High-impact jumping mitigates the short-term effects of low energy availability on bone resorption but not formation in regularly menstruating females:A randomized control trial

Low energy availability (LEA) is prevalent in active individuals and negatively impacts bone turnover in young females. High-impact exercise can promote bone health in an energy efficient manner and may benefit bone during periods of LEA. Nineteen regularly menstruating females (aged 18–31 years) participated in two three-day conditions providing 15 (LEA) and 45 kcals kg fat-free mass−1 day−1 (BAL) of energy availability, each beginning 3 ± 1 days following the self-reported onset of menses. Participants either did (LEA+J, n = 10) or did not (LEA, n = 9) perform 20 high-impact jumps twice per day during LEA, with P1NP, β-CTx (circulating biomarkers of bone formation and resorption, respectively) and other markers of LEA measured pre and post in a resting and fasted state. Data are presented as estimated marginal mean ± 95% CI. P1NP was significantly reduced in LEA (71.8 ± 6.1–60.4 ± 6.2 ng mL−1, p 0.999, d = 0.19), and these effects were significantly different (time by condition interaction: p = 0.007). Morning basal bone formation rate is reduced following 3 days LEA, induced via dietary restriction, with or without high-impact jumping in regularly menstruating young females. However, high-impact jumping can prevent an increase in morning basal bone resorption rate and may benefit long-term bone health in individuals repeatedly exposed to such bouts

Sudden cardiac death in patients with ischemic heart failure undergoing coronary artery bypass grafting results from the STICH randomized clinical trial (Surgical Treatment for Ischemic Heart Failure)

Background—The risk of sudden cardiac death (SCD) in patients with heart failure following CABG has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing and clinical predictors of SCD after CABG. Methods—Patients enrolled in the Surgical Treatment of Ischemic Heart Failure (STICH) trial who underwent CABG with or without surgical ventricular reconstruction (SVR) were included. We excluded patients with prior ICD and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results—Over a median follow-up of 46 months, 113 patients of 1411 patients who received CABG without (n = 934) or with SVR (n = 477) had SCD; 311 died of other causes. The mean LVEF at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than those who died for reasons other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-90 day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy and LV function, ESVI and BNP were most strongly associated with SCD. Conclusions—The monthly risk of SCD shortly after CABG among patients with a low LVEF is highest between the first and third month, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative ESVI and/or BNP

A prognostic signature of G₂ checkpoint function in melanoma cell lines

As DNA damage checkpoints are barriers to carcinogenesis, G2 checkpoint function was quantified to test for override of this checkpoint during melanomagenesis. Primary melanocytes displayed an effective G2 checkpoint response to ionizing radiation (IR)-induced DNA damage. Thirty-seven percent of melanoma cell lines displayed a significant defect in G2 checkpoint function. Checkpoint function was melanoma subtype-specific with “epithelial-like” melanoma lines, with wild type NRAS and BRAF displaying an effective checkpoint, while lines with mutant NRAS and BRAF displayed defective checkpoint function. Expression of oncogenic B-Raf in a checkpoint-effective melanoma attenuated G2 checkpoint function significantly but modestly. Other alterations must be needed to produce the severe attenuation of G2 checkpoint function seen in some BRAF-mutant melanoma lines. Quantitative trait analysis tools identified mRNA species whose expression was correlated with G2 checkpoint function in the melanoma lines. A 165 gene signature was identified with a high correlation with checkpoint function (p < 0.004) and low false discovery rate (≤ 0.077). The G2 checkpoint gene signature predicted G2 checkpoint function with 77–94% accuracy. The signature was enriched in lysosomal genes and contained numerous genes that are associated with regulation of chromatin structure and cell cycle progression. The core machinery of the cell cycle was not altered in checkpoint-defective lines but rather numerous mediators of core machinery function were. When applied to an independent series of primary melanomas, the predictive G2 checkpoint signature was prognostic of distant metastasis-free survival. These results emphasize the value of expression profiling of primary melanomas for understanding melanoma biology and disease prognosis

Delayed plastic responses to anodal tDCS in older adults

Despite the abundance of research reporting the neurophysiological and behavioral effects of transcranial direct current stimulation (tDCS) in healthy young adults and clinical populations, the extent of potential neuroplastic changes induced by tDCS in healthy older adults is not well understood. The present study compared the extent and time course of anodal tDCS-induced plastic changes in primary motor cortex (M1) in young and older adults. Furthermore, as it has been suggested that neuroplasticity and associated learning depends on the brain-derived neurotrophic factor (BDNF) gene polymorphisms, we also assessed the impact of BDNF polymorphism on these effects. Corticospinal excitability was examined using transcranial magnetic stimulation before and following (0, 10, 20, 30 min) anodal tDCS (30 min, 1 mA) or sham in young and older adults. While the overall extent of increases in corticospinal excitability induced by anodal tDCS did not vary reliably between young and older adults, older adults exhibited a delayed response; the largest increase in corticospinal excitability occurred 30 min following stimulation for older adults, but immediately post-stimulation for the young group. BDNF genotype did not result in significant differences in the observed excitability increases for either age group. The present study suggests that tDCS-induced plastic changes are delayed as a result of healthy aging, but that the overall efficacy of the plasticity mechanism remains unaffected

DNA methylation profiles in primary cutaneous melanomas are associated with clinically significant pathologic features

