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1.  Individual‐patient meta‐analysis of three randomized trials comparing endovascular versus open repair for ruptured abdominal aortic aneurysm 
Sweeting, M. J. | Balm, R. | Desgranges, P. | Ulug, P. | Powell, J. T. | Balm, R. | Koelemay, M. J. W. | Idu, M. M. | Kox, C. | Legemate, D. A. | Huisman, L. C. | Willems, M. C. M. | Reekers, J. A. | van Delden, O. M. | van Lienden, K. P. | Hoornweg, L. L. | Reimerink, J. J. | van Beek, S. C. | Vahl, A. C. | Leijdekkers, V. J. | Bosma, J. | Montauban van Swijndregt, A. D. | de Vries, C. | van der Hulst, V. P. M. | Peringa, J. | Blomjous, J. G. A. M. | Visser, M. J. T. | van der Heijden, F. H. W. M. | Wisselink, W. | Hoksbergen, A. W. J. | Blankensteijn, J. D. | Visser, M. T. J. | Coveliers, H. M. E. | Nederhoed, J. H. | van den Berg, F. G. | van der Meijs, B. B. | van den Oever, M. L. P. | Lely, R. J. | Meijerink, M. R. | Voorwinde, A. | Ultee, J. M. | van Nieuwenhuizen, R. C. | Dwars, B. J. | Nagy, T. O. M. | Tolenaar, P. | Wiersema, A. M. | Lawson, J. A. | van Aken, P. J. | Stigter, A. A. | van den Broek, T. A. A. | Vos, G. A. | Mulder, W. | Strating, R. P. | Nio, D. | Akkersdijk, G. J. M. | van der Elst, A. | Exter, P.van | Desgranges, P. | Becquemin, J.‐P. | Allaire, E. | Cochennec, F. | Marzelle, J. | Louis, N. | Schneider, J. | Majewski, M. | Castier, Y. | Leseche, G. | Francis, F. | Steinmetz, E. | Berne, J.‐P. | Favier, C. | Haulon, S. | Koussa, M. | Azzaoui, R. | Piervito, D. | Alimi, Y. | Boufi, M. | Hartung, O. | Cerquetta, P. | Amabile, P. | Piquet, P. | Penard, J. | Demasi, M. | Alric, P. | Canaud, L. | Berthet, J.‐P. | Julia, P. | Fabiani, J.‐N. | Alsac, J. M. | Gouny, P. | Badra, A. | Braesco, J. | Favre, J.‐P. | Albertini, J.‐N. | Martinez, R. | Hassen‐Khodja, R. | Batt, M. | Jean, E. | Sosa, M. | Declemy, S. | Destrieux‐Garnier, L. | Lermusiaux, P. | Feugier, P. | Powell, J. T. | Ashleigh, R. | Gomes, M. | Greenhalgh, R. M. | Grieve, R. | Hinchliffe, R. | Sweeting, M. | Thompson, M. M. | Thompson, S. G. | Ulug, P. | Cheshire, N. J. | Boyle, J. R. | Serracino‐Inglott, F. | Smyth, J. V. | Thompson, M. M. | Hinchliffe, R. J. | Bell, R. | Wilson, N. | Bown, M. | Dennis, M. | Davis, M. | Ashleigh, R. | Howell, S. | Wyatt, M. G. | Valenti, D. | Bachoo, P. | Walker, P. | MacSweeney, S. | Davies, J. N. | Rittoo, D. | Parvin, S. D. | Yusuf, W. | Nice, C. | Chetter, I. | Howard, A. | Chong, P. | Bhat, R. | McLain, D. | Gordon, A. | Lane, I. | Hobbs, S. | Pillay, W. | Rowlands, T. | El‐Tahir, A. | Asquith, J. | Cavanagh, S. | Dubois, L. | Forbes, T. L.
The British Journal of Surgery  2015;102(10):1229-1239.
