Local government's roles in community health and wellbeing in Australia: Insights from Tasmania.

ISSUE ADDRESSED: Local governments are well-placed to respond to communities' health and wellbeing needs. However, in the Australian state of Tasmania, the sector's roles in that respect are unclear. METHODS: We interviewed 10 municipal personnel in Tasmania to understand their views on local governments' community health and wellbeing functions. RESULTS: Participants had an integrative understanding of community health and wellbeing and recognised that collective effort from all tiers of government, community members, and other place-based stakeholders would improve outcomes. They identified several roles local governments have to support and drive such improvements, including in relation to diverse place-specific determinants of health and wellbeing. Capacity and capability to fulfil what is needed varied, with rural and remote councils generally less able than urban counterparts to respond consistently or comprehensively to community members' complex needs. However, in the presence of clear expectations and parameters, and appropriate support from other tiers of government, participants were eager for their councils to do more to improve their communities' health and wellbeing, including via a mandate in legislation. CONCLUSION: Local governments have the potential to do more to improve health and wellbeing outcomes in Tasmania, and the greatest gains could be made by addressing spatial inequalities faced by the sector. That insight is extensible to other comparable jurisdictions. SO WHAT?: We argue the need both for a shared societal goal of equitable wellbeing supported by all tiers of government and for actions proportionate to the needs of council areas.

Impact of Playing Surface on Concussion Symptoms in Young American Football Players.

OBJECTIVE: It has been suggested that sport-related concussion (SRC) occurs more commonly on natural grass compared with artificial turf in contact sports. As playing surface is a potentially modifiable risk factor, this study sought to identify differences in symptoms following SRC on these 2 surfaces in a sample of young American football players. DESIGN: Prospective. SETTING: Part of the multi-institutional North Texas Concussion Registry (ConTex) research project. PARTICIPANTS: Ten-year-old to 24-year-old male American football players (n = 62) who had sustained a helmet-to-ground SRC and presented to a specialty concussion clinic within 14 days of injury. INDEPENDENT VARIABLES: Helmeted impact with grass (n = 33) or artificial turf (n = 29). MAIN OUTCOME MEASURES: Severity and number of symptoms endorsed on the Sport Concussion Assessment Tool 5th Edition (SCAT5) Symptom Evaluation at the time of initial clinical evaluation. RESULTS: Both groups were similar in mean time since injury, concussion history, and history of headache, but the artificial turf group was slightly older, with a mean age of 14.6 versus 13.6 years (P = 0.039). Athletes who sustained a SRC on grass reported significantly higher mean total symptom severity scores (26.6 vs 11.6, P = 0.005) and total number of symptoms (10.3 vs 5.9, P = 0.006) compared with those who were injured on artificial turf. CONCLUSIONS: This may be the first study to examine postconcussive symptoms after SRC as they relate to playing surface. This small sample of young American football players reported higher symptom severity scores and higher total number of symptoms after SRC on natural grass compared with artificial turf.

The Utility of Novel Urinary Biomarkers in Mice for Drug Development Studies.

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there are few reports on the utility of these renal biomarkers in mice, another important and widely used preclinical animal species for drug development studies. The purpose of this study was to assess the value of these recently qualified biomarkers for the early detection of drug-induced kidney injury (DIKI) in different strains of mice using multiple assay panels. To this end, we evaluated biomarker response to kidney injury induced by several nephrotoxic agents including amphotericin B, compound X, and compound Y. Several of the biomarkers were shown to be sensitive to DIKI in mice. When measured, urinary albumin and neutrophil gelatinase-associated lipocalin were highly sensitive to renal tubular injury, regardless of the assay platforms, mouse strain, and nephrotoxic agents. Depending on the type of renal tubular injury, kidney injury molecule-1 was also highly sensitive, regardless of the assay platforms and mouse strain. Osteopontin and cystatin C were modestly to highly sensitive to renal tubular injury, but the assay type and/or the mouse strain should be considered before using these biomarkers. Calbindin D28 was highly sensitive to injury to the distal nephron in mice. To our knowledge, this is the first report that demonstrates the utility of novel urinary biomarkers evaluated across multiple assay platforms and nephrotoxicants in different mice strains with DIKI. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in mice for toxicology studies.

