Subpubic cartilaginous cyst: an unusual cause of urinary tract infection.

It is important to consider alternative causes when treating refractory cases of urinary tract infection in the elderly population.

Outcomes and costs of pre-school and school-based fluoride varnish pilots.

Objective Fluoride varnish (FV) applications reduce the risk of dental decay in research trials. These pilots were conducted to test the feasibility and costs of providing FV applications in schools. Changes in dental decay levels were also monitored.Methods Data were collected on the proportion of children with dental decay, mean number of teeth affected and whether the child had attended for dental care. The cost of delivering the intervention was calculated.Results More children were reported to be attending for dental care by the end of the pilot than at the start. The proportion of children with dental decay and the mean number of teeth affected increased, but more children seemed to have received treatment. The intervention cost about £88 per child per year, with most of the costs due to the intensive efforts needed to recruit and maintain participation in the pilots.Conclusions Establishing community FV programmes requires significant investment and the long-term benefits in practice are unclear. If dental decay levels are to be reduced, there is a need to improve diets, alongside fluoride strategies. This may be best achieved by integrating oral health improvement programmes into other health programmes, particularly sugar-reduction strategies.

Rehabilitation Enablement in Chronic Heart Failure-a facilitated self-care rehabilitation intervention in patients with heart failure with preserved ejection fraction (REACH-HFpEF) and their caregivers: rationale and protocol for a single-centre pilot randomised controlled trial.

INTRODUCTION: The Rehabilitation EnAblement in CHronic Heart Failure in patients with Heart Failure (HF) with preserved ejection fraction (REACH-HFpEF) pilot trial is part of a research programme designed to develop and evaluate a facilitated, home-based, self-help rehabilitation intervention to improve self-care and quality of life (QoL) in heart failure patients and their caregivers. We will assess the feasibility of a definitive trial of the REACH-HF intervention in patients with HFpEF and their caregivers. The impact of the REACH-HF intervention on echocardiographic outcomes and bloodborne biomarkers will also be assessed. METHODS AND ANALYSIS: A single-centre parallel two-group randomised controlled trial (RCT) with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention) or usual care alone (control) in 50 HFpEF patients and their caregivers. The REACH-HF intervention comprises a REACH-HF manual with supplementary tools, delivered by trained facilitators over 12 weeks. A mixed methods approach will be used to assess estimation of recruitment and retention rates; fidelity of REACH-HF manual delivery; identification of barriers to participation and adherence to the intervention and study protocol; feasibility of data collection and outcome burden. We will assess the variance in study outcomes to inform a definitive study sample size and assess methods for the collection of resource use and intervention delivery cost data to develop the cost-effectiveness analyses framework for any future trial. Patient outcomes collected at baseline, 4 and 6 months include QoL, psychological well-being, exercise capacity, physical activity and HF-related hospitalisation. Caregiver outcomes will also be assessed, and a substudy will evaluate impact of the REACH-HF manual on resting global cardiovascular function and bloodborne biomarkers in HFpEF patients. ETHICS AND DISSEMINATION: The study is approved by the East of Scotland Research Ethics Service (Ref: 15/ES/0036). Findings will be disseminated via journals and presentations to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN78539530; Pre-results .

Home-based versus centre-based cardiac rehabilitation: abridged Cochrane systematic review and meta-analysis.

