Exercise intensity and the protection from postprandial vascular dysfunction in adolescents

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this recordBACKGROUND: Acute exercise transiently improves endothelial function, and protects the vasculature from the deleterious effects of a high fat meal (HFM). We sought to identify whether this response is dependent on exercise intensity in adolescents. METHODS: Twenty adolescents (10 male, 14.3 ± 0.3 y) completed three 1-day trials: 1) rest (CON); 2) 8x1 min cycling at 90% peak power with 75s recovery (high-intensity interval exercise; HIIE); 3) cycling at 90% of the gas exchange threshold (moderate-intensity exercise; MIE) one hour before consuming a HFM (1.50 g∙kg(-1) fat). Macrovascular and microvascular endothelial function were assessed before and immediately after exercise, and three hours after the HFM by flow mediated dilation (FMD) and laser Doppler imaging (peak reactive hyperaemia; PRH). RESULTS: FMD and PRH increased one hour after HIIE (P<0.001, ES=1.20 and P=0.048, ES=0.56) but were unchanged after MIE. FMD and PRH were attenuated three hours after the HFM in CON (P<0.001, ES=1.78 and P=0.02, ES=0.59). FMD remained greater three hours after the HFM in HIIE compared to MIE (P<0.001, ES=1.47) and CON (P<0.001, ES=2.54), and in MIE compared to CON (P<0.001, ES=1.40). Compared to CON, PRH was greater three hours after the HFM in HIIE (P=0.02, ES=0.71) and MIE (P=0.02, ES=0.84), with no differences between HIIE and MIE (P=0.72, ES=0.16). Plasma [triacylglycerol] and [total antioxidant status] were not different between trials. CONCLUSIONS: Exercise intensity plays an important role in protecting the vasculature from the deleterious effects of a HFM. Performing HIIE may provide superior vascular benefits than MIE in adolescent groups

Making a HIIT: study protocol for assessing the feasibility and effects of co-designing high-intensity interval training workouts with students and teachers

This is the final version. Available on open access from BMC via the DOI in this recordBACKGROUND: High-intensity interval training (HIIT) is an effective strategy for improving a variety of health outcomes within the school setting. However, there is limited research on the implementation of school-based HIIT interventions and the integration of HIIT within the Health and Physical Education (HPE) curriculum. The aims of the Making a HIIT study are to: 1) describe the methodology and evaluate the feasibility of co-designing HIIT workouts with students and teachers in HPE; 2) determine the effect of co-designed HIIT workouts on cardiorespiratory and muscular fitness, and executive function; 3) understand the effect of co-design on students' motivation, enjoyment, and self-efficacy towards the workouts; and 4) evaluate the implementation of the intervention. METHODS: Three schools will participate. Within each school, three different groups will be formed from Year 7 and 8 classes: 1) Co-Designers; 2) HIIT Only; and 3) Control. The study will include two phases. In phase one, Group 1 will co-design HIIT workouts as part of the HPE curriculum using an iterative process with the researcher, teacher, and students as collaborators. This process will be evaluated using student discussions, student surveys, and teacher interviews. In phase two, Groups 1 and 2 will use the co-designed 10-minute HIIT workouts in HPE for 8-weeks. Group 3 (control) will continue their regular HPE lessons. All students will participate in cardiorespiratory fitness, muscular fitness, and executive function assessments before and after the HIIT program or control period. Students will complete questionnaires on their motivation, enjoyment, and self-efficacy of the workouts. Differences between groups will be assessed using linear regressions to account for covariates. Heart rate and rating of perceived exertion will be collected during each HIIT session. The implementation will be evaluated using the Framework for Effective Implementation. Ethical approval was granted by the University of Queensland Human Research Ethics Committee and other relevant bodies. DISCUSSION: This study will be the first to co-design HIIT workouts with teachers and students within the HPE curriculum. As this study relies on co-design, each HIIT workout will differ, which will add variability between HIIT workouts but increase the ecological validity of the study. TRIAL REGISTRATION: ACTRN, ACTRN12622000534785, Registered 5 April 2022 - Retrospectively registered, https://www.anzctr.org.au/ACTRN12622000534785.aspx.QUEX Institute for Global ExcellenceSports Medicine Australia

Binomial Mitotic Segregation of MYCN-Carrying Double Minutes in Neuroblastoma Illustrates the Role of Randomness in Oncogene Amplification

