Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits.

Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes, and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade, or are also present in other mammals. Here, we investigate regulatory evolution in the heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptations in metabolic and functional pathways and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state of the art by addressing known limitations of inter-species comparisons of epigenomic profiles and has broad implications in the field of comparative functional genomics.

Propranolol's effects on the sleep of infants with hemangiomas: A prospective pilot study.

OBJECTIVE: To assess propranolol's impact on sleep when used in infants and toddlers with infantile hemangioma (80% under 6 months old). METHODS: Parents and caregivers of infants and toddlers with infantile hemangioma presenting to a tertiary pediatric hospital's dermatology clinic and assessed by their dermatologist as requiring propranolol treatment were invited to participate. All participants completed an extended version of the Brief Infant Sleep Questionnaire (BISQ) prior to propranolol treatment initiation, which acted as the control, and 5 weeks after treatment commencement. Objective data were gathered through actigraphy, which utilizes a small wristwatch-like device that measures sleep-wake patterns, for 1 week prior to initiation and again 5 weeks after commencement. BISQ responses and actigraphy values from the two time points were compared. RESULTS: 55 infants and toddlers (aged 0-2.8 years, 80% under 6 months) were included. Sleep was reported as only a minor problem by most parents 5 weeks after starting propranolol (P = .049). Subgroup analysis of 45 infants <6 months old showed no significant difference in sleep while taking propranolol. Whole cohort BISQ data analysis showed a statistically significant increase in night-time sleep (P = .024), and a decrease in the number (P = .003) and duration of daytime naps (P = .025) following commencement of propranolol. Actigraphy data completed in 10 infants showed no significant difference in sleep quality before and 5 weeks after commencing propranolol. CONCLUSION: Propranolol did not significantly impair sleep quality and pattern in our cohort of infants and toddlers with infantile hemangioma. Most parents considered the impact on sleep to be only a minor problem.

The contribution of non-coding regulatory elements to cardiovascular disease.

Cardiovascular disease collectively accounts for a quarter of deaths worldwide. Genome-wide association studies across a range of cardiovascular traits and pathologies have highlighted the prevalence of common non-coding genetic variants within candidate loci. Here, we review genetic, epigenomic and molecular approaches to investigate the contribution of non-coding regulatory elements in cardiovascular biology. We then discuss recent insights on the emerging role of non-coding variation in predisposition to cardiovascular disease, with a focus on novel mechanistic examples from functional genomics studies. Lastly, we consider the clinical significance of these findings at present, and some of the current challenges facing the field.

Multiple enhancer regions govern the transcription of CCN2 during embryonic development.

CCN2 is a critical matricellular protein that is expressed in several cells with major implications in physiology and different pathologies. However, the transcriptional regulation of this gene remains obscure. We used the Encyclopaedia of DNA Elements browser (ENCODE) to visualise the region spanning from 300 kb upstream to the CCN2 start site in silico in order to identify enhancer regions that regulate transcription of this gene. Selection was based on three criteria associated with enhancer regions: 1) H3K4me1 and H3K27ac histone modifications, 2) DNase I hypersensitivity of chromatin and 3) inter-species conservation. Reporter constructs were created with sequences spanning each of the regions of interest placed upstream of an Hsp68 silent proximal promoter sequence in order to drive the expression of ß-galactosidase transgene. Each of these constructs was subsequently used to create transgenic mice in which reporter gene production was assessed at the E15.5 developmental stage. Four functional enhancers were identified, with each driving distinct, tissue-specific patterns of transgene expression. An enhancer located -100 kb from the CCN2 transcription start site facilitated expression within vascular tissue. An enhancer -135 kb upstream of CCN2 drove expression within the articular chondrocytes of synovial joints. The other two enhancers, located at -198 kb and -229 kb, mediated transgene expression within dermal fibroblasts, however the most prevalent activity was found within hypertrophic chondrocytes and periosteal tissue, respectively. These findings suggest that the global expression of CCN2 during development results from the activity of several tissue-specific enhancer regions in addition to proximal regulatory elements that have previously been demonstrated to drive transcription of the gene during development.

Overweight and obesity among low-income women in rural West Virginia and urban Los Angeles County.