OBJECTIVE: To update the Cochrane review comparing the effects of home-based and supervised centre-based cardiac rehabilitation (CR) on mortality and morbidity, quality of life, and modifiable cardiac risk factors in patients with heart disease. METHODS: Systematic review and meta-analysis. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and CINAHL were searched up to October 2014, without language restriction. Randomised trials comparing home-based and centre-based CR programmes in adults with myocardial infarction, angina, heart failure or who had undergone coronary revascularisation were included. RESULTS: 17 studies with 2172 patients were included. No difference was seen between home-based and centre-based CR in terms of: mortality (relative risk (RR) 0.79, 95% CI 0.43 to 1.47); cardiac events; exercise capacity (mean difference (MD) -0.10, -0.29 to 0.08); total cholesterol (MD 0.07 mmol/L, -0.24 to 0.11); low-density lipoprotein cholesterol (MD -0.06 mmol/L, -0.27 to 0.15); triglycerides (MD -0.16 mmol/L, -0.38 to 0.07); systolic blood pressure (MD 0.2 mm Hg, -3.4 to 3.8); smoking (RR 0.98, 0.79 to 1.21); health-related quality of life and healthcare costs. Lower high-density lipoprotein cholesterol (MD -0.07 mmol/L, -0.11 to -0.03, p=0.001) and lower diastolic blood pressure (MD -1.9 mm Hg, -0.8 to -3.0, p=0.009) were observed in centre-based participants. Home-based CR was associated with slightly higher adherence (RR 1.04, 95% CI 1.01 to 1.07). CONCLUSIONS: Home-based and centre-based CR provide similar benefits in terms of clinical and health-related quality of life outcomes at equivalent cost for those with heart failure and following myocardial infarction and revascularisation.

Clinical effectiveness and cost-effectiveness of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) facilitated self-care rehabilitation intervention in heart failure patients and caregivers: rationale and protocol for a multicentre randomised controlled trial.

INTRODUCTION: The Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) trial is part of a research programme designed to develop and evaluate a health professional facilitated, home-based, self-help rehabilitation intervention to improve self-care and health-related quality of life in people with heart failure and their caregivers. The trial will assess the clinical effectiveness and cost-effectiveness of the REACH-HF intervention in patients with systolic heart failure and impact on the outcomes of their caregivers. METHODS AND ANALYSIS: A parallel two group randomised controlled trial with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention group) or usual care alone (control group) in 216 patients with systolic heart failure (ejection fraction <45%) and their caregivers. The intervention comprises a self-help manual delivered by specially trained facilitators over a 12-week period. The primary outcome measure is patients' disease-specific health-related quality of life measured using the Minnesota Living with Heart Failure questionnaire at 12 months' follow-up. Secondary outcomes include survival and heart failure related hospitalisation, blood biomarkers, psychological well-being, exercise capacity, physical activity, other measures of quality of life, patient safety and the quality of life, psychological well-being and perceived burden of caregivers at 4, 6 and 12 months' follow-up. A process evaluation will assess fidelity of intervention delivery and explore potential mediators and moderators of changes in health-related quality of life in intervention and control group patients. Qualitative studies will describe patient and caregiver experiences of the intervention. An economic evaluation will estimate the cost-effectiveness of the REACH-HF intervention plus usual care versus usual care alone in patients with systolic heart failure. ETHICS AND DISSEMINATION: The study is approved by the North West-Lancaster Research Ethics Committee (ref 14/NW/1351). Findings will be disseminated via journals and presentations to publicise the research to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN86234930; Pre-results.

Review and analysis of global agricultural N2O emissions relevant to the UK.

