An evaluation of computer-aided disproportionality analysis for post-marketing signal detection.

To understand the value of computer-aided disproportionality analysis (DA) in relation to current pharmacovigilance signal detection methods, four products were retrospectively evaluated by applying an empirical Bayes method to Merck's post-marketing safety database. Findings were compared with the prior detection of labeled post-marketing adverse events. Disproportionality ratios (empirical Bayes geometric mean lower 95% bounds for the posterior distribution (EBGM05)) were generated for product-event pairs. Overall (1993-2004 data, EBGM05> or =2, individual terms) results of signal detection using DA compared to standard methods were sensitivity, 31.1%; specificity, 95.3%; and positive predictive value, 19.9%. Using groupings of synonymous labeled terms, sensitivity improved (40.9%). More of the adverse events detected by both methods were detected earlier using DA and grouped (versus individual) terms. With 1939-2004 data, diagnostic properties were similar to those from 1993 to 2004. DA methods using Merck's safety database demonstrate sufficient sensitivity and specificity to be considered for use as an adjunct to conventional signal detection methods.

Postexposure chemoprophylaxis: approval criteria for clinical trials.

Five scenarios are proposed that investigators and clinicians might consider in the evaluation of an investigational drug for postexposure chemoprophylaxis. They are (a) safety as the only standard required for an indication for postexposure chemoprophylaxis; (b) efficacy of the drug for treatment of HIV-infected patients as a sufficient criterion for an indication for postexposure chemoprophylaxis; (c) a classic placebo-controlled trial as the basis for evaluation of postexposure chemoprophylaxis; (d) a clinical trial design that evaluates outcome in relation to varying times from exposure to initiation of treatment; and (e) combination therapy. Federal regulations are sufficiently flexible to allow demonstration of safety and efficacy of an investigational drug for this indication. The necessary element is that both safety and efficacy be demonstrated in an objective and reliable manner.

Physical and genetic mapping of the Salmonella dublin virulence plasmid pSDL2. Relationship to plasmids from other Salmonella strains.

Plasmids of approximately 80 kb in size are found in nearly all clinical isolates of Salmonella dublin and are believed to be essential for virulence. We have shown previously that the 80-kb plasmid pSDL2 is required for the S. dublin Lane strain to establish a lethal systemic infection in BALB/c mice after oral or intraperitoneal inoculation. We now present a physical and genetic characterization of pSDL2. We have established a complete restriction endonuclease cleavage map of pSDL2 for five enzymes: Xba I, Bam HI, Xho I, Sal I, and Hind III. The region specifying autonomous replication has been localized to a 10.5-kb region of the Sal I A fragment by subcloning on the vector pBR322. Using transposon insertion mutagenesis with Tn5-oriT, a region encoding the virulence phenotype has been mapped within a 6.4-kb portion of the Sal I B fragment. Deletions generated by partial Eco RI restriction digestion demonstrate that at least 50 kb of the plasmid DNA are not required for replication or virulence functions, confirming the map location of these phenotypes. Plasmids of different sizes and restriction patterns were found in mouse virulent strains of S. dublin Vi+, S. enteritidis, and S. choleraesuis. By Southern hybridization, these putative virulence plasmids share a common 4-kb Eco RI fragment with the virulence region of pSDL2, and the plasmids from S. dublin Vi+ and S. enteritidis were shown to express mouse virulence comparable to pSDL2.

Light microscopic findings of liver biopsy specimens from patients with hepatitis type A and comparison with type B.

We compared the light microscopic features of liver biopsy specimens taken within 15 days of onset of symptoms from 17 patients with serologically verified hepatitis type A and 10 patients with serologically verified hepatitis type B. On admission, patients with hepatitis type A experienced higher serum transaminase concentrations and lower total serum bilirubin concentrations than patients with type B. On examination of H & E preparations, specimens from both type A and type B displayed simultaneous hepatocellular degeneration, parenchymal and portal tract inflammatory cell infiltration, and sinusoidal lining cell activation. Hepatitis type A was characterized by conspicuous, mononuclear inflammatory cell infiltration of the portal tract with frequent disruption of the limiting plate, and periportal hepatocyte focal necrosis with virtual sparing of parenchyma about the central vein tributary. Specimens from 10 patients also displayed mild cholestasis. In contrast, hepatitis type B was characterized by modest portal tract infiltration, and extensive parenchymal changes and infiltration, particularly about the central vein tributary.

Detection of hepatitis A antigen in human liver.

For the first time, hepatitis A viral antigen (HAAg) was shown in liver biopsy tissue from a patient in the acute phase of hepatitis type A by light and electron microscopy, using the peroxidase-antibody technique. Under light microscopy, the staining for HAAg appeared as a fine, granular reaction product, scattered throughout the cytoplasm of hepatocytes and sinusoidal lining cells. Standard thin-section electron microscopy revealed virus-like particles, 24 to 27 nm in diameter, in cytoplasmic vesicles of hepatocytes and Kupffer cells. By immunoperoxidase electron microscopy, HAAg was detected on particles aggregated within cytoplasmic vesicles of hepatocytes, thus demonstrating that the virus-like particles (24 to 27 nm) are hepatitis A virus. The surrounding membrane of the vesicles was also positive for HAAg. The distribution patterns of HAAg in human liver were virtually identical to those described for experimentally infected marmosets. It is notable that most HAAg was detected within vesicles of liver cell cytoplasm, suggesting the possibility of vesicle-oriented morphogenesis of hepatitis A virus.