Drainage, irrigation and fibrinolytic therapy (DRIFT) for posthaemorrhagic ventricular dilatation: 10-year follow-up of a randomised controlled trial.

BACKGROUND: Progressive ventricular dilatation after intraventricular haemorrhage (IVH) in preterm infants has a very high risk of severe disability and death. Drainage, irrigation and fibrinolytic therapy (DRIFT), in a randomised controlled trial (RCT), reduced severe cognitive impairment at 2 years. OBJECTIVE: To assess if the cognitive advantage of DRIFT seen at 2 years persisted until school age. PARTICIPANTS: The RCT conducted in four centres recruited 77 preterm infants with IVH and progressive ventricular enlargement over specified measurements. Follow-up was at 10 years of age. INTERVENTION: Intraventricular injection of a fibrinolytic followed by continuous lavage, until the drainage was clear, and standard care consisting of control of expansion by lumbar punctures and if expansion persisted via a ventricular access device. PRIMARY OUTCOME: Cognitive quotient (CQ), derived from the British Ability Scales and Bayley III Scales, and survival without severe cognitive disability. RESULTS: Of the 77 children randomised, 12 died, 2 could not be traced, 10 did not respond and 1 declined at 10-year follow-up. 28 in the DRIFT group and 24 in the standard treatment group were assessed by examiners blinded to the intervention. The mean CQ score was 69.3 (SD=30.1) in the DRIFT group and 53.7 (SD=35.7) in the standard treatment group (unadjusted p=0.1; adjusted p=0.01, after adjustment for the prespecified variables sex, birth weight and IVH grade). Survival without severe cognitive disability was 66% in the DRIFT group and 35% in the standard treatment group (unadjusted p=0.019; adjusted p=0.003). CONCLUSION: DRIFT is the first intervention for posthaemorrhagic ventricular dilatation to objectively demonstrate sustained cognitive improvement. TRIAL REGISTRATION NUMBER: ISRCTN80286058.

Ten-year follow-up of a randomised trial of drainage, irrigation and fibrinolytic therapy (DRIFT) in infants with post-haemorrhagic ventricular dilatation.