The benefits of endovascular repair of ruptured abdominal aortic aneurysm remain controversial, without any strong evidence about advantages in specific subgroups.
An individual‐patient data meta‐analysis of three recent randomized trials of endovascular versus open repair of abdominal aortic aneurysm was conducted according to a prespecified analysis plan, reporting on results to 90 days after the index event.
The trials included a total of 836 patients. The mortality rate across the three trials was 31·3 per cent for patients randomized to endovascular repair/strategy and 34·0 per cent for those randomized to open repair at 30 days (pooled odds ratio 0·88, 95 per cent c.i. 0·66 to 1·18), and 34·3 and 38·0 per cent respectively at 90 days (pooled odds ratio 0·85, 0·64 to 1·13). There was no evidence of significant heterogeneity in the odds ratios between trials. Mean(s.d.) aneurysm diameter was 8·2(1·9) cm and the overall in‐hospital mortality rate was 34·8 per cent. There was no significant effect modification with age or Hardman index, but there was indication of an early benefit from an endovascular strategy for women. Discharge from the primary hospital was faster after endovascular repair (hazard ratio 1·24, 95 per cent c.i. 1·04 to 1·47). For open repair, 30‐day mortality diminished with increasing aneurysm neck length (adjusted odds ratio 0·69 (95 per cent c.i. 0·53 to 0·89) per 15 mm), but aortic diameter was not associated with mortality for either type of repair.
Survival to 90 days following an endovascular or open repair strategy is similar for all patients and for the restricted population anatomically suitable for endovascular repair. Women may benefit more from an endovascular strategy than men and patients are, on average, discharged sooner after endovascular repair.
Strong evidence of equivalence
PMCID: PMC4744980  PMID: 26104471
2.  Remote transient Lactobacillus animalis bacteremia causing prosthetic hip joint infection: a case report 
BMC Infectious Diseases  2016;16:634.
Lactobacillus spp. are uncommon pathogens in immunocompetent hosts, and even rarer causes of prosthetic device infections.
Case presentation
A case of chronic hip prosthetic joint infection (PJI) caused by L. animalis is described. This occurred 5 years after a transient bacteremia with the same organism. Whole genome sequencing of both isolates proved this PJI infection resulted from this remote bacteremia.
We document that prosthetic joint infections may be a consequence of bacteremia as much as 3 years before the onset of symptoms.
PMCID: PMC5097402  PMID: 27814684
Bacteremia; Prosthetic joint infection; Lactobacillus
3.  Seasonal Genetic Changes of Aedes aegypti (Diptera: Culicidae) Populations in Selected Sites of Cebu City, Philippines 
Journal of Medical Entomology  2015;52(4):638-646.
Aedes aegypti (L.) is the primary vector of dengue virus in the Philippines, where dengue is endemic. We examined the genetic changes of Ae. aegypti collected from three selected sites in Cebu city, Philippines, during the relatively wet (2011–2012) and dry seasons (2012 and 2013). A total of 493 Ae. aegypti adults, reared in the laboratory from field-collected larvae, were analyzed using 11 microsatellite loci. Seasonal variation was observed in allele frequencies and allelic richness. Average genetic differentiation (DEST = 0.018; FST = 0.029) in both dry seasons was higher, due to reduced Ne, than in the wet season (DEST=0.006; FST=0.009). Thus, average gene flow was higher in the wet season than in the dry seasons. However, the overall FST estimate (0.02) inclusive of the two seasons showed little genetic differentiation as supported by Bayesian clustering analysis. Results suggest that during the dry season the intense selection that causes a dramatic reduction of population size favors heterozygotes, leading to small pockets of mosquitoes (refuges) that exhibit random genetic differentiation. During the wet season, the genetic composition of the population is reconstituted by the expansion of the refuges that survived the preceding dry season. Source reduction of mosquitoes during the nonepidemic dry season is thus recommended to prevent dengue re-emergence in the subsequent wet season.