As part of a UK government funded research project to update the UK N2O inventory methodology, a systematic review of published nitrous oxide (N2O) emission factors was carried out of non-UK research, for future comparison and synthesis with the UK measurement based evidence base. The aim of the study is to assess how the UK IPCC default emission factor for N2O emissions derived from synthetic or organic fertiliser inputs (EF1) compares to international values reported in published literature. The availability of data for comparing and/or refining the UK IPCC default value and the possibility of analysing sufficient auxiliary data to propose a Tier 2 EF1 reporting strategy is evaluated. The review demonstrated a lack of consistency in reporting error bounds for fertiliser-derived EFs and N2O flux data with 8% and 44% of publications reporting EF and N2O flux error bounds respectively. There was also poor description of environmental (climate and soil) and experimental design auxiliary data. This is likely to be due to differences in study objectives, however potential improvements to soil parameter reporting are proposed. The review demonstrates that emission factors for agricultural-derived N2O emissions ranged -0.34% to 37% showing high variation compared to the UK Tier 1 IPCC EF1 default values of 1.25% (IPCC 1996) and 1% (IPPC 2006). However, the majority (83%) of EFs reported for UK-relevant soils fell within the UK IPCC EF1 uncertainty range of 0.03% to 3%. Residual maximum likelihood (REML) analysis of the data collated in the review showed that the type and rate of fertiliser N applied and soil type were significant factors influencing EFs reported. Country of emission, the length of the measurement period, the number of splits, the crop type, pH and SOC did not have a significant impact on N2O emissions. A subset of publications where sufficient data was reported for meta-analysis to be conducted was identified. Meta-analysis of effect sizes of 41 treatments demonstrated that the application of fertiliser has a significant effect on N2O emissions in comparison to control plots and that emission factors were significantly different to zero. However no significant relationships between the quantity of fertiliser applied and the effect size of the amount of N2O emitted from fertilised plots compared to control plots were found. Annual addition of fertiliser of 35 to 557 kg N/ha gave a mean increase in emissions of 2.02 ± 0.28 g N2O/ha/day compared to control treatments (p<0.01). Emission factors were significantly different from zero, with a mean emission factor estimated directly from the meta analysis of 0.17 ± 0.02%. This is lower than the IPCC 2006 Tier 1 EF1 value of 1% but falling within the uncertainty bound for the IPCC 2006 Tier 1 EF1 (0.03% to 3%). As only a small number of papers were viable for meta analysis to be conducted due to lack of reporting of the key controlling factors, the estimates of EF in this paper cannot include the true variability under conditions similar to the UK. Review-derived EFs of 0.34% to 37% and mean EF from meta-analysis of 0.17 ± 0.02% highlight variability in reporting EFs depending on the method applied and sample size. A protocol of systematic reporting of N2O emissions and key auxiliary parameters in publications across disciplines is proposed. If adopted this would strengthen the community to inform IPCC Tier 2 reporting development and reduce the uncertainty surrounding reported UK N2O emissions.

Recruitment and participation in pre-school and school-based fluoride varnish pilots - the South Central experience.

OBJECTIVE: To assess recruitment and participation within seven school/pre-school-based programmes for fluoride varnish applications. METHOD: Year-long pilots were undertaken in six primary schools (ages four to seven years) and one pre-school (ages three to four years). Three applications of fluoride varnish were carried out coinciding with the three school terms. RESULTS: In spite of intensive recruitment efforts, only 78% of the total 589 children were enrolled in the pilot; 15% had to be excluded because no response could be obtained from their parents. At the end of 12 months, 79% of enrolled children (62% of total) had received all three applications. Children did not receive applications because they were absent on the days when the dental team were carrying out the screening or fluoride varnish applications, were ill, or because the child refused. The highest refusal rate was in the pre-school. CONCLUSIONS: Younger children need to be targeted if improvement in the oral health of five-year-olds is to be achieved, the only dental measure in the Public Health Outcomes Framework, but they were less likely to cooperate. More research is needed on approaches to maximise participation in community programmes such as this, if they are to achieve significant population-level improvements in child dental health.

Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus.

Status epilepticus (SE) triggers abnormal expression of genes in the hippocampus, such as glutamate receptor subunit epsilon-2 (Grin2b/Nr2b) and brain-derived neurotrophic factor (Bdnf), that is thought to occur in temporal lobe epilepsy (TLE). We examined the underlying DNA methylation mechanisms and investigated whether these mechanisms contribute to the expression of these gene targets in the epileptic hippocampus. Experimental TLE was provoked by kainic acid-induced SE. Bisulfite sequencing analysis revealed increased Grin2b/Nr2b and decreased Bdnf DNA methylation levels that corresponded to decreased Grin2b/Nr2b and increased Bdnf mRNA and protein expression in the epileptic hippocampus. Blockade of DNA methyltransferase (DNMT) activity with zebularine decreased global DNA methylation levels and reduced Grin2b/Nr2b, but not Bdnf, DNA methylation levels. Interestingly, we found that DNMT blockade further decreased Grin2b/Nr2b mRNA expression whereas GRIN2B protein expression increased in the epileptic hippocampus, suggesting that a posttranscriptional mechanism may be involved. Using chromatin immunoprecipitation analysis we found that DNMT inhibition restored the decreases in AP2alpha transcription factor levels at the Grin2b/Nr2b promoter in the epileptic hippocampus. DNMT inhibition increased field excitatory postsynaptic potential in hippocampal slices isolated from epileptic rats. Electroencephalography (EEG) monitoring confirmed that DNMT inhibition did not significantly alter the disease course, but promoted the latency to seizure onset or SE. Thus, DNA methylation may be an early event triggered by SE that persists late into the epileptic hippocampus to contribute to gene expression changes in TLE.

