Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms.

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K. brevis in seawater and carried inland within marine aerosol. Exposure to K. brevis occurs during residential, recreational, and occupational activities and has been associated with upper respiratory tract (URT) symptoms in healthy and medically vulnerable individuals. Additionally, ingestion of brevetoxin-contaminated seafood causes neurotoxic shellfish poisoning (NSP), and severe headaches prompting emergency department visits which occur in excess during K. brevis blooms. The current study examined a dose-response relationship between K. brevis in coastal waters and URT and NSP-like symptoms and headaches among southwest Florida residents. Data on past medical history (PMH) and medical symptoms were collected from the participants (n = 258) in five southwest Florida counties between June 2019 to August 2021. A dose-response relationship was observed between K. brevis blooms and reporting of URT and NSP-like symptoms and headaches. Reporting of NSP-like symptoms was higher among participants with a PMH of migraines, chronic fatigue syndrome (CFS) and mild memory loss, while the association of headaches with K. brevis blooms was accentuated among individuals with a PMH of migraines. These results suggest further investigations into the threshold of aerosolized brevetoxin dose required to elicit URT, headaches and/or NSP-like symptoms. These symptoms ultimately cause significant public health safety concerns, primarily among vulnerable populations with preexisting neurological conditions.

Asymmetric mass ratios for bright double neutron-star mergers.

The discovery of a radioactively powered kilonova associated with the binary neutron-star merger GW170817 remains the only confirmed electromagnetic counterpart to a gravitational-wave event1,2. Observations of the late-time electromagnetic emission, however, do not agree with the expectations from standard neutron-star merger models. Although the large measured ejecta mass3,4 could be explained by a progenitor system that is asymmetric in terms of the stellar component masses (that is, with a mass ratio q of 0.7 to 0.8)5, the known Galactic population of merging double neutron-star systems (that is, those that will coalesce within billions of years or less) has until now consisted only of nearly equal-mass (q > 0.9) binaries6. The pulsar PSR J1913+1102 is a double system in a five-hour, low-eccentricity (0.09) orbit, with an orbital separation of 1.8 solar radii7, and the two neutron stars are predicted to coalesce in [Formula: see text] million years owing to gravitational-wave emission. Here we report that the masses of the pulsar and the companion neutron star, as measured by a dedicated pulsar timing campaign, are 1.62 ± 0.03 and 1.27 ± 0.03 solar masses, respectively. With a measured mass ratio of q = 0.78 ± 0.03, this is the most asymmetric merging system reported so far. On the basis of this detection, our population synthesis analysis implies that such asymmetric binaries represent between 2 and 30 per cent (90 per cent confidence) of the total population of merging binaries. The coalescence of a member of this population offers a possible explanation for the anomalous properties of GW170817, including the observed kilonova emission from that event.

Complication rate among people with diabetes at low risk of foot ulceration in Fife, UK: an analysis of routinely collected data.

AIMS: To estimate the rate at which people with diabetes and a low risk of foot ulceration change diabetic foot ulceration risk status over time, and to estimate the rate of ulceration, amputation and death among this population. METHODS: We conducted an observational study of 10 421 people with diabetes attending foot screening in an outpatient setting in NHS Fife, UK, using routinely collected data from a national diabetes register, NHS SCI Diabetes. We estimated the proportion of people who changed risk status and the cumulative incidence of ulceration, amputation and death, respectively, among people with diabetes at low risk of diabetic foot ulceration at 2-year follow-up. RESULTS: At 2-year follow-up, 5.1% (95% CI 4.7, 5.6) of people with diabetes classified as low risk at their first visit had progressed to moderate risk. The cumulative incidence of ulceration, amputation and death was 0.4% (95% CI 0.3, 0.6), 0.1% (95% CI 0.1, 0.2) and 3.4% (95% CI 3.1, 3.8), respectively. CONCLUSIONS: At 2-year follow-up, 5% of people at low risk of diabetic foot ulceration changed clinical risk status and <1% of people experienced foot ulceration or amputation. These findings provide information which will help to inform the current debate regarding optimal foot screening intervals.

The development and validation of a multivariable prognostic model to predict foot ulceration in diabetes using a systematic review and individual patient data meta-analyses.