BACKGROUND: The drainage, irrigation and fibrinolytic therapy (DRIFT) trial, conducted in 2003-6, showed a reduced rate of death or severe disability at 2 years in the DRIFT compared with the standard treatment group, among preterm infants with intraventricular haemorrhage (IVH) and post-haemorrhagic ventricular dilatation. OBJECTIVES: To compare cognitive function, visual and sensorimotor ability, emotional well-being, use of specialist health/rehabilitative and educational services, neuroimaging, and economic costs and benefits at school age. DESIGN: Ten-year follow-up of a randomised controlled trial. SETTING: Neonatal intensive care units (Bristol, Katowice, Glasgow and Bergen). PARTICIPANTS: Fifty-two of the original 77 infants randomised. INTERVENTIONS: DRIFT or standard therapy (cerebrospinal fluid tapping). MAIN OUTCOME MEASURES: Primary - cognitive disability. Secondary - vision; sensorimotor disability; emotional/behavioural function; education; neurosurgical sequelae on magnetic resonance imaging; preference-based measures of health-related quality of life; costs of neonatal treatment and of subsequent health care in childhood; health and social care costs and impact on family at age 10 years; and a decision analysis model to estimate the cost-effectiveness of DRIFT compared with standard treatment up to the age of 18 years. RESULTS: By 10 years of age, 12 children had died and 13 were either lost to follow-up or had declined to participate. A total of 52 children were assessed at 10 years of age (DRIFT, n = 28; standard treatment, n = 24). Imbalances in gender and birthweight favoured the standard treatment group. The unadjusted mean cognitive quotient (CQ) score was 69.3 points [standard deviation (SD) 30.1 points] in the DRIFT group compared with 53.7 points (SD 35.7 points) in the standard treatment group, a difference of 15.7 points, 95% confidence interval (CI) -2.9 to 34.2 points; p = 0.096. After adjusting for the prespecified covariates (gender, birthweight and grade of IVH), this evidence strengthened: children who received DRIFT had a CQ advantage of 23.5 points (p = 0.009). The binary outcome, alive without severe cognitive disability, gave strong evidence that DRIFT improved cognition [unadjusted odds ratio (OR) 3.6 (95% CI 1.2 to 11.0; p = 0.026) and adjusted OR 10.0 (95% CI 2.1 to 46.7; p = 0.004)]; the number needed to treat was three. No significant differences were found in any secondary outcomes. There was weak evidence that DRIFT reduced special school attendance (adjusted OR 0.27, 95% CI 0.07 to 1.05; p = 0.059). The neonatal stay (unadjusted mean difference £6556, 95% CI -£11,161 to £24,273) and subsequent hospital care (£3413, 95% CI -£12,408 to £19,234) costs were higher in the DRIFT arm, but the wide CIs included zero. The decision analysis model indicated that DRIFT has the potential to be cost-effective at 18 years of age. The incremental cost-effectiveness ratio (£15,621 per quality-adjusted life-year) was below the National Institute for Health and Care Excellence threshold. The cost-effectiveness results were sensitive to adjustment for birthweight and gender. LIMITATIONS: The main limitations are the sample size of the trial and that important characteristics were unbalanced at baseline and at the 10-year follow-up. Although the analyses conducted here were prespecified in the analysis plan, they had not been prespecified in the original trial registration. CONCLUSIONS: DRIFT improves cognitive function when taking into account birthweight, grade of IVH and gender. DRIFT is probably effective and, given the reduction in the need for special education, has the potential to be cost-effective as well. A future UK multicentre trial is required to assess efficacy and safety of DRIFT when delivered across multiple sites. TRIAL REGISTRATION: Current Controlled Trials ISRCTN80286058. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 4. See the NIHR Journals Library website for further project information. The DRIFT trial and 2-year follow-up was funded by Cerebra and the James and Grace Anderson Trust.

Testing fine motor coordination via telehealth: Effects of video characteristics on reliability and validity.

Background There is limited research about the effects of video quality on the accuracy of assessments of physical function. Methods A repeated measures study design was used to assess reliability and validity of the finger-nose test (FNT) and the finger-tapping test (FTT) carried out with 50 veterans who had impairment in gross and/or fine motor coordination. Videos were scored by expert raters under eight differing conditions, including in-person, high definition video with slow motion review and standard speed videos with varying bit rates and frame rates. Results FTT inter-rater reliability was excellent with slow motion video (ICC 0.98-0.99) and good (ICC 0.59) under the normal speed conditions. Inter-rater reliability for FNT 'attempts' was excellent (ICC 0.97-0.99) for all viewing conditions; for FNT 'misses' it was good to excellent (ICC 0.89) with slow motion review but substantially worse (ICC 0.44) on the normal speed videos. FTT criterion validity (i.e. compared to slow motion review) was excellent (ß = 0.94) for the in-person rater and good ( ß = 0.77) on normal speed videos. Criterion validity for FNT 'attempts' was excellent under all conditions ( r ≥ 0.97) and for FNT 'misses' it was good to excellent under all conditions ( ß = 0.61-0.81). Conclusions In general, the inter-rater reliability and validity of the FNT and FTT assessed via video technology is similar to standard clinical practices, but is enhanced with slow motion review and/or higher bit rate.

Cross sectional, qualitative thematic analysis of patient perspectives of disease impact in juvenile idiopathic arthritis-associated uveitis.

