Risk of reproductive complications following chlamydia testing:a population-based retrospective cohort study in Denmark

SummaryBackgroundUncertainty in the risk of reproductive complications (pelvic inflammatory disease, ectopic pregnancy, and tubal factor infertility) following chlamydia infection and repeat infection hampers the design of evidence-based chlamydia control programmes. We estimate the association between diagnosed chlamydia and episodes of hospital health care (inpatient, outpatient, and emergency department) for a reproductive complication.MethodsWe constructed and analysed a retrospective population-based cohort of women aged 15–44 years from administrative records in Denmark (1995–2012). We used a subset of the national Danish Chlamydia Study. The master dataset contains all residents of Denmark (including Greenland) who had a positive chlamydia test recorded by a public health microbiology laboratory from Jan 1, 1992, to Nov 2, 2011. Individuals were randomly matched (by age and sex) to four individuals drawn from the population register (Danish Civil Registration System) who did not have a positive chlamydia test during this interval. The outcomes in the study were hospital episodes of health-care (inpatient, outpatient, and emergency department) with a diagnosis of pelvic inflammatory disease, ectopic pregnancy, or tubal factor infertility.FindingsThe 516 720 women (103 344 positive, 182 879 negative, 230 497 never-tested) had a mean follow-up of 7·96 years. Compared with women with only negative tests, the risk of each complication was 30% higher in women with one or more positive tests (pelvic inflammatory disease, adjusted hazard ratio [AHR] 1·50 [95% CI 1·43–1·57]; ectopic pregnancy, AHR 1·31 [1·25–1·38]; tubal factor infertility, AHR 1·37 [1·24–1·52]) and 60% lower in women who were never-tested (pelvic inflammatory disease, AHR 0·33 [0·31–0·35]; ectopic pregnancy, AHR 0·42 [0·39–0·44]; tubal factor infertility AHR 0·29 [0·25–0·33]). A positive test had a minor absolute impact on health as the difference in the lifetime incidence of complications was small between women who tested positive and those who tested negative (pelvic inflammatory disease, 0·6%; ectopic pregnancy, 0·2%; tubal factor infertility, 0·1%). Repeat infections increased the risk of pelvic inflammatory disease by a further 20% (AHR 1·20, 95% CI 1·11–1·31).InterpretationA single diagnosed chlamydia infection increased the risk of all complications and a repeat diagnosed infection further increased the risk of pelvic inflammatory disease. Therefore, control programmes must prevent first and repeat infections to improve women's reproductive health.FundingUnrestricted partial funding from Frederiksberg Kommune, Frederiksberg, Denmark. BD held an Medical Research Council Population Health Scientist Fellowship (G0902120). KT held an National Institute for Health Research Post-Doctoral Fellowship 2009-02-055

Photo-antagonism of the GABAA receptor

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation. These compounds are based on the competitive antagonist gabazine and incorporate a variety of photoactive groups. By using site-directed mutagenesis and ligand-docking studies, they reveal new areas of the GABA binding site at the interface between receptor β and α subunits. These compounds enable the selected inactivation of native GABAA receptor populations providing new insight into the function of inhibitory synapses and extrasynaptic receptors in controlling neuronal excitation

Use of interrupter technique in assessment of bronchial responsiveness in normal subjects

BACKGROUND: A number of subjects, especially the very young and the elderly, are unable to cooperate and to perform forced expiratory manoeuvres in the evaluation of bronchial hyperresponsiveness (BHR). The objective of our study was to investigate the use of the interrupter technique as a method to measure the response to provocation and to compare it with the conventional PD(20 )FEV(1). METHODS: We studied 170 normal subjects, 100 male and 70 female (mean ± SD age, 38 ± 8.5 and 35 ± 7.5 years, respectively), non-smoking from healthy families. These subjects had no respiratory symptoms, rhinitis or atopic history. A dosimetric cumulative inhalation of methacholine was used and the response was measured by the dose which increases baseline end interruption resistance by 100% (PD(100)Rint, EI) as well as by percent dose response ratio (DRR). RESULTS: BHR at a cut-off level of 0.8 mg methacholine exhibited 31 (18%) of the subjects (specificity 81.2%), 21 male and 10 female, while 3% showed a response in the asthmatic range. The method was reproducible and showed good correlation with PD(20)FEV(1 )(r = 0.76, p < 0.005), with relatively narrow limits of agreement at -1.39 μmol and 1.27 μmol methacholine, respectively, but the interrupter methodology proved more sensitive than FEV(1 )in terms of reactivity (DRR). CONCLUSIONS: Interrupter methodology is clinically useful and may be used to evaluate bronchial responsiveness in normal subjects and in situations when forced expirations cannot be performed