Farmer decision-making and risk perceptions towards outwintering cattle.

Increasing financial pressures has led farmers to manage cattle outside for the winter months. In temperate areas the environmental risks of outwintering cattle are exacerbated by cooler and wetter weather and identifying how farmers perceive these risks is essential to understanding how potential hazards could be mitigated. A series of workshops were conducted with cattle producers in England and Wales to understand their perceptions of the risks, their decision-making with respect to outwintering and their options for mitigating these risks. A range of risks were identified, but emphasis was placed on environmentally-related risks, such as soil damage, and on social risks, such as public perception of their treatment of the animals. The uncertainties due to the weather were highlighted as the most unmanageable risk. Another significant barrier to mitigating environmental impacts emerged from the lack of options towards choosing appropriate fields in which to conduct outwintering. We argue that the farmer-led nature of outwintering and the development of a wide range of systems is evidence of outwintering being a systems-innovation. We conclude that there is a role for Government intervention through the provision of information which clarifies cross-compliance breaches, but also encourages farmer-led innovation to develop more responsive outwintering systems.

Edited GluR2, a gatekeeper for motor neurone survival?

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of motor neurones. Although the genetic basis of familial forms of ALS has been well explored, the molecular basis of sporadic ALS is less well understood. Recent evidence has linked sporadic ALS with the failure to edit key residues in ionotropic glutamate receptors, resulting in excessive influx of calcium ions into motor neurones which in turn triggers cell death. Here we suggest that edited AMPA glutamate (GluR2) receptor subunits serve as gatekeepers for motor neurone survival.

Concentrations and fluxes of dissolved organic carbon in UK topsoils.

Dissolved organic carbon (DOC) concentrations in soil water samples collected from depths of 5 to 20 cm at 10 moorland and 11 forest sites during the period 2000-2006 were obtained from new measurements and from the monitoring programmes of the UK Environmental Change Network and the International Cooperative Programme (ICP) on Forests. Data on soil properties and vegetation type were also assembled. Considering data from Prenart tension collectors, which were used at nearly all the sites, mean annual concentrations ranged from 1.3 to 97.5 g m(-3) with means of 19.5 (standard deviation 15.2) and 27.6 (SD 23.3) g m(-3) for moorland and forest sites respectively. Interannual mean DOC concentration at an individual site varied by only 1.5-fold, averaged over all sites with at least three years' data. Concentrations during summer months (April to September) were on average 17% greater than those in winter (October to March). If data from two sites (the single peatland and an unusual forest site) were ignored, DOC concentrations were strongly inversely related to water flux, estimated from rainfall and evaporation data. Fluxes of DOC, calculated by combining concentration with water flux, ranged from 2.2 to 71.9 gC m(-2) yr(-1) over all sites and years, with overall means of 19.2 (SD 13.6) and 12.2 (SD 13.9) gC m(-2) yr(-1) for the moorland and forest sites respectively. However, if the two exceptional sites were omitted, the overall mean was 9.1 gC m(-)(2) yr(-1) with a standard deviation of only 4.9 gC m(-2) yr(-1). Annual DOC flux was strongly dependent upon annual water flux, varying by 3.5-fold between years when averaged over all sites. On average, 75.5% of the DOC was exported during the winter period (October to March).

Contributions from Caenorhabditis elegans functional genetics to antiparasitic drug target identification and validation: nicotinic acetylcholine receptors, a case study.

