Uva-ursi extract and ibuprofen as alternative treatments for uncomplicated urinary tract infection in women (ATAFUTI): a factorial randomized trial.

OBJECTIVES: The aim was to investigate if offering symptomatic therapy (Uva-ursi or ibuprofen) alongside a delayed prescription would relieve symptoms and reduce the consumption of antibiotics for adult women presenting with acute uncomplicated urinary tract infection (UTI). METHODS: A 2 × 2 factorial placebo controlled randomized trial in primary care. The participants were 382 women aged 18-70 years with symptoms of dysuria, urgency, or frequency of urination and suspected by a clinician to have a lower UTI. The interventions were Uva-ursi extract and/or ibuprofen advice. All women were provided with a delayed or 'back-up' prescription for antibiotics. Missing data were imputed using multiple imputation methods (ISRCTN registry: ISRCTN43397016). RESULTS: An ITT analysis of mean score for frequency symptoms assessed on Days 2-4 found no evidence of a difference between Uva-ursi vs. placebo -0.06 (95% CI -0.33 to 0.21; p 0.661), nor ibuprofen vs. no ibuprofen advice -0.01 (95% CI -0.27 to 0.26; p 0.951). There was no evidence of a reduction in antibiotic consumption with Uva-ursi (39.9% vs. placebo 47.4%; logistic regression odds ratio (OR) 0.59 (95% CI 0.22-1.58; p 0.293) but there was a significant reduction for ibuprofen advice (34.9% vs. no advice 51.0%; OR 0.27 (95% CI 0.10 to 0.72; p 0.009). There were no safety concerns and no episodes of upper tract infection were recorded. CONCLUSIONS: We found no evidence of an effect of either intervention on the severity of frequency symptoms. There is evidence that advice to take ibuprofen will reduce antibiotic consumption without increasing complications. For every seven women given this advice, one less will use antibiotics.

First Results from the DEAP-3600 Dark Matter Search with Argon at SNOLAB.

This Letter reports the first results of a direct dark matter search with the DEAP-3600 single-phase liquid argon (LAr) detector. The experiment was performed 2 km underground at SNOLAB (Sudbury, Canada) utilizing a large target mass, with the LAr target contained in a spherical acrylic vessel of 3600 kg capacity. The LAr is viewed by an array of PMTs, which would register scintillation light produced by rare nuclear recoil signals induced by dark matter particle scattering. An analysis of 4.44 live days (fiducial exposure of 9.87 ton day) of data taken during the initial filling phase demonstrates the best electronic recoil rejection using pulse-shape discrimination in argon, with leakage <1.2×10^{-7} (90% C.L.) between 15 and 31 keV_{ee}. No candidate signal events are observed, which results in the leading limit on weakly interacting massive particle (WIMP)-nucleon spin-independent cross section on argon, <1.2×10^{-44} cm^{2} for a 100 GeV/c^{2} WIMP mass (90% C.L.).

Chaos-induced pulse trains in the ionization of hydrogen.

We predict that a hydrogen atom in parallel electric and magnetic fields, excited by a short laser pulse to an energy above the classical saddle, ionizes via a train of electron pulses. These pulses are a consequence of classical chaos induced by the magnetic field. We connect the structure of this pulse train (e.g., pulse size and spacing) to fractal structure in the classical dynamics. This structure displays a weak self-similarity, which we call "epistrophic self-similarity." We demonstrate how this self-similarity is reflected in the pulse train.

BipA is required for growth of Escherichia coi K12 at low temperature.

The bipA gene encodes a ribosome-associated GTPase postulated to be involved in regulatory functions in enteropathogenic Escherichia coli. Previous studies demonstrated that BipA is tyrosine phosphorylated in EPEC strains, but not in E. coli strain K12. Results presented here indicate that BipA function is required at low temperatures in E. coli K12, suggesting a regulatory role independent of phosphorylation and of pathogenicity.

SecG function and phospholipid metabolism in Escherichia coli.

SecG is an auxiliary protein in the Sec-dependent protein export pathway of Escherichia coli. Although the precise function of SecG is unknown, it stimulates translocation activity and has been postulated to enhance the membrane insertion-deinsertion cycle of SecA. Deletion of secG was initially reported to result in a severe export defect and cold sensitivity. Later results demonstrated that both of these phenotypes were strain dependent, and it was proposed that an additional mutation was required for manifestation of the cold-sensitive phenotype. The results presented here demonstrate that the cold-sensitive secG deletion strain also contains a mutation in glpR that causes constitutive expression of the glp regulon. Introduction of both the glpR mutation and the secG deletion into a wild-type strain background produced a cold-sensitive phenotype, confirming the hypothesis that a second mutation (glpR) contributes to the cold-sensitive phenotype of secG deletion strains. It was speculated that the glpR mutation causes an intracellular depletion of glycerol-3-phosphate due to constitutive synthesis of GlpD and subsequent channeling of glycerol-3-phosphate into metabolic pathways. In support of this hypothesis, it was demonstrated that addition of glycerol-3-phosphate to the growth medium ameliorated the cold sensitivity, as did introduction of a glpD mutation. This depletion of glycerol-3-phosphate is predicted to limit phospholipid biosynthesis, causing an imbalance in the levels of membrane phospholipids. It is hypothesized that this state of phospholipid imbalance imparts a dependence on SecG for proper function or stabilization of the translocation apparatus.