A Unified Model of the GABA(A) Receptor Comprising Agonist and Benzodiazepine Binding Sites

We present a full-length α(1)β(2)γ(2) GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and the backbone of β(2)S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α(1)R66, β(2)T202, α(1)T129, β(2)E155, β(2)Y205 and β(2)F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β(2)S156 and β(2)Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α(1)T206 and γ(2)T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α(1)H101 and the N-methyl group near α(1)Y159, α(1)T206, and α(1)Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABA(A) receptor is made available as Model S1

Methodological approaches for studying the microbial ecology of drinking water distribution systems

The study of the microbial ecology of drinking water distribution systems (DWDS) has traditionally been based on culturing organisms from bulk water samples. The development and application of molecular methods has supplied new tools for examining the microbial diversity and activity of environmental samples, yielding new insights into the microbial community and its diversity within these engineered ecosystems. In this review, the currently available methods and emerging approaches for characterising microbial communities, including both planktonic and biofilm ways of life, are critically evaluated. The study of biofilms is considered particularly important as it plays a critical role in the processes and interactions occurring at the pipe wall and bulk water interface. The advantages, limitations and usefulness of methods that can be used to detect and assess microbial abundance, community composition and function are discussed in a DWDS context. This review will assist hydraulic engineers and microbial ecologists in choosing the most appropriate tools to assess drinking water microbiology and related aspects

Abstracting Interaction Patterns: A Programming Paradigm for Open Distributed Systems

This paper discusses mechanisms addressing the complexity of building and maintaining Open Distributed Systems. It is argued that a new programming paradigm based on modular specification of interaction patterns is required to address the complexity of such systems. Our research is based on developing abstraction mechanisms to simplify the task of developing and maintaining open systems. We define actors as a model of concurrency for open systems. We then review a number of programming abstractions that are useful in modular specification an..

ANALOGS OF THE LOW-EFFICACY PARTIAL GABA-A AGONIST 4-PIOL - SYNTHESES AND INVITRO PHARMACOLOGICAL STUDIES

4-PIOL (3-hydroxy-5-(4-piperidyl)isoxazole) is a low-efficacy GABA(A) agonist showing a dominating GABA(A) antagonist profile. Three dihydro analogues of 4-PIOL were synthesized, including (RS)-3-hydroxy-5-(4-piperidyl)-2-isoxazoline (1). The synthesis of 1 was based on a regioselective 1,3-dipolar cyclo-addition reaction between 1-benzyloxycarbonyl-4-vinylpiperidine (7) and bromonitrile oxide, prepared in situ from dibromoformoxime. Furthermore, the spiro analogues of 1 3-hydroxy-1-oxa-2,8-diazaspiro{[4.5]dec-2-ene (2) and (RS)-3-hydroxy-1-oxa-2,7-diazaspiro[4.5]dec-2-ene (3) were were synthesized regiospecifically via cycloaddition of bromonitrile oxide to the N-benzyloxycarbonyl-protected forms of 4-methylenepiperidine (11) and 3-methylenepiperidine (15), respectively. In contrast to 4-PIOL, none of the new compounds 1-3 showed detectable effects on the binding of H-3-GABA(A) or the subunit-selective GABA(A) agonist, H-3-THIP, to GABA(A) receptor sites, and they did not significantly affect the muscimol-stimulated binding of H-3-diazepam to the benzodiazepine site of the GABA(A) receptor complex.