Following the complete sequencing of the genome of the free-living nematode, Caenorhabditis elegans, in 1998, rapid advances have been made in assigning functions to many genes. Forward and reverse genetics have been used to identify novel components of synaptic transmission as well as determine the key components of antiparasitic drug targets. The nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels. The functions of these transmembrane proteins and the roles of the different members of their extensive subunit families are increasingly well characterised. The simple nervous system of C. elegans possesses one of the largest nicotinic acetylcholine receptor gene families known for any organism and a combination of genetic, microarray, physiological and reporter gene expression studies have added greatly to our understanding of the components of nematode muscle and neuronal nAChR subtypes. Chemistry-to-gene screens have identified five subunits that are components of nAChRs sensitive to the antiparasitic drug, levamisole. A novel, validated target acting downstream of the levamisole-sensitive nAChR has also been identified in such screens. Physiology and molecular biology studies on nAChRs of parasitic nematodes have also identified levamisole-sensitive and insensitive subtypes and further subdivisions are under investigation.

Sgbeta1, a novel locust (Schistocerca gregaria) non-alpha nicotinic acetylcholine receptor-like subunit with homology to the Drosophila melanogaster Dbeta1 subunit.

The cloning, sequencing and functional expression of Sgbeta1, a novel locust (Schistocerca gregaria) non-alpha nicotinic acetylcholine receptor (nAChR) subunit is described. This subunit shows 80% identity with the Drosophila melanogaster Dbeta1 and 92% identity with the Locusta migratoria beta1, non-alpha subunits but only 38% identity to Sgalpha1 (also referred to as alphaL1), a previously cloned S. gregaria nAChR alpha-subunit. When expressed in Xenopus laevis oocytes, Sgbeta1 does not respond to nicotine. Responses to nicotine are observed, however, in oocytes co-expressing Sgalpha1 and Sgbeta1, but the pharmacology is indistinguishable from that of currents produced by expressing Sgalpha1 alone. We conclude that either Sgbeta1 does not co-assemble with Sgalpha1, or that it is unable to contribute to the functional properties of the receptor, in the Xenopus oocyte expression system.

Immune reconstitution inflammatory syndrome in HIV-infected patients with mycobacterial infections starting highly active anti-retroviral therapy.

AIM: To describe the radiological appearances of immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV)-infected patients with mycobacterial infections starting highly active anti-retroviral therapy (HAART). MATERIALS AND METHODS: Five consecutive HIV infected patients with IRIS due to mycobacterial infection were studied. Intercurrent infection and poor drug compliance were excluded as causes of presentation. The chest radiological appearances at the time of starting HAART and at the time of diagnosis of IRIS were compared. RESULTS: In these five patients there was clinical and radiological deterioration, occurring between 10 days and 7 months after starting HAART, leading to unmasking of previously undiagnosed mycobacterial infection or to worsening of mycobacterial disease. All five patients had HAART-induced increases in CD4+ T lymphocyte counts and reductions in peripheral blood HIV "viral load". Chest radiographic abnormalities due to IRIS included marked mediastinal lymphadenopathy in three patients-severe enough to produce tracheal compression in two patients (one of whom had stridor)-and was associated with new pulmonary infiltrates in two patients. The other two patients had new infiltrates, which in one patient was associated with a pleural effusion. CONCLUSION: These cases illustrate the diverse chest radiographic appearances of IRIS occurring after HAART in patients with mycobacterial and HIV co-infection. Marked mediastinal lymphadenopathy occurred in three of these five patients (with associated tracheal narrowing in two patients); four patients developed pulmonary infiltrates and one had an effusion. The cases further highlight that the onset of IRIS may be delayed for several months after HAART is started.

Kaposi's sarcoma infiltrating skeletal muscle.

An HIV-1 antibody positive black African man with plasma cell variant Castleman's disease and cutaneous Kaposi's sarcoma, despite receiving chemotherapy, had progressive disease. In addition, he developed pain and swelling behind the right knee. Histology of an ultrasound guided biopsy showed Kaposi's sarcoma infiltrating the head of gastrocnemius.

Intratesticular lipoma.

Benign intratesticular lesions are rare. We describe the second reported case of an intratesticular lipoma and discuss the limitations of ultrasonography in differentiating benign from malignant conditions occurring within the testis.

