The epidemiological features of invasive mycotic infections in the San Francisco Bay area, 1992-1993: results of population-based laboratory active surveillance

Population-based active laboratory surveillance for invasive mycotic infections was conducted during 1992 and 1993 in three California counties: Alameda, Contra Costa, and San Francisco (population, 2.94 million). The cumulative incidence of invasive mycotic infections was 178.3 per million per year. Invasive mycoses were most commonly caused by Candida (72.8 per million per year), Cryptococcus (65.5), Coccidioides (15.3), Aspergillus (12.4), and Histoplasma (7.1). The clinical significance of other, less common fungi was determined by detailed chart review. The cumulative incidence was determined for zygomycosis (1.7 per million per year), hyalohyphomycosis (1.2), and phaeohyphomycosis (1.0). The most common underlying conditions were human immunodeficiency virus infection (47.4%), nonhematologic malignancy (14.7%), diabetes mellitus (9.9%), and chronic lung disease (9.3%). This represents the first population-based epidemiological assessment of invasive mycoses in the United States.     

High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy

BACKGROUND: In the past 4 years, the weekly 24-hour infusion of high dose 5-fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced gastric carcinoma has been prospectively studied at the authors' institution. This has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of gastric carcinoma to 5-FU-based chemotherapy. METHODS: To be eligible for this study, patients were required to have received high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU, 2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system, which ranged from 0 to 3+, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression. RESULTS: Between 1993 and 1996, a total of 30 patients, 18 men and 12 women, with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and 14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients (12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low expression of TS responded to chemotherapy (P < 0.001, chi-square test). The median overall survival was 10 months for patients with low TS expression and 4 months for patients with high TS expression (P < 0.01, log rank test). CONCLUSIONS: The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.     

Rep*: a viral element that can partially replace the origin of plasmid DNA synthesis of Epstein-Barr virus

Replication of the Epstein-Barr viral (EBV) genome occurs once per cell cycle during latent infection. Similarly, plasmids containing EBV's plasmid origin of replication, oriP, are replicated once per cell cycle. Replication from oriP requires EBV nuclear antigen 1 (EBNA-1) in trans; however, its contributions to this replication are unknown. oriP contains 24 EBNA-1 binding sites; 20 are located within the family of repeats, and 4 are found within the dyad symmetry element. The site of initiation of DNA replication within oriP is at or near the dyad symmetry element. We have identified a plasmid that contains the family of repeats but lacks the dyad symmetry element whose replication can be detected for a limited number of cell cycles. The detection of short-term replication of this plasmid requires EBNA-1 and can be inhibited by a dominant-negative inhibitor of EBNA-1. We have identified two regions within this plasmid which can independently contribute to this replication in the absence of the dyad symmetry element of oriP. One region contains native EBV sequences within the BamHI C fragment of the B95-8 genome of EBV; the other contains sequences within the simian virus 40 genome. We have mapped the region contributing to replication within the EBV sequences to a 298-bp fragment, Rep*. Plasmids which contain three copies of Rep* plus the family of repeats support replication more efficiently than those with one copy, consistent with a stochastic model for the initiation of DNA synthesis. Plasmids with three copies of Rep* also support long-term replication in the presence of EBNA-1. These observations together indicate that the latent origin of replication of EBV is more complex than formerly appreciated; it is a multicomponent origin of which the dyad symmetry element is one efficient component. The experimental approach described here could be used to identify eukaryotic sequences which mediate DNA synthesis, albeit inefficiently.