Transcriptional Signatures of Sleep Duration Discordance in Monozygotic Twins.

Introduction: Habitual short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (eg, genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of habitual short sleep duration on gene expression. Therefore, we investigated gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Methods: Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD = 18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with 2 weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Finally, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. Results: The mean 24-hour sleep duration of the total sample was 439.2 minutes (SD = 46.8 minutes; range 325.4-521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD = 21.2; range 45.9-114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such as interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Conclusions: Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of habitual short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular, and inflammatory outcomes.

Dietary intake is associated with respiratory health outcomes and DNA methylation in children with asthma.

BACKGROUND: Asthma is an increasingly common chronic disease among children, and data point toward a complex mechanism involving genetic, environmental and epigenetic factors. Epigenetic modifications such as DNA hypo- or hyper-methylation have been shown to occur in response to environmental exposures including dietary nutrients. METHODS: Within the context of the asthma randomized trial of indoor wood smoke (ARTIS) study, we investigated relationships between diet, asthma health measures, and DNA methylation. Asthma health measures included a quality of life instrument, diurnal peak flow variability (dPFV) and forced expiratory volume in the first second (FEV1). Dietary intake was assessed with a food frequency questionnaire. Methylation levels of LINE-1 repetitive element and two promoter CpG sites for interferon gamma (IFNγ, -186 and -54) from buccal cell DNA were measured using pyrosequencing assays. RESULTS: Data were collected on 32 children with asthma living in western Montana who were recruited to the ARTIS study. Selenium and several methyl donor dietary nutrients were positively associated with the asthma quality of life measure. Intake of methyl donating nutrients including folate was positively associated LINE-1 methylation and negatively associated with IFNγ CpG-186. Higher levels of LINE-1 methylation were associated with greater dPFV. CONCLUSION: We identified several nutrients that were associated with improved quality of life measures among children with asthma. The IFNγ promoter CpG site -186 but not -54 was associated with the intake of selected dietary nutrients. However, in this small population of children with asthma, the IFNγ promoter CpG sites were not associated with respiratory health measures so it remains unclear through which epigenetic mechanism these nutrients are impacting the quality of life measure. These findings add to the evidence that dietary nutrients, particularly foods containing methyl donors, may be important for epigenetic regulation as it pertains to the control of asthma. Trial registration ClincialTrials.gov NCT00807183. Registered 10 December 2008.

A pilot randomized controlled trial comparing effectiveness of prism glasses, visual search training and standard care in hemianopia.

OBJECTIVE: Pilot trial to compare prism therapy and visual search training, for homonymous hemianopia, to standard care (information only). METHODS: Prospective, multicentre, parallel, single-blind, three-arm RCT across fifteen UK acute stroke units. PARTICIPANTS: Stroke survivors with homonymous hemianopia. INTERVENTIONS: Arm a (Fresnel prisms) for minimum 2 hours, 5 days per week over 6 weeks. Arm b (visual search training) for minimum 30 minutes, 5 days per week over 6 weeks. Arm c (standard care-information only). INCLUSION CRITERIA: Adult stroke survivors (>18 years), stable hemianopia, visual acuity better than 0.5 logMAR, refractive error within ±5 dioptres, ability to read/understand English and provide consent. OUTCOMES: Primary outcomes were change in visual field area from baseline to 26 weeks and calculation of sample size for a definitive trial. Secondary measures included Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual, Short Form-12 questionnaires and Radner reading ability. Measures were post-randomization at baseline and 6, 12 and 26 weeks. RANDOMIZATION: Randomization block lists stratified by site and partial/complete hemianopia. BLINDING: Allocations disclosed to patients. Primary outcome assessor blind to treatment allocation. RESULTS: Eighty-seven patients were recruited: 27-Fresnel prisms, 30-visual search training and 30-standard care; 69% male; mean age 69 years (SD 12). At 26 weeks, full results for 24, 24 and 22 patients, respectively, were compared to baseline. Sample size calculation for a definitive trial determined as 269 participants per arm for a 200 degree2 visual field area change at 90% power. Non-significant relative change in area of visual field was 5%, 8% and 3.5%, respectively, for the three groups. Visual Function Questionnaire responses improved significantly from baseline to 26 weeks with visual search training (60 [SD 19] to 68.4 [SD 20]) compared to Fresnel prisms (68.5 [SD 16.4] to 68.2 [18.4]: 7% difference) and standard care (63.7 [SD 19.4] to 59.8 [SD 22.7]: 10% difference), P=.05. Related adverse events were common with Fresnel prisms (69.2%; typically headaches). CONCLUSIONS: No significant change occurred for area of visual field area across arms over follow-up. Visual search training had significant improvement in vision-related quality of life. Prism therapy produced adverse events in 69%. Visual search training results warrant further investigation.