AIMS: Diabetes guidelines recommend screening for the risk of foot ulceration but vary substantially in the underlying evidence base. Our purpose was to derive and validate a prognostic model of independent risk factors for foot ulceration in diabetes using all available individual patient data from cohort studies conducted worldwide. METHODS: We conducted a systematic review and meta-analysis of individual patient data from 10 cohort studies of risk factors in the prediction of foot ulceration in diabetes. Predictors were selected for plausibility, availability and low heterogeneity. Logistic regression produced adjusted odds ratios (ORs) for foot ulceration by ulceration history, monofilament insensitivity, any absent pedal pulse, age, sex and diabetes duration. RESULTS: The 10 studies contained data from 16 385 participants. A history of foot ulceration produced the largest OR [6.59 (95% CI 2.49 to 17.45)], insensitivity to a 10 g monofilament [3.18 (95% CI 2.65 to 3.82)] and any absent pedal pulse [1.97 (95% CI 1.62 to 2.39)] were consistently, independently predictive. Combining three predictors produced sensitivities between 90.0% (95% CI 69.9% to 97.2%) and 95.3% (95% CI 84.5% to 98.7%); the corresponding specificities were between 12.1% (95% CI 8.2% to 17.3%) and 63.9% (95% CI 61.1% to 66.6%). CONCLUSIONS: This prognostic model of only three risk factors, a history of foot ulceration, an inability to feel a 10 g monofilament and the absence of any pedal pulse, compares favourably with more complex approaches to foot risk assessment recommended in clinical diabetes guidelines.

Inhibition of ADAM10 promotes the clearance of Aß across the BBB by reducing LRP1 ectodomain shedding.

BACKGROUND: Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Aß) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer's disease (AD). One of the receptors responsible for the transport of Aß in the BBB is the low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at the cell surface, which prevents endocytic transport of ligands. Previously, we reported a strong inverse correlation between LRP1 shedding in the brain and Aß transit across the BBB. Several proteases contribute to the ectodomain shedding of LRP1 including the α-secretase, a desintegrin and metalloproteinase domain containing protein 10 (ADAM10). METHODS: The role of ADAM10 in the shedding of LRP1 and Aß BBB clearance was assessed through pharmacological inhibition of ADAM10 in an in vitro model of the BBB and through the use of ADAM10 endothelial specific knock-out mice. In addition, an acute treatment paradigm with an ADAM10 inhibitor was also tested in an AD mouse model to assess the effect of ADAM10 inhibition on LRP1 shedding and Aßbrain accumulation. RESULTS: In the current studies, inhibition of ADAM10 reduced LRP1 shedding in brain endothelial cultures and increased Aß42 transit across an in vitro model of the BBB. Similarly, transgenic ADAM10 endothelial knockout mice displayed lower LRP1 shedding in the brain and significantly enhanced Aß clearance across the BBB compared to wild-type animals. Acute treatment with the ADAM10-selective inhibitor GI254023X in an AD mouse model substantially reduced brain LRP1 shedding and increased Aß40 levels in the plasma, indicating enhanced Aß transit from the brain to the periphery. Furthermore, both soluble and insoluble Aß40 and Aß42 brain levels were decreased following GI254023X treatment, but these effects lacked statistical significance. CONCLUSIONS: These studies demonstrate a role for ADAM10 in the ectodomain shedding of LRP1 in the brain and the clearance of Aß across the BBB, which may provide a novel strategy for attenuating Aß accumulation in the AD brain.

A repeating fast radio burst.

Fast radio bursts are millisecond-duration astronomical radio pulses of unknown physical origin that appear to come from extragalactic distances. Previous follow-up observations have failed to find additional bursts at the same dispersion measure (that is, the integrated column density of free electrons between source and telescope) and sky position as the original detections. The apparent non-repeating nature of these bursts has led to the suggestion that they originate in cataclysmic events. Here we report observations of ten additional bursts from the direction of the fast radio burst FRB 121102. These bursts have dispersion measures and sky positions consistent with the original burst. This unambiguously identifies FRB 121102 as repeating and demonstrates that its source survives the energetic events that cause the bursts. Additionally, the bursts from FRB 121102 show a wide range of spectral shapes that appear to be predominantly intrinsic to the source and which vary on timescales of minutes or less. Although there may be multiple physical origins for the population of fast radio bursts, these repeat bursts with high dispersion measure and variable spectra specifically seen from the direction of FRB 121102 support an origin in a young, highly magnetized, extragalactic neutron star.

Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice.

Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4(+) T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (ßGlu69), and HLA-DPB1*02:01 is the most prevalent ßGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4(+) T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T-cell hybridomas expressed TCR Vß6, and a subset of these hybridomas expressed identical or nearly identical ß-chains that were paired with different α-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4(+) T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be(2+) cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity.

MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4⁺ T-cell priming.

Beryllium exposure results in beryllium hypersensitivity in a subset of exposed individuals, leading to granulomatous inflammation and fibrosis in the lung. In addition to its antigenic properties, beryllium has potent adjuvant activity that contributes to sensitization via unknown pathways. Here we show that beryllium induces cellular death and release of interleukin (IL)-1α and DNA into the lung. Release of IL-1α was inflammasome independent and required for beryllium-induced neutrophil recruitment into the lung. Beryllium enhanced classical dendritic cell (cDC) migration from the lung to draining lymph nodes (LNs) in an IL-1R-independent manner, and the accumulation of activated cDCs in the LN was associated with increased priming of CD4(+) T cells. DC migration was reduced in Toll-like receptor 9 knockout (TLR9KO) mice; however, cDCs in the LNs of TLR9-deficient mice were highly activated, suggesting a role for more than one innate receptor in the effects on DCs. The adjuvant effects of beryllium on CD4(+) T-cell priming were similar in wild-type, IL-1R-, caspase-1-, TLR2-, TLR4-, TLR7-, and TLR9-deficient mice. In contrast, DC migration, activation, and the adjuvant effects of beryllium were significantly reduced in myeloid differentiation primary response gene 88 knockout (MyD88KO) mice. Collectively, these data suggest that beryllium exposure results in the release of damage-associated molecular patterns that engage MyD88-dependent receptors to enhance pulmonary DC function.

'Painting a path to wellness': correlations between participating in a creative activity group and improved measured mental health outcome.

Responding to a call for quantitative outcome evidence about the therapeutic relationship between creative activity and mental health, this study examined the mental health outcomes of inpatients participating in art- and craft-based creative therapies at a private psychiatric hospital over a 5-year period. The creative activity group sample (n= 403) improved from admission to discharge across four different psychometric measures with moderate to strong mean effect sizes. Reductions from pre- to post-treatment in both self-reported and clinician-rated symptoms are clearly demonstrated for the creative activity group participant sample. Research findings establish that participation in creative activity has potential benefits for people experiencing mental health problems.

The value of FDG positron emission tomography/computerised tomography (PET/CT) in pre-operative staging of colorectal cancer: a systematic review and economic evaluation.