PMCID: PMC4592349  PMID: 26335470
Aedes aegypti; seasonal fluctuation; temporal genetics; Philippines; yellow fever mosquito
Heat acclimation (HA) evokes numerous physiological adaptations, improves heat tolerance and has also been shown to enhance lactate (LA) responses during exercise, similar to that seen with endurance training. The purpose of this study was to examine whether HA improves the body’s ability to remove LA during recovery following maximal exercise.
Ten healthy men completed two trials of maximal treadmill exercise (PRE- and POST-HA) separated by 5 days of HA. Each day of HA consisted of two 45 minute periods of cycling at ~50% VO2max separated by a 15min rest period in an environmental chamber (Tdb 45°C, RH 20%). In PRE-/POST-HA trials, venous blood was collected during 60 minutes of recovery to determine LA concentrations and removal kinetics (A2: amplitude and y2: velocity constant) using bi-exponential curve fitting.
Physiological adaptation to heat was significantly developed during HA, as evidenced by end-exercise Tre (DAY 1 vs. 5) (38.89±0.56 vs. 38.66±0.44 °C), Tsk (38.07±.51 vs. 37.66±.48 °C), HR (175.0±9.9 vs. 165.0±18.5 beats·min−1), and sweat rate (1.24 ±.26 vs. 1.47 ±.27 L·min−1) (p<.05). However, there was no significant difference in either LA concentrations (LA0min: 8.78±1.08 vs. 8.69±1.23; LApeak: 10.97±1.77 vs. 10.95±1.46; and La60min; 2.88±.82 vs. 2.96±.93 mmol·L−1) or removal kinetics (A2: −13.05±7.05 vs −15.59±7.90 mmol.L−1 and y2: .02±.01 vs .03±.01 min−1).
The present study concluded that, while effective in inducing thermo-physiological adaptations to heat stress, short-term HA does not improve the body’s ability to remove LA following maximal exercise. Therefore, athletes and workers seeking faster LA recovery from intense physical activity may not benefit from short-term HA.
PMCID: PMC4864577  PMID: 25286892
heat stress; heat adaptation; lactate recovery; lactic acidosis; performance
5.  Process evaluation of the Bristol girls dance project 
BMC Public Health  2016;16:349.
The Bristol Girls Dance Project was a cluster randomised controlled trial that aimed to increase objectively measured moderate-to-vigorous physical activity (MVPA) levels of Year 7 (age 11–12) girls through a dance-based after-school intervention. The intervention was delivered in nine schools and consisted of up to forty after-school dance sessions. This paper reports on the main findings from the detailed process evaluation that was conducted.
Quantitative and qualitative data were collected from intervention schools. Dose and fidelity were reported by dance instructors at every session. Intervention dose was defined as attending two thirds of sessions and was measured by attendance registers. Fidelity to the intervention manual was reported by dance instructors. On four randomly-selected occasions, participants reported their perceived level of exertion and enjoyment. Reasons for non-attendance were self-reported at the end of the intervention. Semi-structured interviews were conducted with all dance instructors who delivered the intervention (n = 10) and school contacts (n = 9) in intervention schools. A focus group was conducted with girls who participated in each intervention school (n = 9).
The study did not affect girls’ MVPA. An average of 31.7 girls participated in each school, with 9.1 per school receiving the intervention dose. Mean attendance and instructors’ fidelity to the intervention manual decreased over time. The decline in attendance was largely attributed to extraneous factors common to after-school activities. Qualitative data suggest that the training and intervention manual were helpful to most instructors. Participant ratings of session enjoyment were high but perceived exertion was low, however, girls found parts of the intervention challenging.
The intervention was enjoyed by participants. Attendance at the intervention sessions was low but typical of after-school activities. Participants reported that the intervention brought about numerous health and social benefits and improved their dance-based knowledge and skills. The intervention could be improved by reducing the number of girls allowed to participate in each school and providing longer and more in-depth training to those delivering the intervention.
Trial registration
ISRCTN52882523 Registered 25th April 2013.
