Antibiotic prescribing and admissions with major suppurative complications of respiratory tract infections: a data linkage study.

BACKGROUND: Systematic reviews of antibiotic treatment of common acute respiratory tract infections (RTIs) suggest modest symptomatic benefit, but provide limited evidence that prescribing prevents complications. AIM: To assess the relationship between penicillin prescribing (the most commonly used group of antibiotics for RTIs) and hospital admission with complications. DESIGN OF STUDY: Data linkage study. SETTING: Ninety-six health authorities of England for the year 1997-1998. METHOD: Hospital admissions related to RTIs were linked with prescribing analysis and cost (PACT) data. RESULTS: There was close correlation between items of penicillin use and total antibiotic use (r = 0.96). After controlling for SMR, age, sex, and Townsend score, a one-unit increase in penicillin use (items dispensed per capita) was associated with a reduction in annual incidence per 10,000 of admissions for quinsy (-3.55 admissions, 95% confidence interval [CI] = -6.85 to -0.26), and mastoiditis (square root of incidence of admissions = -1.05, 95% CI = -1.82 to -0.27). This does not represent lower referral thresholds among higher prescribers as higher prescribing was associated with more admissions for tonsillectomy and overall admissions. Increasing prescribing by 2000 items of penicillin for a practice of 10,000 patients could possibly prevent one admission for either mastoiditis or quinsy. CONCLUSION: Higher antibiotic prescribing is associated with significantly fewer admissions with major complications. However, the overall size of the effect is modest and it is difficult to advocate an overall increase in prescribing to prevent complications. Future research should concentrate on finding better methods of targeting antibiotics to individuals at risk of poor outcome.     

The complete nucleotide sequence of Subterranean clover mottle virus

Summary The complete nucleotide sequence of Subterranean clover mottle virus (SCMoV) genomic RNA has been determined. The SCMoV genome is 4,258 nucleotides in length. It shares most nucleotide and amino acid sequence identity with the genome of Lucerne transient streak virus (LTSV). SCMoV RNA encodes four overlapping open reading frames and has a genome organisation similar to that of Cocksfoot mottle virus (CfMV). ORF1 and ORF4 are predicted to encode single proteins. ORF2 is predicted to encode two proteins that are derived from a –1 translational frameshift between two overlapping reading frames (ORF2a and ORF2b). A search of amino acid databases did not find a significant match for ORF1 and the function of this protein remains unclear. ORF2a contains a motif typical of chymotrypsin-like serine proteases and ORF2b has motifs characteristically present in positive-stranded RNA-dependent RNA polymerases. ORF4 is likely to be expressed from a subgenomic RNA and encodes the viral coat protein. The ORF2a/ORF2b overlapping gene expression strategy used by SCMoV and CfMV is similar to that of the poleroviruses and differ from that of other published sobemoviruses. These results suggest that the sobemoviruses could now be divided into two distinct subgroups based on those that express the RNA-dependent RNA polymerase from a single, in-frame polyprotein, and those that express it via a –1 translational frameshifting mechanism.Received December 17, 2001; accepted April 15, 2003 Published online August 7, 2003     

Worldwide genomic diversity of the human papillomaviruses-53, 56, and 66, a group of high-risk HPVs unrelated to HPV-16 and HPV-18

Among more than 200 human papillomavirus (HPV) types presumed to exist, 18 "high-risk" HPV types are frequently found in anogenital cancer. The best studied types are HPV-16 and 18, which are only distantly related to one another and form two separate phylogenetic branches, each including six closely related types. HPV-30, 53, 56, and 66 form a third phylogenetic branch unrelated to HPV-16 and 18. Worldwide comparison of HPV-16 and 18 isolates revealed a distribution of variant genomes that correlated with the geographic origin and the ethnicity of the infected cohort and led to the concept of unique African, European, Asian, and Native American HPV-16 and 18 variants. Here, we address the question whether similar phylogenies are found for HPV-53, 56, and 66 by determining the sequence of the long control regions (LCR) of these HPVs in samples from Europe, Asia, and Africa, and from immigrant societies in North and South America. Phylogenetic trees calculated from point mutations and a few insertions/deletions affecting 2-4.2% of the nucleotide sequences were distinct for each of the three HPVs and divergent from HPV-16 and 18. In contrast to the "star-phylogenies" formed by HPV-16 and 18 variants, 44 HPV-53 isolates represented nine variants, which formed two deep dichotomic branches reminiscent of the beginning split into two new taxa, as recently observed for subtypes of HPV-44 and 68. A total of 66 HPV-56 isolates represented 17 variants, which formed three branches preferentially containing European, Asian, and African variants. Variants of a fourth branch, deeply separated from the other three, were characterized by a 25 bp insertion and created a dichotomy rather than star-like phylogeny. As it contained isolates from cohorts in all continents, it may have evolved before the spread of humans into all continents. 18 of 31 HPV-66 isolates represented the prototype clone, which was found in all parts of the world, while the remaining 13 clones formed 11 branches without any geographic association. Our findings confirm the notion of a quantitatively limited genomic diversity of each HPV type with some correlation to the geographic origin of the sample. In addition, we observed in some variants of these three HPV types mutations that affect the amino acid sequence of the E6 oncoproteins and the L1 capsid protein, supporting the possibility of immunogenic and oncogenic diversity between variants of any HPV type.     