OBJECTIVES: In the UK, colorectal cancer (CRC) is the third most common malignancy (behind lung and breast cancer) with 37,514 cases registered in 2006: around two-thirds (23,384) in the colon and one-third (14,130) in the rectum. Treatment of cancers of the colon can vary considerably, but surgical resection is the mainstay of treatment for curative intent. Following surgical resection, there is a comprehensive assessment of the tumour, it's invasion characteristics and spread (tumour staging). A number of imaging modalities are used in the pre-operative staging of CRCs including; computerised tomography (CT), magnetic resonance imaging, ultrasound imaging and positron emission tomography (PET). This report examines the role of CT in combination with PET scanning (PET/CT 'hybrid' scan). The research objectives are: to evaluate the diagnostic accuracy and therapeutic impact of fluorine-18-deoxyglucose (FDG) PET/CT for the pre-operative staging of primary, recurrent and metastatic cancer using systematic review methods; undertake probabilistic decision-analytic modelling (using Monte Carlo simulation); and conduct a value of information analysis to help inform whether or not there is potential worth in undertaking further research. DATA SOURCES: For each aspect of the research - the systematic review, the handsearch study and the economic evaluation - a database was assembled from a comprehensive search for published and unpublished studies, which included database searches, reference lists search and contact with experts. In the systematic review prospective and retrospective patient series (diagnostic cohort) and randomised controlled trials (RCTs) were eligible for inclusion. Both consecutive series and series that are not explicitly reported as consecutive were included. REVIEW METHODS: Two reviewers extracted all data and applied the criteria independently and resolved disagreements by discussion. Data to populate 2 × 2 contingency tables consisting of the number of true positives, true negatives, false positives and false negatives using the studies' own definitions were extracted, as were data relating to changes in management. Fourteen items from the Quality Assessment of Diagnostic Accuracy Studies checklist were used to assess the methodological quality of the included studies. Patient-level data were used to calculate sensitivity and specificity with confidence intervals (CIs). Data were plotted graphically in forest plots. For the economic evaluation, economic models were designed for each of the disease states: primary, recurrent and metastatic. These were developed and populated based on a variety of information sources (in particular from published data sources) and literature, and in consultation with clinical experts. RESULTS: The review found 30 studies that met the eligibility criteria. Only two small studies evaluated the use of FDG PET/CT in primary CRC, and there is insufficient evidence to support its routine use at this time. The use of FDG PET/CT for the detection of recurrent disease identified data from five retrospective studies from which a pooled sensitivity of 91% (95% CI 0.87% to 0.95%) and specificity of 91% (95% CI 0.85% to 0.95%) were observed. Pooled accuracy data from patients undergoing staging for suspected metastatic disease showed FDG PET/CT to have a pooled sensitivity of 91% (95% CI 87% to 94%) and a specificity of 76% (95% CI 58% to 88%), but the poor quality of the studies means the validity of the data may be compromised by several biases. The separate handsearch study did not yield any additional unique studies relevant to FDG PET/CT. Models for recurrent disease demonstrated an incremental cost-effectiveness ratio of £ 21,409 per quality-adjusted life-year (QALY) for rectal cancer, £ 6189 per QALY for colon cancer and £ 21,434 per QALY for metastatic disease. The value of handsearching to identify studies of less clearly defined or reported diagnostic tests is still to be investigated. CONCLUSIONS: The systematic review found insufficient evidence to support the routine use of FDG PET/CT in primary CRC and only a small amount of evidence supporting its use in the pre-operative staging of recurrent and metastatic CRC, and, although FDG PET/CT was shown to change patient management, the data are divergent and the quality of research is generally poor. The handsearch to identify studies of less clearly defined or reported diagnostic tests did not find additional studies. The primary limitations in the economic evaluations were due to uncertainty and lack of available evidence from the systematic reviews for key parameters in each of the five models. In order to address this, a conservative approach was adopted in choosing DTA estimates for the model parameters. Probabilistic analyses were undertaken for each of the models, incorporating wide levels of uncertainty particularly for the DTA estimates. None of the economic models reported cost-savings, but the approach adopted was conservative in order to determine more reliable results given the lack of current information. The economic evaluations conclude that FDG PET/CT as an add-on imaging device is cost-effective in the pre-operative staging of recurrent colon, recurrent rectal and metastatic disease but not in primary colon or rectal cancers. There would be value in undertaking an RCT with a concurrent economic evaluation to evaluate the therapeutic impact and cost-effectiveness of FDG PET/CT compared with conventional imaging (without PET) for the pre-operative staging of recurrent and metastatic CRC.

Demonstration of safety in Alzheimer's patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study.

BACKGROUND: Nilvadipine may lower rates of conversion from mild-cognitive impairment to Alzheimer's disease (AD), in hypertensive patients. However, it remains to be determined whether treatment with nilvadipine is safe in AD patients, given the higher incidence of orthostatic hypotension (OH) in this population, who may be more likely to suffer from symptoms associated with the further exaggeration of a drop in BP. OBJECTIVE: The aim of this study was to investigate the safety and tolerability of nilvadipine in AD patients. METHODS: AD patients in the intervention group (n = 56) received nilvadipine 8 mg daily over 6-weeks, compared to the control group (n = 30) who received no intervention. Differences in systolic (SBP) and diastolic (DBP) blood pressure, before and after intervention, was assessed using automated sphygmomanometer readings and ambulatory BP monitors (ABP), and change in OH using a finometer. Reporting of adverse events was monitored throughout the study. RESULTS: There was a significant reduction in the SBP of treated patients compared to non-treated patients but no significant change in DBP. Individuals with higher initial blood pressure (BP) had greater reduction in BP but individuals with normal BP did not experience much change in their BP. While OH was present in 84% of the patients, there was no further drop in BP recorded on active stand studies. There were no significant differences in adverse event reporting between groups. CONCLUSION: Nilvadipine was well tolerated by patients with AD. This study supports further investigation of its efficacy as a potential treatment for AD.