BACKGROUND: Amplification of the oncogene MYCN in double minutes (DMs) is a common finding in neuroblastoma (NB). Because DMs lack centromeric sequences it has been unclear how NB cells retain and amplify extrachromosomal MYCN copies during tumour development. PRINCIPAL FINDINGS: We show that MYCN-carrying DMs in NB cells translocate from the nuclear interior to the periphery of the condensing chromatin at transition from interphase to prophase and are preferentially located adjacent to the telomere repeat sequences of the chromosomes throughout cell division. However, DM segregation was not affected by disruption of the telosome nucleoprotein complex and DMs readily migrated from human to murine chromatin in human/mouse cell hybrids, indicating that they do not bind to specific positional elements in human chromosomes. Scoring DM copy-numbers in ana/telophase cells revealed that DM segregation could be closely approximated by a binomial random distribution. Colony-forming assay demonstrated a strong growth-advantage for NB cells with high DM (MYCN) copy-numbers, compared to NB cells with lower copy-numbers. In fact, the overall distribution of DMs in growing NB cell populations could be readily reproduced by a mathematical model assuming binomial segregation at cell division combined with a proliferative advantage for cells with high DM copy-numbers. CONCLUSION: Binomial segregation at cell division explains the high degree of MYCN copy-number variability in NB. Our findings also provide a proof-of-principle for oncogene amplification through creation of genetic diversity by random events followed by Darwinian selection

Middleborns disadvantaged? testing birth-order effects on fitness in pre-industrial finns

Parental investment is a limited resource for which offspring compete in order to increase their own survival and reproductive success. However, parents might be selected to influence the outcome of sibling competition through differential investment. While evidence for this is widespread in egg-laying species, whether or not this may also be the case in viviparous species is more difficult to determine. We use pre-industrial Finns as our model system and an equal investment model as our null hypothesis, which predicts that (all else being equal) middleborns should be disadvantaged through competition. We found no overall evidence to suggest that middleborns in a family are disadvantaged in terms of their survival, age at first reproduction or lifetime reproductive success. However, when considering birth-order only among same-sexed siblings, first-, middle-and lastborn sons significantly differed in the number of offspring they were able to rear to adulthood, although there was no similar effect among females. Middleborn sons appeared to produce significantly less offspring than first-or lastborn sons, but they did not significantly differ from lastborn sons in the number of offspring reared to adulthood. Our results thus show that taking sex differences into account is important when modelling birth-order effects. We found clear evidence of firstborn sons being advantaged over other sons in the family, and over firstborn daughters. Therefore, our results suggest that parents invest differentially in their offspring in order to both preferentially favour particular offspring or reduce offspring inequalities arising from sibling competition

Potential pitfalls in MitoChip detected tumor-specific somatic mutations: a call for caution when interpreting patient data

<p>Abstract</p> <p>Background</p> <p>Several investigators have employed high throughput mitochondrial sequencing array (MitoChip) in clinical studies to search mtDNA for markers linked to cancers. In consequence, a host of somatic mtDNA mutations have been identified as linked to different types of cancers. However, closer examination of these data show that there are a number of potential pitfalls in the detection tumor-specific somatic mutations in clinical case studies, thus urging caution in the interpretation of mtDNA data to the patients. This study examined mitochondrial sequence variants demonstrated in cancer patients, and assessed the reliability of using detected patterns of polymorphisms in the early diagnosis of cancer.</p> <p>Methods</p> <p>Published entire mitochondrial genomes from head and neck, adenoid cystic carcinoma, sessile serrated adenoma, and lung primary tumor from clinical patients were examined in a phylogenetic context and compared with known, naturally occurring mutations which characterize different populations.</p> <p>Results</p> <p>The phylogenetic linkage analysis of whole arrays of mtDNA mutations from patient cancerous and non-cancerous tissue confirmed that artificial recombination events occurred in studies of head and neck, adenoid cystic carcinoma, sessile serrated adenoma, and lung primary tumor. Our phylogenetic analysis of these tumor and control leukocyte mtDNA haplotype sequences shows clear cut evidence of mixed ancestries found in single individuals.</p> <p>Conclusions</p> <p>Our study makes two prescriptions: both in the clinical situation and in research 1. more care should be taken in maintaining sample identity and 2. analysis should always be undertaken with respect to all the data available and within an evolutionary framework to eliminate artifacts and mix-ups.</p

Metabolic profiling of human brain metastases using in vivo proton MR spectroscopy at 3T

<p>Abstract</p> <p>Background</p> <p>Metastases to the central nervous system from different primary cancers are an oncologic challenge as the overall prognosis for these patients is generally poor. The incidence of brain metastases varies with type of primary cancer and is probably increasing due to improved therapies of extracranial metastases prolonging patient's overall survival and thereby time for brain metastases to develop. In addition, the greater access to improved neuroimaging techniques can provide earlier diagnosis. The aim of this study was to investigate the feasibility of using proton magnetic resonance spectroscopy (MRS) and multivariate analyses to characterize brain metastases originating from different primary cancers, to assess changes in spectra during radiation treatment and to correlate the spectra to clinical outcome after treatment.</p> <p>Methods</p> <p>Patients (n = 26) with brain metastases were examined using single voxel MRS at a 3T clinical MR system. Five patients were excluded due to poor spectral quality. The spectra were obtained before start (n = 21 patients), immediately after (n = 6 patients) and two months after end of treatment (n = 4 patients). Principal component analysis (PCA) and partial least square regression analysis (PLS) were applied in order to identify clustering of spectra due to origin of metastases and to relate clinical outcome (survival) of the patients to spectral data from the first MR examination.</p> <p>Results</p> <p>The PCA results indicated that brain metastases from primary lung and breast cancer were separated into two clusters, while the metastases from malignant melanomas showed no uniformity. The PLS analysis showed a significant correlation between MR spectral data and survival five months after MRS before start of treatment.</p> <p>Conclusion</p> <p>MRS determined metabolic profiles analysed by PCA and PLS might give valuable clinical information when planning and evaluating the treatment of brain metastases, and also when deciding to terminate further therapies.</p