BACKGROUND: Chronic health conditions in children can have a significant impact on their quality of life. The aim of this study was to explore the subjective experience of children and young people being treated for chronic, non-infectious uveitis associated with a systemic disease such as juvenile idiopathic arthritis. METHODS: A semi-structured interview was conducted with 10 children and young people aged between 6 and 18 years of age and their parents. RESULTS: Preliminary thematic analysis indicated that both the treatment and complications of the disorder have a significant impact on the quality of life and emotional well-being of patients, not only in terms of the discomfort experienced but also in perceptions of social isolation, anxiety and sense of injustice. CONCLUSION: This study shows that themes including "impact on school", "social factors" and "emotional reactions" are important domains influencing health-related quality of life (HRQoL) in children with chronic uveitis. Inclusion of questions relating to these domains should be considered in future uveitis-specific tools examining HRQoL in these patients.

Adequacy and accuracy of nontrauma center computed tomography: What are we missing?

BACKGROUND: Timely and appropriate use of computed tomography (CT) scans is critical to the evaluation of traumatic injuries. The objective of this study was to assess the adequacy of CT scans performed at nontrauma centers (NTCs) as they pertain to the management of trauma patients. METHODS: Adult patients transferred to our ACS-verified Level I trauma center from any NTC between May and December 2012 were enrolled prospectively. Available CT images from NTCs were reviewed in a blinded fashion by our facility's trauma radiologist; his interpretations were compared with those from the NTC. Interpretations of the trauma centers (TCs) images were compared with the NTC interpretations. Means and proportions were used to summarize the data. RESULTS: A total of 235 consecutive patients with a complete dataset were included, of which, 203 (86.4%) had a CT scan performed at an NTC. Additional imaging was obtained at the TC in 76% of patients with outside CT (154 of 203), with inadequacy of outside CTs for patient workup based on mechanism of injury (76%) and technical inadequacy of outside images (31%) being the main, nonexclusive reasons to repeat imaging. Image interpretation by the trauma radiologist at the TC using NTC images identified missed injuries in 49% of the patients, and 90% of these missed injuries were deemed clinically significant, meaning the injury would have altered patient care had they been identified. When the same body region was imaged at the TC, 54% had missed injuries, of which 76% were deemed significant. CONCLUSION: This study demonstrates inaccuracy in the interpretation of NTC images, which can lead to inappropriate management of trauma patients. Parameters other than imaging need to be used to identify patients requiring a higher level of care. LEVEL OF EVIDENCE: Therapeutic and care management study, level V.

Preoperative Accelerated Partial Breast Irradiation for Early-Stage Breast Cancer: Preliminary Results of a Prospective, Phase 2 Trial.

PURPOSE: To assess the feasibility of utilizing 3-dimensional conformal accelerated partial-breast irradiation (APBI) in the preoperative setting followed by standard breast-conserving therapy. PATIENTS AND METHODS: This was a prospective trial testing the feasibility of preoperative APBI followed by lumpectomy for patients with early-stage invasive ductal breast cancer. Eligible patients had T1-T2 (<3 cm), N0 tumors. Patients received 38.5 Gy in 3.85-Gy fractions delivered twice daily. Surgery was performed >21 days after radiation therapy. Adjuvant therapy was given as per standard of care. RESULTS: Twenty-seven patients completed treatment. With a median follow-up of 3.6 years (range, 0.5-5 years), there have been no local or regional failures. A complete pathologic response according to hematoxylin and eosin stains was seen in 4 patients (15%). There were 4 grade 3 seromas. Patient-reported cosmetic outcome was rated as good to excellent in 79% of patients after treatment. CONCLUSIONS: Preoperative 3-dimensional conformal radiation therapy-APBI is feasible and well tolerated in select patients with early-stage breast cancer, with no reported local recurrences and good to excellent cosmetic results. The pathologic response rates associated with this nonablative APBI dose regimen are particularly encouraging and support further exploration of this paradigm.