A systematic review of non-surgical treatments for lentigo maligna.

Lentigo maligna (LM) is the most common melanocytic malignancy of the head and neck. If left untreated, LM can progress to lentigo maligna melanoma (LMM). Complete surgical excision is the gold standard for treatment, however, due to the location, size, and advanced age of patients, surgery is not always acceptable. As a result, there is ongoing interest in alternative, less invasive treatment modalities. The objective was to provide a structured review of key literature reporting the use of radiotherapy, imiquimod and laser therapy for the management of LM in patients where surgical resection is prohibited. An independent review was conducted following a comprehensive search of the National Library of Medicine using MEDLINE and PubMed, Embase, Scopus, ScienceDirect and Cochrane Library databases. Data were presented in tabular format, and crude data pooled to calculate mean recurrence rates for each therapy. 29 studies met the inclusion criteria: radiotherapy 10; topical imiquimod 10; laser therapies 9. Radiotherapy demostrated recurrence rates of up to 31% (mean 11.5%), with follow-up durations of 1-96 months. Topical imiquimod recurrence rates were up to 50% (mean 24.5%), with follow-up durations of 2-49 months. Laser therapy yielded recurrence rates of up to 100% (mean 34.4%), and follow-up durations of 8-78 months. in each of the treatment series the I(2) value measuring statistical heterogeneity exceeded the accepted threshold of 50% and as such a meta-analysis of included data were inappropriate. For non-surgical patients with LM, radiotherapy and topical imiquimod were efficacious treatments. Radiotherapy produced superior complete response rates and fewer recurrences than imiquimod although both are promising non-invasive modalities. There was no consistent body of evidence regarding laser therapy although response rates of up to 100% were reported in low quality studies. A prospective comparative trial is indicated and would provide accurate data on the long-term efficacy and overall utility of these treatments.

A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol.

INTRODUCTION: Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. METHODS AND ANALYSIS: The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05956042.

Presentation, management and outcomes in acute pituitary apoplexy: a large single-centre experience from the United Kingdom.

OBJECTIVE: To study the presentation, management and outcomes and to apply retrospectively the Pituitary Apoplexy Score (PAS) (United Kingdom (UK) guidelines for management of apoplexy) to a large, single-centre series of patients with acute pituitary apoplexy. DESIGN: Retrospective analysis of casenotes at a single neurosurgical centre in Liverpool, UK. RESULTS: Fifty-five patients [mean age, 52·4 years; median duration of follow-up, 7 years] were identified; 45 of 55 (81%) had nonfunctioning adenomas, four acromegaly and six prolactinomas. Commonest presenting features were acute headache (87%), diplopia (47·2%) and visual field (VF) defects (36%). The most frequent ocular palsy involved the 3rd nerve (81%), followed by 6th nerve (34·6%) and multiple palsies (19%). Twenty-three patients were treated conservatively, and the rest had surgery either within 7 days of presentation or delayed elective surgery. Indications for surgery were deteriorating visual acuity and persistent field defects. Patients presenting with VF defects (n = 20) were more likely to undergo surgery (75%) than to be managed expectantly (25%). There was no difference in the rates of complete/near-complete resolution of VF deficits and cranial nerve palsies between those treated conservatively and those who underwent surgery. Endocrine outcomes were also similar. We were able to calculate the PAS for 46 patients: for the group treated with early surgery mean, PAS was 3·8 and for those managed conservatively or with delayed surgery was 1·8. CONCLUSIONS: Patients without VF deficits or whose visual deficits are stable or improving can be managed expectantly without negative impact on outcomes. Clinical severity based on a PAS ≥ 4 appeared to influence management towards emergency surgical intervention.

Coarse particulate matter and airborne endotoxin within wood stove homes.