Is body size at birth related to circadian salivary cortisol levels in adulthood? Results from a longitudinal cohort study

<p>Abstract</p> <p>Background</p> <p>The hypothesis of fetal origins of adult disease has during the last decades received interest as an explanation of chronic, e.g. cardiovascular, disease in adulthood stemming from fetal environmental conditions. Early programming and enduring dysregulations of the hypothalamic-pituitary-adrenal (HPA axis), with cortisol as its end product, has been proposed as a possible mechanism by which birth weight influence later health status. However, the fetal origin of the adult cortisol regulation has been insufficiently studied. The present study aims to examine if body size at birth is related to circadian cortisol levels at 43 years.</p> <p>Methods</p> <p>Participants were drawn from a prospective cohort study (n = 752, 74.5%). Salivary cortisol samples were collected at four times during one day at 43 years, and information on birth size was collected retrospectively from delivery records. Information on body mass during adolescence and adulthood and on health behavior, medication and medical conditions at 43 years was collected prospectively by questionnaire and examined as potential confounders. Participants born preterm or < 2500 g were excluded from the main analyses.</p> <p>Results</p> <p>Across the normal spectrum, size at birth (birth weight and ponderal index) was positively related to total (area under the curve, AUC) and bedtime cortisol levels in the total sample. Results were more consistent in men than in women. Descriptively, participants born preterm or < 2500 g also seemed to display elevated evening and total cortisol levels. No associations were found for birth length or for the cortisol awakening response (CAR).</p> <p>Conclusions</p> <p>These results are contradictory to previously reported negative associations between birth weight and adult cortisol levels, and thus tentatively question the assumption that only low birth weight predicts future physiological dysregulations.</p

Human Milk Protein Production in Xenografts of Genetically Engineered Bovine Mammary Epithelial Stem Cells

BACKGROUND: In the bovine species milk production is well known to correlate with mammary tissue mass. However, most advances in optimizing milk production relied on improvements of breeding and husbandry practices. A better understanding of the cells that generate bovine mammary tissue could facilitate important advances in milk production and have global economic impact. With this possibility in mind, we show that a mammary stem cell population can be functionally identified and isolated from the bovine mammary gland. We also demonstrate that this stem cell population may be a promising target for manipulating the composition of cow's milk using gene transfer. METHODS AND FINDINGS: We show that the in vitro colony-forming cell assay for detecting normal primitive bipotent and lineage-restricted human mammary clonogenic progenitors are applicable to bovine mammary cells. Similarly, the ability of normal human mammary stem cells to regenerate functional bilayered structures in collagen gels placed under the kidney capsule of immunodeficient mice is shared by a subset of bovine mammary cells that lack aldehyde dehydrogenase activity. We also find that this activity is a distinguishing feature of luminal-restricted bovine progenitors. The regenerated structures recapitulate the organization of bovine mammary tissue, and milk could be readily detected in these structures when they were assessed by immunohistochemical analysis. Transplantation of the bovine cells transduced with a lentivirus encoding human β-CASEIN led to expression of the transgene and secretion of the product by their progeny regenerated in vivo. CONCLUSIONS: These findings point to a common developmental hierarchy shared by human and bovine mammary glands, providing strong evidence of common mechanisms regulating the maintenance and differentiation of mammary stem cells from both species. These results highlight the potential of novel engineering and transplant strategies for a variety of commercial applications including the production of modified milk components for human consumption

Statistical Methods in Recent HIV Noninferiority Trials: Reanalysis of 11 Trials

Background: In recent years the ‘‘noninferiority’ ’ trial has emerged as the new standard design for HIV drug development among antiretroviral patients often with a primary endpoint based on the difference in success rates between the two treatment groups. Different statistical methods have been introduced to provide confidence intervals for that difference. The main objective is to investigate whether the choice of the statistical method changes the conclusion of the trials. Methods: We presented 11 trials published in 2010 using a difference in proportions as the primary endpoint. In these trials, 5 different statistical methods have been used to estimate such confidence intervals. The five methods are described and applied to data from the 11 trials. The noninferiority of the new treatment is not demonstrated if the prespecified noninferiority margin it includes in the confidence interval of the treatment difference. Results: Results indicated that confidence intervals can be quite different according to the method used. In many situations, however, conclusions of the trials are not altered because point estimates of the treatment difference were too far from the prespecified noninferiority margins. Nevertheless, in few trials the use of different statistical methods led to different conclusions. In particular the use of ‘‘exact’ ’ methods can be very confusing. Conclusion: Statistical methods used to estimate confidence intervals in noninferiority trials have a strong impact on th