The effect of anti-lymphocytic IgG on established autoallergic thyroiditis in rats

The autoallergic thyroiditis produced in rats by the injection of rat thyroglobulin in Freund's complete adjuvant can be suppressed by the administration of the IgG immunoglobulin fraction of heterologous (horse) anti-lymphocytic serum when treatment is started immediately after the antigen injection. In contrast anti-lymphocytic IgG failed to prevent the development of thyroiditis when given only 4 hr after the antigen nor did it show any suppressive effect on previously induced thyroiditis. Similar results were obtained when anti-lymphocytic IgG treatment was tested for its effect on the primary immune response to rat thyroglobulin.     

Detection and typing of herpes simplex viruses by using recombinant immunoglobulin fragments produced in bacteria.

Thirty-seven bacterial clones producing human recombinant monoclonal antibody Fab fragments (rFabs) reactive to herpes simplex virus (HSV) antigens were selected from a human combinatorial antibody library constructed in a phage-display vector by a panning procedure against an HSV lysate. Thirty-four of the HSV-specific rFabs were able to specifically recognize HSV-infected cells in indirect immunofluorescence (IF) assays; of these, 25 recognized cells infected by either HSV type 1 (HSV-1) or HSV-2, while 9 recognized only HSV-1-infected cells. One HSV type-common rFab (rFab H37) and one HSV-1-specific rFab (rFab H85) were further evaluated as reagents for viral detection and typing by IF staining in 134 HSV-positive (72 HSV-1 and 62 HSV-2) viral cultures from clinical specimens. The results obtained with these two rFabs were fully consistent with those obtained with a commercial preparation of fluorescein-labeled anti-HSV type-specific murine monoclonal antibodies. The detection sensitivity with the type-common rFab in indirect IF assays was higher overall than that provided by the type-specific murine monoclonal antibodies. Preparations of rFabs suitable for IF staining can be easily and inexpensively obtained in a clinical microbiology laboratory from Escherichia coli cultures. Similar HSV-specific rFabs, therefore, could be advantageous for in vitro diagnostic purposes.     

An IL-2 receptor beta subdomain that controls Bcl-X(L) expression and cell survival

IL-2 binding to its high-affinity receptor regulates signaling events that control both lymphocyte cell survival and cell cycle progression. Although many studies have examined the mechanisms by which IL-2 regulates cell growth, few studies have dissected the pathways involved in promoting cell survival or the coupling of these pathways to the receptor. In the present study, using the pre-B cell line Baf-B03 transfected with a truncated form of the IL-2 receptor (IL-2R) beta chain, we demonstrate that IL-2-dependent cell survival requires only the N-terminal 350 amino acids of the IL-2Rbeta chain. IL-2-dependent survival of cells expressing the truncated receptor correlates with increases in receptor-associated phosphatidylinositol 3-kinase (PI3K) activity and expression of Bcl-X(L), but not with changes in c-Myc expression or proliferation. Inhibition of the PI3K pathway in these cells, but not in cells expressing the wild-type receptor, has a marked effect on the capacity of IL-2 to prevent cell death and diminishes the Bcl-X(L) response. The requirement for IL-2-induced PI3K activity in suppressing the onset of apoptotic cell death is discussed.     

Cystic fibrosis carrier detection using a linked gene probe.

Cloned DNA markers which are closely linked to the gene defect causing cystic fibrosis have recently been described. These markers are sufficiently informative for carrier detection in 80% of families where there is a living cystic fibrosis child and unaffected sibs. The tightly linked DNA marker pJ3.11 was used in this study to identify carriers in six families and exclude carrier status in two subjects. Risk calculations for recessive diseases using linked DNA probes may be complex, but useful information for counselling can be obtained in this way.     

Characterization of nutritionally variant streptococci by biochemical tests and penicillin-binding proteins.

A comparative study of 60 strains of nutritionally variant streptococci (NVS) with 34 strains of Streptococcus mitis and 37 strains of Streptococcus sanguis II showed the presence of a red chromophore which was absent in the other streptococcal species. By using the conventional microbiological tests, only small differences were found between the NVS and the two other related species. In contrast a clear-cut delineation was found by the API 20 Strep system of identification. All NVS contained pyrrolidonylarylamidase, an enzyme which was absent in S. mitis and S. sanguis II strains, and lacked the alkaline phosphatase enzyme which was present in 56% of S. mitis strains and 62% of S. sanguis II strains. According to the additional enzymatic and biochemical tests of the API 20 Strep system, there were three biotypes among NVS. The major biotype included 33 of 60 strains which were characterized by the presence of both alpha- and beta-galactosidases and the capacity to hydrolyze trehalose. This biotype also showed a specific pattern of penicillin-binding proteins. These results show that NVS are recognized as a separate variety distinct from S. mitis and S. sanguis II species, despite some common biochemical properties. Moreover, the delineation of 33 strains with a specific biotype and a specific penicillin-binding protein pattern strongly suggests that a large part of NVS strains belong to an individual species.