Emissions from indoor biomass burning are a major public health concern in developing areas of the world. Less is known about indoor air quality, particularly airborne endotoxin, in homes burning biomass fuel in residential wood stoves in higher income countries. A filter-based sampler was used to evaluate wintertime indoor coarse particulate matter (PM10₋2.5) and airborne endotoxin (EU/m³, EU/mg) concentrations in 50 homes using wood stoves as their primary source of heat in western Montana. We investigated number of residents, number of pets, dampness (humidity), and frequency of wood stove usage as potential predictors of indoor airborne endotoxin concentrations. Two 48-h sampling events per home revealed a mean winter PM10₋2.5 concentration (± s.d.) of 12.9 (± 8.6) µg/m³, while PM2.5 concentrations averaged 32.3 (± 32.6) µg/m³. Endotoxin concentrations measured from PM10₋2.5 filter samples were 9.2 (± 12.4) EU/m³ and 1010 (± 1524) EU/mg. PM10₋2.5 and PM2.5 were significantly correlated in wood stove homes (r = 0.36, P < 0.05). The presence of pets in the homes was associated with PM10₋2.5 but not with endotoxin concentrations. Importantly, none of the other measured home characteristics was a strong predictor of airborne endotoxin, including frequency of residential wood stove usage.

Residential indoor PM2.5 in wood stove homes: follow-up of the Libby changeout program.

UNLABELLED: In 2005 through 2008, a small rural mountain valley community engaged in a woodstove changeout program to address concerns of poor ambient air quality. During this program, we assessed changes to indoor air quality before and after the introduction of a new, lower emission woodstove. We previously reported a >70% reduction in indoor PM(2.5) concentrations in homes following the installation of a new Environmental Protection Agency's-certified stove within the home. We report here on follow-up of the experiences in these and other homes over three winters of sample collection. In 21 homes, we compared pre-changeout PM(2.5) concentrations [mean (s.d.) = 45.0 (33.0) µg/m(3)] to multiple post-changeout measures of PM(2.5) concentrations using a DustTrak. The mean reduction (and 95% confidence interval) from pre-changeout to post-changeout was -18.5 µg/m(3) (-31.9, -5.2), adjusting for ambient PM(2.5) , ambient temperature, and other factors. Findings across homes and across years were highly variable, and a subset of homes did not experience a reduction in PM(2.5) following changeout. Reductions were also observed for organic carbon, elemental carbon, and levoglucosan, but increases were observed for dehydroabietic acid and abietic acid. Despite overall improvements in indoor air quality, the varied response across homes may be due to factors other than the introduction of a new woodstove. PRACTICAL IMPLICATIONS: Biomass combustion is a common source of ambient PM(2.5) in many cold-climate communities. The replacement of older model woodstoves with newer technology woodstoves is a potential intervention strategy to improve air quality in these communities. In addition to ambient air, woodstove changeouts should improve residential indoor air quality. We present results from a multi-winter study to evaluate the efficacy of woodstove changeouts on improving indoor air quality. Reductions in indoor PM(2.5) were evident, but this observation was not consistent across all homes. These findings suggest that other factors beyond the introduction of an improved wood burning device are relevant to improving indoor air quality in wood burning homes.

Intervention for intermittent distance exotropia with overcorrecting minus lenses.

AIM: There are numerous treatment options for intermittent distance exotropia. The aim of this study is to evaluate the use of overcorrecting minus lenses as a primary treatment option for intermittent distance exotropia (IDEX) and determine ocular alignment status after 5 years from commencement of the study. METHODS: Prospective nonrandomised longitudinal cohort study in which 21 patients were recruited with a diagnosis of IDEX. Treatment was instigated with the minimum minus lens required to achieve control of the manifest deviation. The strength of lenses was reduced over time while monitoring the results of orthoptic measurements. The results were evaluated by nonparametric (Wilcoxon) and parametric (paired t-test) analysis. RESULTS: Thirteen female and eight male patients were recruited with a mean age of 5 years at the start of treatment. There was a significant reduction in angle of deviation after treatment. Overcorrecting lenses did not appear to induce myopia. Twenty-four per cent of the patients had a successful outcome, 28% had a good outcome, and 33% required surgery at a later date. CONCLUSIONS: Fifty-two per cent of the patients achieved a successful or good outcome with overcorrecting minus lenses alone, and this was maintained for at least 1 year follow-up. Those requiring surgery had been unable to wean out of lenses but had a successful outcome after one procedure. We recommend overcorrecting minus lenses as a primary treatment option for IDEX with the knowledge that surgery, if subsequently required, is safely delayed to an older age without prior loss of binocular vision.