PMCID: PMC4839166  PMID: 27097646
Physical activity intervention; Dance; Secondary school; Process evaluation; Adolescent; Girls
6.  A parameter to quantify the degree of genetic mixing among individuals in hybrid populations 
Heredity  2014;114(3):249-254.
Hybridization between genetically distinct taxa is a complex evolutionary process. One challenge to studying hybrid populations is quantifying the degree to which non-native genes have become evenly mixed among individuals in the population. In this paper, we present a variance-based parameter, md, that measures the degree to which non-native genes are evenly distributed among individuals in a population. The parameter has a minimum value of 0 for populations in which individuals from multiple taxa are present but have not interbred, and a maximum value of 1 for populations in which all individuals have the same amount of non-native ancestry. A recurrence equation showed that relatively few generations of random mating are required for md to approach 1 (indicating a well-mixed population), and that md is independent of initial amounts of non-native ancestry. The parameter is mathematically equivalent to FST and we show how existing formulae for FST can be used to estimate md when diagnostic loci are available. Computer simulations showed this estimator to have very little bias for realistic amounts of data.
PMCID: PMC4815573  PMID: 25388141
7.  Bacillus anthracis spores germinate extracellularly at air–liquid interface in an in vitro lung model under serum‐free conditions 
Journal of Applied Microbiology  2015;119(3):711-723.
To better understand the parameters that govern spore dissemination after lung exposure using in vitro cell systems.
Methods and Results
We evaluated the kinetics of uptake, germination and proliferation of Bacillus anthracis Sterne spores in association with human primary lung epithelial cells, Calu‐3 and A549 cell lines. We also analysed the influence of various cell culture medium formulations related to spore germination.
We found negligible spore uptake by epithelial cells, but germination and proliferation of spores in the serum‐free extracellular environment was evident. Spore germination was appreciably higher in immortalized cell cultures than in primary epithelial cells. Additionally, spores still germinated apically at a mucus‐secreting air–liquid interface lung barrier that was devoid of cell culture medium much earlier than medium‐only controls.
Significance and Impact of the Study
The role of lung epithelial cells in B. anthracis spore dissemination after inhalation remains poorly defined and rather controversial. These results are novel as they show spore germination is appreciably enhanced in the presence of lung cells in vitro, however, the cell line and cell state (air–liquid interface vs submerged in medium) dictates the extent of germination and in some cases proliferation.
PMCID: PMC4745038  PMID: 26075586
anthrax; Bacillus anthracis; germination; lung epithelial; spore; Sterne
8.  AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers 
Translational Psychiatry  2016;6(2):e738-.
Smoking cannabis daily doubles an individual's risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual's acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis—which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content—and also ±7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.
PMCID: PMC4872423  PMID: 26882038
10.  Variation in gut microbial communities and its association with pathogen infection in wild bumble bees (Bombus) 
The ISME Journal  2014;8(12):2369-2379.
Bacterial gut symbiont communities are critical for the health of many insect species. However, little is known about how microbial communities vary among host species or how they respond to anthropogenic disturbances. Bacterial communities that differ in richness or composition may vary in their ability to provide nutrients or defenses. We used deep sequencing to investigate gut microbiota of three species in the genus Bombus (bumble bees). Bombus are among the most economically and ecologically important non-managed pollinators. Some species have experienced dramatic declines, probably due to pathogens and land-use change. We examined variation within and across bee species and between semi-natural and conventional agricultural habitats. We categorized as ‘core bacteria' any operational taxonomic units (OTUs) with closest hits to sequences previously found exclusively or primarily in the guts of honey bees and bumble bees (genera Apis and Bombus). Microbial community composition differed among bee species. Richness, defined as number of bacterial OTUs, was highest for B. bimaculatus and B. impatiens. For B. bimaculatus, this was due to high richness of non-core bacteria. We found little effect of habitat on microbial communities. Richness of non-core bacteria was negatively associated with bacterial abundance in individual bees, possibly due to deeper sampling of non-core bacteria in bees with low populations of core bacteria. Infection by the gut parasite Crithidia was negatively associated with abundance of the core bacterium Gilliamella and positively associated with richness of non-core bacteria. Our results indicate that Bombus species have distinctive gut communities, and community-level variation is associated with pathogen infection.