We described the prevalence of overweight and obesity among low-income women in rural West Virginia (WV) and urban Los Angeles County (LA County). Both communities participated in the national Communities Putting Prevention to Work program during 2010-2012. In each community, we completed health assessments on adult women recruited from public-sector clinics serving low-income populations. All participants answered survey questions regarding socio-demographics and diets. In both jurisdictions, we assessed obesity using objectively measured height and weight (calculated BMI). As part of each community case study, we performed multivariable regression analyses to describe the relationships between overweight and obesity and selected covariates (e.g., dietary behaviors). Overweight and obesity were prevalent among low-income women from WV (73%, combined) and LA County (67%, combined). In both communities, race and ethnicity appeared to predict the two conditions; however, the associations were not robust. In LA County, for example, African American and Hispanic women were 1.4 times (95% CI=1.12, 1.81) more likely than white women to be overweight and obese. Collectively, these subpopulation health data served as an important guide for further planning of obesity prevention efforts in both communities. These efforts became a part of the subsequent Community Transformation Grants portfolio.

Assessing moderate to vigorous physical activity in rural West Virginia elementary school physical education classes.

BACKGROUND: Physical education (PE) provides a natural opportunity for students to be physically active during the school day; however, the amount and intensity of this activity varies. The Centers for Disease Control and Prevention recommends that students engage in MVPA for at least 50% of their PE class period. The purpose of the present study was to quantify the amount of MVPA that occurs during elementary school PE. METHODS: Accelerometer data were collected from 203 students (100 2nd grade; 103 5th grade) in 10 West Virginia elementary schools. At each school, PE teachers identified three 2nd grade classes and three 5th grade classes in which to collect the physical activity data. For each selected class, the teachers identified the first 4 students on their alphabetic roll to wear the accelerometers. PE teachers recorded the date and time of the class and the gender of the students wearing the accelerometers. RESULTS: Using 5-second epochs and Puyau's cut-offs, results indicated that, on average, students engaged in MVPA for 27% of their PE class. No significant differences were observed in MVPA between 2nd and 5th grade students or between males and females. Male and female students spent equal amounts of PE class in MVPA. CONCLUSION: Findings support policy to increase the required minimum amount of MVPA during each PE class.

Adolescent caffeine consumption and self-reported violence and conduct disorder.

Caffeine is the most widely used psychoactive substance in the world and currently the only one legally available to children and adolescents. The sale and use of caffeinated beverages has increased markedly among adolescents during the last decade. However, research on caffeine use and behaviors among adolescents is scarce. We investigate the relationship between adolescent caffeine use and self-reported violent behaviors and conduct disorders in a population-based cross-sectional sample of 3,747 10th grade students (15-16 years of age, 50.2 % girls) who were enrolled in the Icelandic national education system during February 2012. Through a series of multiple regression models, while controlling for background factors, Attention Deficit Hyperactivity Disorder symptoms and current medication and peer delinquency, and including measures on substance use, our findings show robust additive explanatory power of caffeine for both violent behaviors and conduct disorders. In addition, the association of caffeine to the outcomes is significantly stronger for girls than boys for both violent behaviors and conduct disorders. Future studies are needed to examine to what extent, if at all, these relationships are causal. Indication of causal connections between caffeine consumption and negative outcomes such as those reported here would call into question the acceptability of current policies concerning the availability of caffeine to adolescents and the targeting of adolescence in the marketing of caffeine products.

Mandatory reporting in the context of home visitation programs: intimate partner violence and children's exposure to intimate partner violence.

The mandatory reporting of intimate partner violence (IPV) is a controversial issue that is receiving increased attention. A related concern is whether children's exposure to IPV constitutes child maltreatment, making it reportable to child protective services. These issues have been relatively unexplored within the context of home visitation programs. A secondary analysis of qualitative data collected from community stakeholders, clients, and home visiting nurses in the Nurse-Family Partnership program was carried out. Participants' perceptions about mandatory reporting of IPV and reporting of children's exposure to IPV are highlighted. Emergent themes and implications for research, practice, and policy are discussed.

Effects of the built environment on physical activity of adults living in rural settings.