Tele-Assessment of the Berg Balance Scale: Effects of Transmission Characteristics.

OBJECTIVE: To compare Berg Balance Scale (BBS) rating using videos with differing transmission characteristics with direct in-person rating. DESIGN: Repeated-measures study for the assessment of the BBS in 8 configurations: in person, high-definition video with slow motion review, standard-definition videos with varying bandwidths and frame rates (768 kilobytes per second [kbps] videos at 8, 15, and 30 frames per second [fps], 30 fps videos at 128, 384, and 768 kbps). SETTING: Medical center. PARTICIPANTS: Patients with limitations (N=45) in ≥1 of 3 specific aspects of motor function: fine motor coordination, gross motor coordination, and gait and balance. INTERVENTIONS: Not applicable. MAIN OUTCOMES MEASURES: Ability to rate the BBS in person and using videos with differing bandwidths and frame rates in frontal and lateral views. RESULTS: Compared with in-person rating (7%), 18% (P=.29) of high-definition videos and 37% (P=.03) of standard-definition videos could not be rated. Interrater reliability for the high-definition videos was .96 (95% confidence interval, .94-.97). Rating failure proportions increased from 20% in videos with the highest bandwidth to 60% (P<.001) in videos with the lowest bandwidth, with no significant differences in proportions across frame rate categories. Both frontal and lateral views were critical for successful rating using videos, with 60% to 70% (P<.001) of videos unable to be rated on a single view. CONCLUSIONS: Although there is some loss of information when using videos to rate the BBS compared to in-person ratings, it is feasible to reliably rate the BBS remotely in standard clinical spaces. However, optimal video rating requires frontal and lateral views for each assessment, high-definition video with high bandwidth, and the ability to carry out slow motion review.

Benefits and Challenges of Delivering Tele-rehabilitation Services to Rural Veterans.

Veterans residing in underserved rural areas face many barriers to accessing high-quality rehabilitation services. This article describes the benefits and challenges of using technology for delivery of rehabilitation services to rural Veterans using TeleHOME, an innovative tele-rehabilitation program. TeleHOME enables rehabilitation providers to remotely assess the Veteran's functional abilities and needs in his or her own home where these tasks must be performed. This technology increases the ability of all team members to contribute to interdisciplinary care, but also requires greater levels of team integration. One month after the completion of the TeleHOME project, we met with clinicians to discuss their perceptions of whether and how use of the technology affected interdisciplinary care processes, and what approaches were used to meet team-based goals. TeleHOME can improve access to rehabilitation services for rural Veterans, but will also bring about novel integrative care processes that may improve the effectiveness of such services. Recommendations to overcome challenges to optimize the implementation and delivery of TeleHOME services as well as to better inform clinicians working with rural Veterans are discussed.

One size does not fit all-mobility device type affects speed, collisions, fatigue, and pain.

OBJECTIVE: To determine whether differences could be detected in mobility outcomes during community mobility and home mobility tasks according to type of mobility assistive device. DESIGN: Randomized, repeated measures. SETTING: Community mobility task: traversing 341.4m between the rehabilitation clinic and hospital entrance; home mobility task: traversing 39m into and out of a patient training bathroom and bedroom. PARTICIPANTS: Community-dwelling, cognitively intact ambulatory veterans (N=59) who used a mobility device within the 14 days prior to the study. INTERVENTIONS: Participants tested 3 types of mobility assistive devices with wheels: 4-wheeled walker (WW), manual wheelchair (MWC), and powered wheelchair (PWC). The first and last devices used by each participant were randomly assigned as either MWC or WW. The PWC was always the second device. MAIN OUTCOMES MEASURES: Speed (m/s), collisions (total), fatigue (0-10 Likert scale), and pain (0-10 Likert scale, diagram). RESULTS: The community mobility task was performed with all 3 devices by 52 (88%) veterans, and the home mobility task was performed with all 3 devices by 53 (90%) participants. In each task, 28 participants used the WW and 28 participants used the MWC as the final device. In the community mobility task, statistically significant differences (P<.05) were seen with ≥1 device comparison for all studied outcomes (eg, standardized mean difference for the MWC compared with the PWC showed -.67 fewer collisions for the MWC). In the home mobility task, speed, collisions, and fatigue showed statistically significant (P<.05) device-related differences (eg, standardized mean difference for the WW compared with the MWC showed -.88 fewer collisions for the WW). CONCLUSIONS: We found statistically significant and substantively different effects from 3 commonly used mobility assistive devices with wheels on diverse mobility outcomes when used in typical community mobility and home mobility tasks, providing proof of concept support for a research methodology applicable to comparative outcome studies of diverse mobility aids.