Results of a residential indoor PM2.5 sampling program before and after a woodstove changeout.

UNLABELLED: During 2005-2007, a woodstove changeout program was conducted in a Rocky Mountain valley community in an effort to reduce ambient levels of PM(2.5). In addition to changes in ambient PM(2.5), an opportunity was provided to evaluate the changes in indoor air quality when old stoves were replaced with US Environmental Protection Agency (EPA)-certified woodstoves. PM(2.5) samples were measured in 16 homes prior to and following the changeout. For each sampling event, PM(2.5) mass was continuously measured throughout the 24-h sampling periods, and organic/elemental carbon (OC/EC) and associated chemical markers of woodsmoke were measured from quartz filters. Results showed that average PM(2.5) concentrations and maximum PM(2.5) concentrations were reduced by 71% and 76%, respectively (as measured by TSI DustTraks). Levoglucosan was reduced by 45% following the introduction of the new woodstove. However, the concentrations of resin acids, natural chemicals found in the bark of wood, were increased following the introduction of the new woodstove. There were no discernible trends in methoxphenol levels, likely due to the semi-volatile nature of the species that were measured. Although there is some uncertainty in this study regarding the amount of ambient PM infiltration to the indoor environment, these findings demonstrated a large impact on indoor air quality following this intervention. PRACTICAL IMPLICATIONS: Emissions from residential woodstoves are an important air quality issue (both indoors and ambient) in many regions throughout the US and the world. More specifically, woodstoves have been identified as a major source of PM(2.5) in valley locations throughout the Northern Rocky Mountains, where biomass combustion is the predominant source of home heating. In this study, we present results that demonstrate the dramatic reduction in PM(2.5) concentrations (as measured by TSI, Inc. DustTrak PM(2.5) air samplers) inside homes following the replacement of old, polluting woodstove with new EPA-certified woodstoves.

Exposure matrix development for the Libby cohort.

The Libby, MT, cohort includes current and former residents with potential historical exposure to asbestos-contaminated vermiculite. This cohort includes individuals with a broad range of exposure experiences and work histories. While both occupational and nonoccupational exposure pathways were found to be relevant in recent investigations of health effects among this cohort, there has not been a comprehensive approach to characterizing these varied exposure pathways. Any approach toward assessing historical exposures among this population must account for three general categories: (1) occupational exposures, (2) residential exposures, and (3) exposures related to a variety of nonoccupational activities thought to be associated with vermiculite/asbestos exposure in this community. First, a job exposure matrix is commonly used in occupational epidemiology to assess historical worker exposures, allowing for the incorporation of numerous occupational categories and weighting factors applied to specific jobs for different time periods. Second, residential exposures can best be quantified by integrating individuals' residential histories with data on environmental asbestos contamination in the community. Previous soil or sediment sampling as well as air modeling could inform estimates of time- and spatial-dependent exposure concentrations for a residential exposure matrix. Finally, exposure opportunities due to nonoccupational activities could be weighted by factors such as time, geography, environmental sampling, and an assessment of the relative importance for each pathway. These three matrices for occupational, residential, and activity exposure pathways could be combined or used separately to provide a more comprehensive and quantitative, or semiquantitative, assessment of individual exposure in future epidemiological studies of this cohort.

Indoleamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer's disease hippocampus.

The present immunohistochemical study provides evidence that the kynurenine pathway is up-regulated in Alzheimer's disease (AD) brain, leading to increases in the excitotoxin quinolinic acid (QUIN). We show that the regulatory enzyme of the pathway leading to QUIN synthesis, indoleamine 2,3 dioxygenase (IDO) is abundant in AD compared with controls. In AD hippocampus, both IDO- and QUIN-immunoreactivity (-IR) was detected in cortical microglia, astrocytes and neurones, with microglial and astrocytic expression of IDO and QUIN highest in the perimeter of senile plaques. QUIN-IR was present in granular deposits within the neuronal soma of AD cortex and was also seen uniformly labelling neurofibrillary tangles. Our data imply that QUIN may be involved in the complex and multifactorial cascade leading to neuro-degeneration in AD. These results may open a new therapeutic door for AD patients.

Healthcare waste management: a case study from the National Health Service in Cornwall, United Kingdom.