Reducing postoperative pain by changing the process.

Untreated postoperative pain is an important ethical and financial issue that can lead to unnecessary suffering and prolonged stays in hospital. Despite the availability of effective analgesics and a growing body of published material that supports their use, postoperative pain remains a problem worldwide. To reduce acute postoperative pain, we introduced an intervention combining evidence-based analgesic protocols with the education of staff and patients on a surgical ward. The experiences of 68 patients before and 80 patients after the intervention were compared (worst pain scores, duration of pain, and satisfaction). Inadequately controlled pain was significantly reduced after the intervention, which suggests that the introduction of analgesic protocols supported by the education of staff and patients can be beneficial. Despite this, severe pain remained relatively common, indicating room for improvement. Duration of pain and patient satisfaction were not affected by the intervention, and patient satisfaction remained high throughout the study.

The risk of foot ulceration in people with diabetes screened in community settings: findings from a cohort study.

BACKGROUND: Annual foot checks are recommended in patients with diabetes mellitus (DM) to identify those at risk of foot ulceration. Systematic reviews have found few studies evaluating the predictive value of tests in community-based diabetic populations. AIM: To quantify the predictive value of clinical risk factors in relation to foot ulceration in a community population. METHODS: A cohort of 1192 people with diabetes receiving care in community settings was recruited and a screening procedure, covering symptoms, signs and diagnostic tests was conducted at baseline. At an average 1-year follow-up patients who developed a foot ulcer were identified by an independent blind assessor. Multivariable analysis was performed to identify clinical predictors of foot ulceration. FINDINGS: The incidence of foot ulceration was 1.93% [95% confidence interval (CI) 1.27-2.89). Three time-independent clinical predictors with five factors were selected: previous amputation [odds ratio (OR) 14.7, 95% CI 3.1-69.5), use of insulin before 3 months with inability to distinguish between cool and cold temperatures (OR 2.97, 95% CI 1.9-4.5) and failure to obtain at least one blood pressure reading for the calculation of ankle-brachial index with the failure to feel touch with a 10-g monofilament (OR 1.7, 95% CI 1.3-2.2). INTERPRETATION: Recommendations for annual diabetic foot check in low-risk, community-based patients should be reviewed as absolute events of ulceration are low. The accuracy of foot risk assessment tools to predict ulceration requires evaluation in randomized controlled trials with concurrent economic evaluations.

Practice-based cone-beam computed tomography: a review.

Sectional imaging is a useful tool for the dental practitioner, especially in the fields of oral surgery and implant dentistry. Until recently, the most readily available way to gain three-dimensional information has been computed tomography (CT). The main drawbacks to using this technique have been the substantial dose of ionising radiation and accessibility. Cone-beam computed tomography (CBCT) allows 3D imaging to be made using bespoke equipment designed for the dental practice environment. Exposure to ionising radiation is substantially lower than that for an average x-ray CT scan, but in most cases is still greater than when other dental radiographs are taken. Various guidelines are now in the public domain and these are referenced within this review of CBCT. The concepts of appropriate selection criteria and optimisation of imaging parameters are stressed, along with compliance with the regulations relating to the use of ionising radiation-Ionising Radiation Regulations 1999 and Ionising Radiation (Medical Exposure) Regulations 2000-and training requirements.

Pulsar discovery by global volunteer computing.

Einstein@Home aggregates the computer power of hundreds of thousands of volunteers from 192 countries to mine large data sets. It has now found a 40.8-hertz isolated pulsar in radio survey data from the Arecibo Observatory taken in February 2007. Additional timing observations indicate that this pulsar is likely a disrupted recycled pulsar. PSR J2007+2722's pulse profile is remarkably wide with emission over almost the entire spin period; the pulsar likely has closely aligned magnetic and spin axes. The massive computing power provided by volunteers should enable many more such discoveries.

How will area regeneration impact on health? Learning from the GoWell study.