A pilot study on delirium in the intensive care unit: a creative inquiry project with undergraduate nursing students.

INTRODUCTION: Delirium continues to be a major issue in intensive care units (ICUs). Sedation and lack of rapid eye movement (REM) sleep could be important factors in the development of delirium. Improper sedation may interfere with a patient's sleep pattern, specifically time spent in REM sleep, and could be a contributor to the development of delirium. The research team has discovered through this pilot study that there is a possible correlation between sedation, disruptions, and sleep. The goal of our research was to determine the relationship between these variables using a sleep monitor to capture actual sleep activity compared with patient characteristics and real-time activity in the ICU environment. MATERIALS AND METHODS: This was a pilot study of 7 new patients, aged 65 years or older, who were intubated and sedated. Data on patient sleep cycles were collected using a wireless sleep monitor. A time sheet was placed outside each room to record time and type of interruption during nighttime hours (9 PM-6 AM). The patients were observed for 1 to 7 nights dependent on their length of stay in the ICU. RESULTS: Preliminary results demonstrated that, on average, between 9 PM and 6 AM, 48% remained awake (range, 8%-88%), 30% were in light sleep (range, 2%-50%), 18.5% were in REM (range, 2%-60%), and 3.4% were in a deep sleep (range, 0%-9%). Subject 1 remained awake 52% to 88% of the time during the entire admission of 7 days, had an Intensive Care Delirium Screening Checklist score of 5, and had a self-extubation; sedation ordered was Versed as needed. Subject 5 had no interventions done between 12 midnight and 4:50 AM, with the exception of turning once, and had an REM recorded of 60% on 1 night, which equals to 4 hours 49 minutes of rest. All patients with the exception of 1 were on fentanyl and Versed drips with varying dose adjustments throughout their admission. IMPLICATIONS: Preliminary results show that there is a relationship between lack of REM sleep and delirium. The pilot study was a useful model to demonstrate the need for further investigation in a larger population.

Targeting of Acyl-CoA synthetase 5 decreases jejunal fatty acid activation with no effect on dietary long-chain fatty acid absorption.

BACKGROUND: The absorption of dietary long chain fatty acids (LCFA) largely occurs in the jejunum. LCFA are activated via conjugation with Coenzyme A (CoA), a reaction catalyzed by Acyl-CoA synthetases (ACS). Acyl-CoA sythesis is critical for dietary LCFA absorption; yet, the jejunal ACS enzymes that catalyze the reaction are largely unknown. FINDINGS: High throughput mRNA sequencing of the mouse jejunum revealed that the expression of acyl-CoA synthetase 5 (Acsl5) and fatty-acid transport protein 4 (Fatp4) largely exceeded all other annotated ACS genes that activate LCFA. Interestingly, Acsl5 knockout (KO) mice displayed a decrease of 60% in jejunal total long chain acyl-CoA synthesis rate. Nevertheless, and despite of this decrease, dietary LCFA absorption and body-weight gain in response to high fat diet remained unaffected. CONCLUSION: Acsl5 is a major activator of dietary LCFA, yet in Acsl5 KO mice residual ACS activity is sufficient for maintaining a normal LCFA absorption. Our findings provide further evidence for a robust small intestine LCFA absorption capacity.