Pneumococcal meningitis in children: relationship of antibiotic resistance to clinical characteristics and outcomes.

BACKGROUND: The relationship of antibiotic susceptibility to clinical outcome in children with pneumococcal meningitis is uncertain. Previous studies have been limited by inclusion of relatively few patients infected with nonsusceptible pneumococci and inconsistent use of empiric vancomycin. METHODS: Medical records of 86 children with culture-confirmed pneumococcal meningitis at a single institution from October, 1991, to October, 1999, were retrospectively reviewed, and differences in presentation and outcome based on antibiotic susceptibility of pneumococcal isolates were assessed. RESULTS: Of 86 isolates 34 were nonsusceptible to penicillin (12 resistant). Of 60 isolates for which cefotaxime susceptibility data were available, 17 were nonsusceptible (12 resistant). Antibiotic susceptibility was not significantly associated with death, intensive care unit admission, mechanical ventilation, focal neurologic deficits, seizures, secondary fever, abnormal neuroimaging studies or hospital days. Children with penicillin-resistant isolates had significantly higher median blood leukocyte counts (24,100/microliter vs. 15,700/microliter, P = 0.03) and lower median CSF protein concentrations (85 mg/dl vs. 219 mg/dl, P = 0.04), were more likely to have a CSF glucose concentration of > or = 50 mg/dl (7 of 11 vs. 15 of 68, P = 0.009) and had lower rates of sensorineural hearing loss (1 of 8 vs. 25 of 40, P = 0.02) than children with isolates that were not resistant to penicillin. Children with cefotaxime-nonsusceptible isolates had an increased median duration of primary fever compared with those with nonsusceptible strains (6 days vs. 3.5 days, P = 0.02). CONCLUSIONS: In children with pneumococcal meningitis, penicillin resistance was associated with a reduced risk of hearing loss, while cefotaxime resistance was associated with a longer duration of fever. Other outcome measures were not significantly influenced by the antibiotic susceptibility of pneumococcal isolates.

Neonicotinoids: insecticides acting on insect nicotinic acetylcholine receptors.

Imidacloprid is increasingly used worldwide as an insecticide. It is an agonist at nicotinic acetylcholine receptors (nAChRs) and shows selective toxicity for insects over vertebrates. Recent studies using binding assays, molecular biology and electrophysiology suggest that both alpha- and non-alpha-subunits of nAChRs contribute to interactions of these receptors with imidacloprid. Electrostatic interactions of the nitroimine group and bridgehead nitrogen in imidacloprid with particular nAChR amino acid residues are likely to have key roles in determining the selective toxicity of imidacloprid. Chemical calculation of atomic charges of the insecticide molecule and a site-directed mutagenesis study support this hypothesis.

Alternative splicing of a Drosophila GABA receptor subunit gene identifies determinants of agonist potency.

Alternative splicing of the Drosophila melanogaster Rdl gene yields four ionotropic GABA receptor subunits. The two Rdl splice variants cloned to date, RDL(ac) and RDL(bd) (DRC17-1-2), differ in their apparent agonist affinity. Here, we report the cloning of a third splice variant of Rdl, RDL(ad). Two-electrode voltage clamp electrophysiology was used to investigate agonist pharmacology of this expressed subunit following cRNA injection into Xenopus laevis oocytes. The EC(so) values for GABA and its analogues isoguvacine, muscimol, isonipecotic acid and 3-amino sulphonic acid on the RDL(ad) homomeric receptor differed from those previously described for RDL(ac) and DRC17-1-2 receptors. In addition to providing a possible physiological role for the alternative splicing of Rdl, these data delineate a hitherto functionally unassigned region of the N-terminal domain of GABA receptor subunits, which affects agonist potency and aligns closely with known determinants of potency in nicotinic acetylcholine receptors. Thus, using expression in Xenopus oocytes, we have demonstrated differences in agonist potency for the neurotransmitter GABA (and four analogues) between splice variant products of the Drosophila melanogaster Rdl gene encoding homomer-forming GABA receptor subunits.