SecG is an auxiliary component of the protein export apparatus of Escherichia coli.

SecY, SecE and SecG form the membrane-embedded core complex of the Escherichia coli protein export apparatus. These three proteins co-purify and can be co-immunoprecipitated, demonstrating that they are closely associated. While SecE and SecY are generally accepted as essential components of translocase, the role of SecG is more ambiguous. It is commonly believed that deletion of secG causes a cold-sensitive phenotype and a severe defect in export, even though some reports have indicated otherwise. However, we demonstrate that deletion of secG does not produce a cold-sensitive phenotype or a strong export defect in most genetic backgrounds. The more common result is that deletion of secG causes only a mild export defect and does not result in conditional lethality. We propose that the role of SecG is not fundamental to the export process, but is merely auxiliary--as suggested previously by biochemical data--and is physiologically important only when cells are otherwise compromised.

The allele-specific synthetic lethality of prlA-prlG double mutants predicts interactive domains of SecY and SecE.

The secretion of proteins from the cytoplasm of Escherichia coli requires the interaction of two integral inner membrane components, SecY and SecE. We have devised a genetic approach to probe the molecular nature of the SecY-SecE interaction. Suppressor alleles of secY and secE, termed prlA and prlG, respectively, were analyzed in pair-wise combinations for synthetic phenotypes. From a total of 115 combinations, we found only seven pairs of alleles that exhibit a synthetic defect when present in combination with one another. The phenotypes observed are not the result of additive defects caused by the prl alleles, nor are they the consequence of multiple suppressors functioning within the same strain. In all cases, the synthetic defect is recessive to wild-type secY or secE provided in trans. The recessive nature argues for a defective interaction between the Prl suppressors. The extreme allele specificity and topological coincidence of the mutations represented by these seven pairs of alleles identify domains of interaction between SecY/PrlA and SecE/PrlG.

A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps/rubella vaccines.

We describe a new method for active post-marketing surveillance of vaccine safety based on patient records. We studied the association between diphtheria/tetanus/pertussis (DTP) vaccination and febrile convulsion, and between measles/mumps/rubella (MMR) vaccination and febrile convulsion and idiopathic thrombocytopenic purpura (ITP) in five district health authorities in England by linking vaccination records with computerised hospital admission records. We found an increased relative incidence for convulsions 0-3 days after DTP vaccination. The effect was limited to the third dose of vaccine for which the attributable risk (all ages) was 1 in 12,500 doses. Completion of vaccination by 4 months instead of 10 months after the change in the UK to an accelerated immunisation schedule may have resulted in a 4-fold decrease in febrile convulsions attributable to DTP vaccine. 67% of admissions for a convulsion 6-11 days after MMR vaccination were attributable to the measles component of the vaccine (risk 1 in 3000 doses). An excess of admissions for a convulsion 15-35 days after MMR vaccination was found only for vaccines containing the Urabe mumps strain (1 in 2600 Urabe doses). There was a causal association between MMR vaccination and ITP resulting in admission 15-35 days subsequently; there was no evidence of a mumps strain-specific effect. The estimated absolute risk of 1 in 24,000 doses was 5 times that calculated from cases passively reported by clinicians. This finding emphasises the need for active surveillance of adverse events. The record linkage method that we used is an effective way to identify vaccine-attributable adverse events.

PrlA and PrlG suppressors reduce the requirement for signal sequence recognition.

Selection for suppressors of defects in the signal sequence of secretory proteins has led most commonly to identification of prlA alleles and less often to identification of prlG alleles. These genes, secY/prlA and secE/prlG, encode integral membrane components of the protein translocation system of Escherichia coli. We demonstrate that an outer membrane protein, LamB, that lacks a signal sequence can be exported with reasonable efficiency in both prlA and prlG suppressor strains. Although the signal sequence is not absolutely required for export of LamB, the level of export in the absence of prl suppressor alleles is exceedingly low. Such strains are phenotypically LamB-, and functional LamB can be detected only by using sensitive infectious-center assays. Suppression of the LamB signal sequence deletion is dependent on normal components of the export pathway, indicating that suppression is not occurring through a bypass mechanism. Our results indicate that the majority of the known prlA suppressors function by an identical mechanism and, further, that the prlG suppressors work in a similar fashion. We propose that both PrlA and PrlG suppressors lack a proofreading activity that normally rejects defective precursors from the export pathway.