OBJECTIVE: To conduct a systematic review of the literature to examine the influence of the built environment (BE) on the physical activity (PA) of adults in rural settings. DATA SOURCE: Key word searches of Academic Search Premier, PubMed, CINAHL, Web of Science, and Sport Discus were conducted. STUDY INCLUSION AND EXCLUSION CRITERIA: Studies published prior to June 2008 were included if they assessed one or more elements of the BE, examined relationships between the BE and PA, and focused on rural locales. Studies only reporting descriptive statistics or assessing the reliability of measures were excluded. DATA EXTRACTION: Objective(s), sample size, sampling technique, geographic location, and definition of rural were extracted from each study. Methods of assessment and outcomes were extracted from the quantitative literature, and overarching themes were identified from the qualitative literature. DATA SYNTHESIS: Key characteristics and findings from the data are summarized in Tables 1 through 3. RESULTS: Twenty studies met inclusion and exclusion criteria. Positive associations were found among pleasant aesthetics, trails, safety/crime, parks, and walkable destinations. CONCLUSIONS: Research in this area is limited. Associations among elements of the BE and PA among adults appear to differ between rural and urban areas. Considerations for future studies include identifying parameters used to define rural, longitudinal research, and more diverse geographic sampling. Development and refinement of BE assessment tools specific to rural locations are also warranted.

The role of Gamma Knife Radiosurgery in the management of unresectable gross disease or gross residual disease after surgery in ependymoma.

PURPOSE/OBJECTIVE: To evaluate the efficacy and the toxicity of Gamma Knife (GK)-based stereotactic radiosurgery (SRS) in the management of gross disease in ependymoma. MATERIALS AND METHODS: Eight patients with 13 ependymomas were treated with GK-based SRS in our institution for gross disease. Five patients were treated for recurrent disease that developed after surgery and external beam radiotherapy (EBRT), two received SRS to the gross disease after surgery and EBRT, and one received SRS alone (in a 1.3 year old child). Median EBRT dose was 54.4 Gy (range 50-55.8 Gy). Median SRS dose was 14 Gy (range 12-20 Gy). Seven of eight (87.5%) patients had SRS to a single lesion and one of eight (12.5%) patients had treatment to six tumors in three different sessions. RESULTS: The median follow up was 30.2 months (range 8-65.4 months). Out of the eight patients treated with SRS, six (75%) were alive, four (50%) were alive with no recurrence, two (25%) were alive with recurrence, and two (25%) died of recurrent disease. Both patients treated with SRS as a boost were alive and without recurrence. Out of the five patients who received SRS as salvage treatment, three (60%) were alive, two (40%) were alive without recurrence, two (40%) developed distant failure, and three (60%) had in-field control. Two patients who received SRS to their brainstem lesions developed symptoms related to radionecrosis and were successfully treated with steroid with good control of symptoms. CONCLUSIONS: GK-based SRS appears to be a feasible and safe treatment modality for patients with ependymoma with unresectable gross disease or gross residual disease after surgery. SRS provides reasonable local control but out-of-field tumor progression remains an issue. For patients who receive SRS as a boost, the local control appears to be excellent.

Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer.

INTRODUCTION: Surgical resection is standard therapy for patients with stage I non-small cell lung cancer (NSCLC), however, many patients are medically inoperable. We set out to investigate a new therapy akin to brain radiosurgery called extracranial stereotactic radioablation (ESR) in a phase I trial. PATIENTS AND METHODS: Eligible patients included those with clinically staged T1 or T2 (tumor size, < or = 7 cm) N0M0 biopsy confirmed NSCLC. All patients had comorbid medical problems that precluded thoracotomy. The median age was 75 years, and the median Karnofsky performance status was 80. ESR was administered in three separate fractions over 2 weeks. Three to five patients were treated within each dose cohort starting at 800 cGy per fraction (total, 2,400 cGy) followed by successive dose escalations of 200 cGy per fraction (total increase per cohort, 600 cGy). Waiting periods occurred between dose cohorts to observe toxicity. Patients with T1 vs T2 tumors underwent separate independent dose escalations. RESULTS: A total of 37 patients were enrolled since February 2000. One patient experienced grade 3 pneumonitis, and another patient had grade 3 hypoxia. For the entire population, there was no appreciable decline in cardiopulmonary function as measured by symptoms, physical examination, need for oxygen supplementation, pulmonary function testing, arterial blood gas determinations, or regular chest imaging. Both T-stage groups ultimately reached and tolerated 2,000 cGy per fraction for three fractions (total, 6,000 cGy). The maximum tolerated dose for this therapy in either T-stage group has yet to be reached. Tumors responded to treatment in 87% of patients (complete response, 27%). After a median follow-up period of 15.2 months, six patients experienced local failure, all of whom had received doses of < 1,800 cGy per fraction. CONCLUSIONS: Very high radiation dose treatments were tolerated in this population of medically inoperable patients with stage I NSCLC using ESR techniques.