This paper looks at steps taken towards the development of a 10-year strategy for the management of healthcare waste from the National Health Service (NHS) in Cornwall, United Kingdom. The major issues and challenges that affect the management of waste by the NHS, including its organisational structure and collection infrastructure, are outlined. The waste flows of the main acute medical site are detailed, using waste audits of domestic and clinical bags, redundant equipment, bulky waste, and special waste. Some of the common barriers to change, such as staff habits and public perceptions, are also identified. Recommendations are made with respect to improvements in the overall organisational infrastructure and increased localised control. The recommendations also centre around the formation of strategic partnerships, within the site, between sites and at the broader level between the NHS and its surrounding community. An important challenge to be overcome is the need to progress from the concept of "waste management", to one of sustainable decision making regarding resource use, including methods of waste minimisation at the source and recycling. Staff training and awareness underpin several of the short and medium/long term solutions suggested to reduce the waste at the source and recover value from that produced. These measures could potentially reduce disposal quantities by as much as 20-30% (wt.) and costs by around 25-35%.

Melatonin metabolite excretion among cellular telephone users.

PURPOSE: The relationship between cellular telephone use and excretion of the melatonin metabolite 6-hydroxymelatonin sulfate (6-OHMS) was evaluated in two populations of male electric utility workers (Study 1, n=149; Study 2, n=77). MATERIALS AND METHODS: Participants collected urine samples and recorded cellular telephone use over 3 consecutive workdays. Personal 60-Hz magnetic field (MF) and ambient light exposures were characterized on the same days using EMDEX II meters. A repeated measures analysis was used to assess the effects of cellular telephone use, alone and combined with MF exposures, after adjustment for age, participation month and light exposure. RESULTS: No change in 6-OHMS excretion was observed among those with daily cellular telephone use >25 min in Study 1 (5 worker-days). Study 2 workers with >25 min cellular telephone use per day (13 worker-days) had lower creatinine-adjusted mean nocturnal 6-OHMS concentrations (p=0.05) and overnight 6-OHMS excretion (p=0.03) compared with those without cellular telephone use. There was also a linear trend of decreasing mean nocturnal 6-OHMS/creatinine concentrations (p=0.02) and overnight 6-OHMS excretion (p=0.08) across categories of increasing cellular telephone use. A combined effect of cellular telephone use and occupational 60-Hz MF exposure in reducing 6-OHMS excretion was also observed in Study 2. CONCLUSIONS: Exposure-related reductions in 6-OHMS excretion were observed in Study 2, where daily cellular telephone use of >25 min was more prevalent. Prolonged use of cellular telephones may lead to reduced melatonin production, and elevated 60-Hz MF exposures may potentiate the effect.

Binocular fixation pattern and visual acuity in children with strabismic amblyopia.

BACKGROUND: A prospective study was undertaken to compare the binocular fixation pattern and presence of amblyopia in strabismic children. METHODS: Fifty-three children with manifest strabismus and the ability to cooperate with an optotype acuity test were examined. The binocular fixation pattern and logMAR visual acuity were recorded by separate, masked observers under standardized conditions. The binocular fixation pattern was divided into four grades from alternation to uniocular fixation. RESULTS: Patients who freely alternated did not have amblyopia, while those who maintained or preferred fixation with a given eye tended to have amblyopia in the nonpreferred eye. CONCLUSION: The binocular fixation pattern can be rapidly assessed with minimal equipment and training. These findings confirm the usefulness of a graded assessment of the binocular fixation pattern in the detection of amblyopia.

Melatonin metabolite levels in workers exposed to 60-Hz magnetic fields: work in substations and with 3-phase conductors.

Melatonin suppression by 50/60-Hz magnetic fields represents a plausible biological mechanism for explaining increased health risks in workers. Personal exposure to magnetic fields and ambient light, and excretion of the melatonin metabolite 6-hydroxymelatonin sulfate (6-OHMS), were measured over 3 consecutive workdays in electric utility workers. There was a magnetic field-dependent reduction in adjusted mean nocturnal and post-work 6-OHMS levels among men working more than 2 hours per day in substation and 3-phase environments and no effect among those working 2 hours or less. No changes were observed among men working in 1-phase environments. The results suggest that circular or elliptical magnetic field polarization, or another factor linked to substations and 3-phase electricity, is associated with magnetic field induced melatonin suppression in humans.