OBJECTIVES: To establish the theoretical and perceived links between area regeneration and health in a Scottish context in order to inform a comprehensive evaluation of regeneration activity. The evaluation will include health outcomes. STUDY DESIGN: Mixed method combining and comparing key informant interviews with policy analysis. METHODS: Analysis of identified links between elements of regeneration activity and health was undertaken of published policies and strategies which described regeneration for Scotland and the city of Glasgow. Interviews with key informants explored their understanding of the inputs to regeneration, and the pathways between regeneration and better health outcomes. RESULTS: The policy analysis and interviews revealed a holistic approach to a complex problem. Both identified a need for action to improve housing, neighbourhoods and services, education, employment, community participation and social issues. Improved health was identified as an emergent property. Interviewees identified a need to augment the established structural components with a more person-centred approach, fostering confidence and higher aspirations, but were uncertain how to achieve this. The interviews revealed a lack of confidence that current practice would deliver all the components of the holistic model. CONCLUSIONS: A holistic model of regeneration appears to inform policy, but is proving difficult to deliver. Improved health and reduced health inequalities were not primary objectives but emergent properties. In light of this, the ability of regeneration to actively maximize positive health impacts, particularly if this requires focused planning or opportunity costs to other activities, is questioned.

Apolipoprotein E genotype and oxidative stress response to traumatic brain injury.

Traumatic Brain Injury (TBI) is known to result in oxidative stress, and as variation at the Apolipoprotein E (APOE) gene has been shown to influence outcome following TBI, but through as yet unclear mechanisms, we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI. We administered a controlled cortical impact (CCI) injury or sham injury to transgenic mice expressing either human APOE3 or APOE4 on a murine APOE-deficient background. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray analysis was performed on unpooled samples from three mice per group to determine the genomic response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI or sham injury for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect of injury compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype dependent effects on outcome following TBI.

Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury.

The different alleles of the apolipoprotein E gene (APOE-gene, ApoE-protein) have been reported to influence recovery after traumatic brain injury (TBI) in both human patients and animal models, with the e4 allele typically conferring poorer prognosis for recovery. How the E4 allele, and consequently the ApoE4 isoform, affects recovery is unknown, but proposed mechanisms include neurogenesis, inflammatory response and amyloid processing or metabolism. Using the controlled cortical impact (CCI) model of brain injury and microarray technology we have characterized the genomic response to injury in the brains of APOE2, APOE3 and APOE4 transgenic mice and identified quantitatively and qualitatively significantly different profiles of gene expression in both the hippocampus and the cortex of the APOE3 mice compared to APOE4. The observed gene regulation predicts functional consequences including effects on inflammatory processes, cell growth and proliferation, and cellular signaling, and may suggest that the poor recovery post-TBI in APOE4 animals and human patients is less likely to result from a specific activation of neurodegenerative mechanisms than a loss of reparative capability.

The use of the Index of Orthodontic Treatment Need in dental primary care.

OBJECTIVES: The primary objective of this survey was to assess the use of the Index of Orthodontic Treatment Need (IOTN) in dental primary care (Scottish general dental services - SGDS), and to compare orthodontic specialists (OS) and general dental practitioners (GDPs). The secondary objective was to explore the attitudes to mandatory introduction of the IOTN into the SGDS. DESIGN: Postal, self completed questionnaire. SETTING: Dental primary care, Scotland.Subjects Randomly selected sample of general dental practitioners (GDPs), n = 315, and all orthodontic specialist practitioners (OS), n = 49, identified as working in the SGDS. MAIN OUTCOME MEASURES: Prevalence and experience of using the IOTN in the SGDS. RESULTS: Response rate was 46% (n = 169). Eighty-four percent of respondents did not use the IOTN. Thirty-five percent of respondent GDPs had never heard of the IOTN. Respondents reported using the IOTN as an inter-colleague communication tool and to grade case complexity. GDPs perceived the IOTN as beneficial in setting national standards of practice; OS saw it as a tool to justify the allocation of NHS resources to patients. Responses indicate concerns that IOTN introduction will restrict access to orthodontic care. CONCLUSIONS: The IOTN is not widely used in the SGDS but is perceived as standardising treatment need assessment by GDPs and justifying the allocation of NHS orthodontic resources to patients amongst OS. Introduction of mandatory IOTN grading is likely to be contentious - the following needs to be considered: the index profile should be raised; its advantages highlighted; concerns about restricted access to orthodontic care addressed; and perceived need for locally accessed training met.