A quality assurance study on the accuracy of measuring physical function under current conditions for use of clinical video telehealth.

OBJECTIVE: To determine whether conditions for use of clinical video telehealth technology might affect the accuracy of measures of physical function. DESIGN: Repeated measures. SETTING: Veterans Administration Medical Center. PARTICIPANTS: Three healthy adult volunteers for a sample size of n=30 independent trials for each of 3 physical function tasks. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Three tasks capturing differing aspects of physical function: fine-motor coordination (number of finger taps in 30s), gross-motor coordination (number of gait deviations in 10ft [3.05m]), and clinical spatial relations (identifying the proper height for a cane randomly preset ±0-2in [5.1cm] from optimal), with performance simultaneously assessed in person and video recorded. Interrater reliability and criterion validity were determined for the measurement of these 3 tasks scored according to 5 methods: (1) in person (community standard), (2) slow motion review of the video recording (criterion standard), and (3-5) full speed review at 3 Internet bandwidths (64kps, 384kps, and 768kps). RESULTS: Fine-motor coordination-Interrater reliability was variable (r=.43-.81) and criterion validity was poor at 64kps and 384kps, but both were acceptable at 768kps (reliability r=.74, validity ß=.81). Gross-motor coordination-Interreliability was variable (range r=.53-.75) and criterion validity was poor at all bandwidths (ß=.28-.47). Motionless spatial relations-Excellent reliability (r=.92-.97) and good criterion validity (ß=.84-.89) at all the tested bandwidths. CONCLUSIONS: Internet bandwidth had differing effects on measurement validity and reliability for the fine-motor task, the gross-motor task, and spatial relations, with results for some tasks at some transmission speeds well below acceptable quality standards and community standards.

Multiple Mechanisms Contribute To Telomere Maintenance.

The unlimited growth potential of tumors depends on telomere maintenance and typically depends on telomerase, an RNA-dependent DNA polymerase, which reverse transcribes the telomerase RNA template, synthesizing telomere repeats at the ends of chromosomes. Studies in various model organisms genetically deleted for telomerase indicate that several recombination-based mechanisms also contribute to telomere maintenance. Understanding the molecular basis of these mechanisms is critical since some human tumors form without telomerase, yet the sequence is maintained at the telomeres. Recombination-based mechanisms also likely contribute at some frequency to telomere maintenance in tumors expressing telomerase. Preventing telomere maintenance is predicted to impact tumor growth, yet inhibiting telomerase may select for the recombination-based mechanisms. Telomere recombination mechanisms likely involve altered or unregulated pathways of DNA repair. The use of some DNA damaging agents may encourage the use of these unregulated pathways of DNA repair to be utilized and may allow some tumors to generate resistance to these agents depending on which repair pathways are altered in the tumors. This review will discuss the various telomere recombination mechanisms and will provide rationale regarding the possibility that L1 retrotransposition may contribute to telomere maintenance in tumors lacking telomerase.

Binge alcohol exposure modulates rodent expression of biomarkers of the immunoinflammatory response to orthopaedic trauma.