Transmission of hepatitis B virus analyzed by conformation-dependent polymorphisms of single-stranded viral DNA.

Hepatitis B virus (HBV) DNA from regions coding for surface and core antigens were amplified and radiolabeled from hepatitis B surface antigen (HBsAg)-positive serum samples by polymerase chain reaction, heat-denatured, and analyzed for conformation-dependent polymorphisms by gel electrophoresis under nondenaturation conditions. Analysis of serum samples representative of diverse and identical HBsAg subtypes showed a wide range of autoradiographic banding patterns, each unique to the specimen. Serial samples of a long-term carrier showed relative stability of banding patterns over time. Epidemiologic analyses using this procedure showed banding patterns of case subjects to be identical to those of persons implicated as the source. This facile and discriminatory approach to the differentiation of viral strains should be useful in the study of HBV transmission.

Risk of aseptic meningitis after measles, mumps, and rubella vaccine in UK children.

Cases of aseptic meningitis associated with measles/mumps/rubella vaccine were sought in thirteen UK health districts following a reported cluster in Nottingham which suggested a risk of 1 in 4000 doses, substantially higher than previous estimates based on cases reported by paediatricians (4 per million). Cases were ascertained by obtaining vaccination records of children with aseptic meningitis diagnosed from cerebrospinal fluid samples submitted to Public Health Laboratories or discharged from hospital with a diagnosis of viral meningitis. Both methods identified vaccination 15-35 days before onset as a significant risk factor and therefore indicative of a causal association. With both, half the aseptic meningitis cases identified in children aged 12-24 months were vaccine-associated with onset 15-35 days after vaccine. The study confirmed that the true risk was substantially higher than suggested by case reports from paediatricians, probably about 1 in 11,000 doses. However, the possibility that the aseptic meningitis induced by vaccination was largely asymptomatic and a chance laboratory finding in children investigated for other clinical conditions, particularly febrile convulsions, could not be excluded. Comparison of national reports of virus-positive mumps meningitis cases before and after the introduction of this vaccine indicated that the risk from wild mumps was about 4-fold higher than from vaccine. Altogether, 28 vaccine-associated cases were identified, all in recipients of vaccines containing the Urabe mumps strain. The absence of cases in recipients of vaccine containing the Jeryl Lynn strain, despite its 14% market share, suggested a higher risk from Urabe vaccine. A prospective adverse event surveillance system using the study methods is currently being established to assess the risk, if any, from the Jeryl Lynn strain which is now the only mumps vaccine used in the UK.

Vaccination against hepatitis B: comparison of intradermal and intramuscular administration of plasma derived and recombinant vaccines.

A retrospective analysis of levels of antibody to hepatitis B surface antigen in 1419 health care workers was carried out to compare the efficacy of intramuscular and intradermal administration of plasma derived and recombinant hepatitis B vaccines. No significant difference was detected between the response to intradermal and intramuscular plasma derived vaccine. However of those who received intramuscular recombinant vaccine 81.6%, 13.8% and 4.7% were good (> or = 100 miu/ml), low (10-99 miu/ml) and non-responders (< 10 miu/ml) respectively, compared with 51.1%, 29.8% and 19.2% of the intradermal group (P < 0.0001). Low dose intradermal administration of recombinant vaccine did not produce satisfactory levels of antibody to hepatitis B surface antigen.

Transcriptional organization of the Escherichia coli dnaX gene.

We have determined the transcriptional organization of the Escherichia coli dnaX gene, the structural gene for both the gamma and tau subunits of DNA polymerase III holoenzyme. By S1 nuclease protection and primer extension mapping of transcripts encoding the dnaX products, one primary promoter of dnaX has been identified that initiates transcription 37 nucleotides upstream from the first codon. dnaX resides in an operon with two recently sequenced genes, orf12, encoding an unidentified product, and recR, the structural gene for a protein involved in the recF pathway of recombination. Under conditions of balanced growth, a very small amount of transcription from the upstream apt promoter (less than 5%) contributes to the expression of tau and gamma, too low for apt to be considered to be on an operon with dnaX, orf12, and recR are transcribed from an independent promoter as well as from the dnaX promoter, providing a mechanism for orf12 and recR to be regulated independent of dnaX. Transcription of the dnaX-orf12-recR operon is terminated upstream from the previously characterized heat shock gene htpG. The dnaX and orf12-recR promoters, cloned into a promoter detection vector, efficiently direct the expression of the downstream reporter gene, lacZ. These results extend our knowledge of the genetic and transcriptional organization of this region of the E. coli chromosome. The transcriptional organization has been defined as follows: apt, dnaX-orf12-recR, htpG. All of these genes are transcribed in the clockwise direction and only dnaX, orf12 and recR are contained in the dnaX operon.