DNA methylation studies have elucidated a methylation signature distinguishing primary melanomas from benign nevi and provided new insights about genes that may be important in melanoma development. However, it is unclear whether methylation differences among primary melanomas are related to tumor pathologic features with known clinical significance. We utilized the Illumina Golden Gate Cancer Panel array to investigate the methylation profiles of 47 primary cutaneous melanomas. Array-wide methylation patterns revealed a positive association of methylation with Breslow thickness and mutated BRAF, a negative association with mitotic rate, and a weak association with ulceration. Hierarchical clustering on CpG sites exhibiting the most variable methylation (n=235) divided the melanoma samples into three clusters, including a highly-methylated cluster that was positively associated with Breslow thickness and an intermediately-methylated cluster associated with Breslow thickness and mitotic rate. Our findings provide support for the existence of methylation-defined subsets in melanomas, with increased methylation associated with Breslow thickness

Longitudinal changes in sedentary time and physical activity during adolescence

BACKGROUND: Low levels of physical activity and high time spent in sedentary activities have been associated with unfavourable health outcomes in adolescents. During adolescence, physical activity declines and sedentary time increases, however little is known about whether the magnitude of these changes differs within or between school-time, after-school time, or at weekends. METHODS: Adolescents (n = 363) participating in the PEACH (Personal and Environmental Associations with Children’s Health) project provided accelerometer data at 12 and 15 years of age. Data were collected in 2008/2009 and 2012/2013. Time spent sedentary (<100 cpm), in light physical activity (LPA (100-2295 cpm) and in moderate to vigorous physical activity (MVPA: ≥ 2296 cpm) were generated for school-time, after-school time and for weekends using school-specific start and finish times. All data were analysed in 2014. RESULTS: The proportion of time spent sedentary significantly increased during school (+8.23%, 95% CI = 7.35 to 9.13), after-school (+6.99%, 95% CI = 5.91 to 8.07) and at weekends (+6.86%, 95% CI = 5.10 to 8.62). A parallel decrease was found in the proportion of time spent in LPA during school (-7.62%, 95% CI = -8.26 to -6.98), after-school (-7.01%, 95% CI = -7.74 to -6.28) and at weekends (-6.72%, 95% CI = -7.80 to -5.65). The proportion of time spent in MVPA remained relatively stable during school (-0.64, 95% CI = -1.11 to -0.18), after-school (0.04%, 95% CI = -0.58 to 0.67) and at weekends (-0.14%, 95% CI = -1.18 to 0.90). CONCLUSIONS: Objectively measured sedentary time increased between 12 and 15 years of age during-school, after-school, and at weekends, suggesting that interventions aiming to reduce the age-associated changes in sedentary time are needed in all three time contexts. Future work should identify which sedentary activities change more than others to inform interventions which aim to minimise the increase in time spent sedentary during adolescence

Targeted next generation sequencing identifies clinically actionable mutations in patients with melanoma

Somatic sequencing of cancers has produced new insight into tumorigenesis, tumor heterogeneity, and disease progression, but the vast majority of genetic events identified are of indeterminate clinical significance. Here we describe a NextGen sequencing approach to fully analyze 248 genes, including all those of known clinical significance in melanoma. This strategy features solution capture of DNA followed by multiplexed, high-throughput sequencing, and was evaluated in 31 melanoma cell lines and 18 tumor tissues from patients with metastatic melanoma. Mutations in melanoma cell lines correlated with their sensitivity to corresponding small molecule inhibitors, confirming, for example, lapatinib sensitivity in ERBB4 mutant lines and identifying a novel activating mutation of BRAF. The latter event would not have been identified by clinical sequencing and was associated with responsiveness to a BRAF kinase inhibitor. This approach identified focal copy number changes of PTEN not found by standard methods, such as comparative genomic hybridization (CGH). Actionable mutations were found in 89% of the tumor tissues analyzed, 56% of which would not be identified by standard-of-care approaches. This work shows that targeted sequencing is an attractive approach for clinical use in melanoma

A prognostic signature of defective p53-dependent G1 checkpoint function in melanoma cell lines: A signature of defective p53 function in melanoma

Melanoma cell lines and normal human melanocytes were assayed for p53-dependent G1 checkpoint response to ionizing radiation-induced DNA damage. Sixty six percent of melanoma cell lines displayed a defective G1 checkpoint. Checkpoint function was correlated with sensitivity to ionizing radiation with checkpoint-defective lines being radio-resistant. Microarray analysis identified 316 probes whose expression was correlated with G1 checkpoint function in melanoma lines (P≤0.007) including p53 transactivation targets CDKN1A, DDB2 and RRM2B. The 316 probe list predicted G1 checkpoint function of the melanoma lines with 86% accuracy using a binary analysis and 91% accuracy using a continuous analysis. When applied to microarray data from primary melanomas, the 316 probe list was prognostic of four year distant metastases-free survival. Thus, p53 function, radio-sensitivity and metastatic spread may be estimated in melanomas from a signature of gene expression

The Pine River Statement: Human Health Consequences of DDT Use

Objectives: Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. Data sources and extraction: We conducted a PubMed search in October 2008 and retrieved 494 studies. Data synthesis: Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. Conclusions: Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDT.Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. Data sources and extraction We conducted a PubMed search in October 2008 and retrieved 494 studies. Data synthesis Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. Conclusions Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDThttp://dx.doi.org/10.1289/ehp.1174

COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): a multicentre randomised controlled trial protocol

Background The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. Methods/Design The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants’ views of the intervention and factors that acted as facilitators and barriers to participation. Discussion This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. Trial registration Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT0232554