BACKGROUND: Alcohol is a known modulator of the immune system and host-defense response. Alcohol abuse is common in trauma patients, although the influence of alcohol intoxication on the inflammatory response following major orthopaedic injury remains unknown. The aim of this investigation was to examine the influence of binge alcohol exposure on biomarkers of the systemic inflammatory response following bilateral traumatic femoral fracture in a rodent model. METHODS: Ninety-two Sprague-Dawley rats were administered intraperitoneal injections of either saline solution or alcohol for three days. These animals then underwent a sham procedure or bilateral femoral intramedullary pinning and mid-diaphyseal closed fracture via blunt guillotine. The animals were killed at specific time points after the injury. Serum and lung tissue were collected, and twenty-five inflammatory markers were analyzed by immunoassay. Histological sections of lung tissue were evaluated by a board-certified pathologist. RESULTS: Bilateral femoral fracture significantly (p < 0.05) increased multiple serum biomarkers of inflammation. Binge alcohol treatment prior to injury significantly suppressed the increase in serum levels of interleukin (IL)-6, white blood cells, IL-2, IL-10, and C-reactive protein after the fracture. However, alcohol-treated animals were found to have increased pulmonary levels of IL-6, IL-1ß, IL-2, and macrophage inflammatory protein-1α following bilateral femoral fracture. In addition, lung tissue harvested following alcohol treatment and injury demonstrated increased pathologic changes, including parenchymal, alveolar, and peribronchial leukocyte infiltration and significantly elevated pulmonary wet-to-dry ratio, indicative of pulmonary edema. CONCLUSIONS: Our results indicate that acute alcohol intake prior to bilateral femoral fracture with fixation in rats modulates the inflammatory response after injury in a tissue-dependent manner. Although serum biomarkers of inflammation were suppressed in alcohol-treated animals following injury, several measures of pulmonary inflammation including cytokine levels, histological changes, and findings of pulmonary edema were significantly increased following fracture with the presence of alcohol.

The effect of radiation quality on genomic DNA methylation profiles in irradiated human cell lines.

It has been acknowledged for many years that radiation exposure induces delayed, non-targeted effects in the progeny of the irradiated cell. Evidence is beginning to demonstrate that among these delayed effects of radiation are epigenetic aberrations, including altered DNA methylation. To test the hypothesis that differences in radiation quality affect radiation-induced DNA methylation profiles, normal AG01522 and RKO colon carcinoma cells were exposed to low-LET X rays and protons or high-LET iron ions. DNA methylation was then evaluated at delayed times using assays for p16 and MGMT promoter, LINE-1 and alu repeat element, and global methylation. The results of these experiments demonstrated radiation-induced changes in repeat element and global DNA methylation patterns at ∼20 population doublings postirradiation. Further, radiation-induced changes in repeat element and global DNA methylation were more similar between proton- and iron-ion-irradiated cells than X-irradiated cells, suggesting that radiation quality rather than LET alone affects the radiation-induced epigenetic profile. Since alterations in DNA methylation have also emerged as one of the most consistent molecular alterations in cancer, these data also suggest the possibility that radiation-induced carcinogenic risk might be affected by radiation quality.

Decreased pulmonary inflammation after ethanol exposure and burn injury in intercellular adhesion molecule-1 knockout mice.

Clinical and laboratory evidence suggests that alcohol consumption dysregulates immune function. Burn patients who consume alcohol before their injuries demonstrate higher rates of morbidity and mortality, including acute respiratory distress syndrome, than patients without alcohol at the time of injury. Our laboratory observed higher levels of proinflammatory cytokines and leukocyte infiltration in the lungs of mice after ethanol exposure and burn injury than with either insult alone. To understand the mechanism of the increased pulmonary inflammatory response in mice treated with ethanol and burn injury, we investigated the role of intercellular adhesion molecule (ICAM)-1. Wild-type and ICAM-1 knockout (KO) mice were treated with vehicle or ethanol and subsequently given a sham or burn injury. Twenty-four hours postinjury, lungs were harvested and analyzed for indices of inflammation. Higher numbers of neutrophils were observed in the lungs of wild-type mice after burn and burn with ethanol treatment. This increase in pulmonary inflammatory cell accumulation was significantly lower in the KO mice. In addition, levels of KC, interleukin-1beta, and interleukin-6 in the lung were decreased in the ICAM-1 KO mice after ethanol exposure and burn injury. Interestingly, no differences were observed in serum or lung tissue content of soluble ICAM-1 24 hours postinjury. These data suggest that upregulation of adhesion molecules such as ICAM-1 on the vascular endothelium may play a critical role in the excessive inflammation seen after ethanol exposure and burn injury.