milk consumption or by breakdowns in the proper production of pasteurized products still occur.

Relevance of peptide avidity to the T cell receptor for cytomegalovirus-specific ex vivo CD8 T cell cytotoxicity.

CD8(+) T cells contribute to the control of viral infection by several effector mechanisms, including lysis of virally infected cells and interferon (IFN)-gamma secretion. Ex vivo cytotoxicity and potent secretion of IFN-gamma in response to cytomegalovirus (CMV) epitope peptides was seen in freshly prepared unstimulated peripheral blood mononuclear cells from human immunodeficiency virus-infected patients with high T cell receptor (TCR)/peptide avidity. Lymphocytes with low TCR/peptide avidity had no ex vivo cytotoxicity, secreted minimal IFN-gamma, and could not recognize autologous infected targets. Despite this, ex vivo responding and nonresponding patients had substantial frequencies of tetramer-positive and IFN-gamma-secreting lymphocytes. Levels of activation and memory markers were also similar in tetramer-positive populations of both groups. However, cytolytic capacity remained in nonresponders; their lymphocytes regained cytotoxicity after in vitro stimulation with peptide without coactivators or interleukin-2. High-avidity CD8(+) T cells are likely important in viral control, and their generation should be a goal of therapeutic vaccination.

Relative dominance of HLA-B*07 restricted CD8+ T-lymphocyte immune responses to human cytomegalovirus pp65 in persons sharing HLA-A*02 and HLA-B*07 alleles.

CD8(+) T-cell responses to three human cytomegalovirus (CMV) pp65 epitopes were studied in panels of healthy seropositive HLA-A*02/HLA-B*07 individuals, and HLA-A*02 donors mismatched for HLA-B*07. The majority of the latter had significant responses to a HLA-A*02-restricted epitope within the CMV pp65 antigen. By contrast, the strongest responses to CMV in the first group were to HLA-B*07-restricted epitopes. Similar immunodominance of HLA-B*07 over HLA-A*02 was found in two immunocompromised HIV-infected HLA-A*02/HLA-B*07 patients, and in the reconstituting immune system of three stem cell transplant recipients. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from two immunocompetent HLA-A*02/HLA-B*07 individuals indicated that cytotoxic T lymphocyte (CTL) precursors specific for both HLA-A*02 and HLA-B*07 restricted epitopes were present and could be expanded by stimulation with the cognate peptides. However, if stimulation was performed by antigen presenting cells infected with recombinant vaccinia expressing full-length native pp65, only HLA-B*07 epitope-specific cells were seen. In one patient the HLA-B*07 dominance was partially broken by using recombinant vaccinia expressing ubiquitinated pp65, suggesting that enhanced protein processing can reveal weaker immune responses. Our results indicate that CMV-specific cellular immune responses restricted by HLA-B*07 dominate those restricted by HLA-A*02 in both immunocompetent and immunocompromised individuals. This may have significant consequences for the design of epitope-specific vaccines.

1963 epidemic of poliomyelitis in Barbados, West indies

From March 23 through June 19, 1963, 68 cases of paralytic poliomyelitis occurred in Barbados, the island's first epidemic in 30 years. Poliovirus type I was isolated from three patients with paralyic disease. The age distribution of the patients, with illness concentrated in the 0-5 age group, was typical of that usually encountered in a developing tropical country. Only one case occurred in a member of the upper socioeconomics groups, perhaps reflecting the use of inactivated poliovirus vaccine by this segment of the population. Enterovirus carriage studies on June 4 and 5, near the peak of the epodemic, showed that 6 of 46 (13 percent) well children aged 1-3 years harbored type I poliovirus, indicating moderately widespread seeding of this agent in small children. Concomitant studies of antibody prevalence in serums from 22 of these children revealed that 55 percent lacked antibodies to poliovirus type I. The epidemic terminated abruptly within 6 days of a mass feeding of oral poliovirus vaccine in which some 27 percent of the 0-5 year-olds were fed within a 3-day period. It is believed that the mass vaccine feeding was instrumental in effecting an early termination of the epidemic (AU)