Influenza virus contains eight single-stranded RNA segments of negative polarity as the genome and an RNA-dependent RNA polymerase as a virion component (26). Influenza virus RNA polymerase catalyzes both transcription [the synthesis of plus-strand mRNA containing the host cell-derived cap I structure at the 5'-terminus and poly (A) tail at the 3'-terminus] and replication [the synthesis of full-length plus-strand complementary RNA (cRNA) and the cRNA-dependent synthesis of minus-strand viral RNA (vRNA)] (14,17,18,24,50). The viral RNA polymerase also catalyzes polyadenylation at the 3'-termini of mRNA in vitro (43). The viral RNA polymerase also performs templatedependent capped RNA cleavage (21, 41) and apparent proofreading of nascent RNA chains (19).The RNA polymerase purified from influenza virus consists of one part each of three subunits, PB1, PB2 and PA (15). In vitro reconstitution studies of enzymatically active RNA polymerase using individual P proteins purified either from baculovirus-infected cells (23), Pichia pastoris cells (16) or by SDS-polyacrylamide gel electrophoresis of virions (49) confirmed the subunit structure. The function of each subunit of influenza virus RNA polymerase has been genetically and biochemically characterized. For instance, PB1 subunit can be cross-linked with nucleotide substrates (3, 4, 6), and nuclear extracts containing PB1 subunit alone or cells expressing both PB1 and NP can catalyze RNA synthesis, depending on the model RNA templates (22,35,52), indicating that PB1 is involved in polymerization of RNA chains. PB1 bound with both negative and positive sense RNAs (10, 28). Cap I analog was cross-linked with PB2 in vitro (6,13,29,53), and RNA synthesized in cells without PB2 lacks the 5'-cap structure (35), suggesting that PB2 is required for cap binding and synthesis of capped mRNAs. The cap-dependent RNase active site has been mapped in PB1 recently (29). However, the information about the role of PA on viral replication remains limited. Temperature-sensitive (ts) mutations in the PA gene affected only vRNA synthesis, but not mRNA synthesis (25,30,33,45,46). Nakagawa et al. demonstrated that PA was essential for cRNA-dependent vRNA synthesis (36). We identified a unique protease activity in purified PA protein (12).The subunit binding sites of the influenza virus RNA polymerase were mapped, which demonstrated that PB1
The objective ofthis study was to assess, in a developing country setting, the effect of dexamethasone therapy on bacterial meningitis outcomes. A prospective double blind placebo controlled trial was conducted in 89 children aged from 2 months to 12 years suffering from bacterial meningitis. Neurological, developmental, and hearing assessments were conducted at one, four, and 12 months after discharge. Forty eight patients received dexamethasone and 41 placebo. Initial antimicrobial drugs used were ampicillin and chloramphenicol. For all patients at the time of admission the mean duration of illness was 5.7 days; 47% had had seizures and 56% had impaired consciousness. Seventeen of 89 (19%) patients died. The mortality for the dexamethasone group was 25% as compared with 12% in the group receiving placebo. Presentation to the hospital after four days of symptoms and with impaired conscious state were independent predictors of death. Of the dexamethasone group survivors, 26.5% had neurological sequelae and 42.3% had hearing impairment, whereas in the placebo group it was 24% and 30% respectively. Altered state of consciousness was a predictor of neurological sequelae. The presence of neurological sequelae and high cerebrospinal fluid protein independently predicted hearing loss. No beneficial effect of dexamethasone was observed on morbidity or mortality of this group of patients with bacterial meningitis. Dexamethasone is therefore not useful in developing countries as adjunctive treatment in patients seriously ill with bacterial meningitis, who present late for treatment and have been partially treated. (Arch Dis Child 1996;75:482-488)
The pharmacokinetics and bacteriological efficacies of penicillin G, ceftriaxone, vancomycin, and imipenem were determined in rabbits with experimental meningitis caused by Streptococcus pneumoniae strains with different penicillin susceptibilities. Drug dosages were adjusted to attain peak concentrations in serum that were similar to those observed in infants and children. In animals infected with a penicillin-susceptible (MBC, 0.008 ,ug/ml) pneumococcus, penicillin G and ceftriaxone reduced the number of organisms in cerebrospinal fluid (CSF) by .4.14 logl0 CFU/ml after single doses and after 9-h continuous infusions. A single large dose (50 mg/kg) of penicillin G was comparatively ineffective (-2.15 log10 CFU/ml) against a relatively penicillin-resistant (MBC, 0.5 ,ug/ml) strain, whereas ceftriaxone therapy resulted in a 3.66-and 4.77-loglo CFU/ml reduction after single doses and 9-h continuous infusions, respectively. In animals in which meningitis was caused by a penicillin-resistant (MBC, 8.0 ,ug/ml) (1,3,8,9,11,(16)(17)(18). Relatively resistant S. pneumoniae strains have MICs of 0.1 to 1.0 pig of penicillin per ml and a prevalence rate of 3 to 16% (1, 2, 9). We recently reported that, of S. pneumoniae strains obtained from cultures of infants and children at Children's Medical Center, Dallas, Tex., in a 17-month period from 1981 to 1983, 8% were relatively penicillin resistant (9). In this report, two infants with meningitis caused by these strains failed to respond to conventional doses of penicillin (250,000 U/kg per day); one infant was successfully treated with chloramphenicol, but the second required vancomycin for cure because the strain was also resistant to chloramphenicol. Others have also used chloramphenicol alone or with penicillin for therapy of meningitis caused by relatively resistant S. pneumoniae strains (1,11,16,17
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