PMCID: PMC4260702  PMID: 24763369
Bombus; Gilliamella; gut microbiota; land-use change; pyrosequencing
11.  Factors influencing the adoption of self-management solutions: an interpretive synthesis of the literature on stakeholder experiences 
In a research context, self-management solutions, which may range from simple book diaries to complex telehealth packages, designed to facilitate patients in managing their long-term conditions, have often shown cost-effectiveness, but their implementation in practice has frequently been challenging.
We conducted an interpretive qualitative synthesis of relevant articles identified through systematic searches of bibliographic databases in July 2014. We searched PubMed (Medline/NLM), Web of Science, LISTA (EBSCO), CINAHL, Embase and PsycINFO. Coding and analysis was inductive, using the framework method to code and to categorise themes. We took a sensemaking approach to the interpretation of findings.
Fifty-eight articles were selected for synthesis. Results showed that during adoption, factors identified as facilitators by some were experienced as barriers by others, and facilitators could change to barriers for the same adopter, depending on how adopters rationalise the solutions within their context when making decisions about (retaining) adoption. Sometimes, when adopters saw and experienced benefits of a solution, they continued using the solution but changed their minds when they could no longer see the benefits. Thus, adopters placed a positive value on the solution if they could constructively rationalise it (which increased adoption) and attached a negative rationale (decreasing adoption) if the solution did not meet their expectations. Key factors that influenced the way adopters rationalised the solutions consisted of costs and the added value of the solution to them and moral, social, motivational and cultural factors.
Considering ‘barriers’ and ‘facilitators’ for implementation may be too simplistic. Implementers could instead iteratively re-evaluate how potential facilitators and barriers are being experienced by adopters throughout the implementation process, to help adopters to retain constructive evaluations of the solution. Implementers need to pay attention to factors including (a) cost: how much resource will the intervention cost the patient or professional; (b) moral: to what extent will people adhere because they want to be ‘good’ patients and professionals; (c) social: the expectations of patients and professionals regarding the interactive support they will receive; (d) motivational: motivations to engage with the intervention and (e) cultural: how patients and professionals learn and integrate new skills into their daily routines, practices and cultures.
PMCID: PMC4644277  PMID: 26566623
Human values; Self-management; Chronic illness; Barriers; Facilitators; Stakeholder experiences; Sensemaking
12.  Measurement Accuracy of Heart Rate and Respiratory Rate during Graded Exercise and Sustained Exercise in the Heat Using the Zephyr BioHarness™ 
The Zephyr BioHarness™ was tested to determine the accuracy of heart rate (HR) and respiratory rate (RR) measurements during 2 exercise protocols in conjunction with either a laboratory metabolic cart (Vmax) or a previously validated portable metabolic system (K4b2). In one protocol, HR and RR were measured using the BioHarness and Vmax during a graded exercise up to V̇O2max (n = 12). In another protocol, HR and RR were measured using the BH and K4b2 during sustained exercise (30 % and 50 % V̇O2max for 20 min each) in a hot environment (30°C, 50 % relative humidity) (n = 6). During the graded exercise, HR but not RR, obtained from the BioHarness was higher compared to the Vmax at baseline and 30 % V̇O2max (p < 0.05), but showed no significant difference at other stages with high correlation coefficients for both HR (r = 0.87–0.96) and RR (r = 0.90–0.99 above 30 % V̇O2max). During the exercise in the heat, there were no significant differences between the BioHarness and K4b2 system. Correlation coefficients between the methods were low for HR but moderately to highly correlated (0.49–0.99) for RR. In conclusion, the BioHarness is comparable to Vmax and K4b2 over a wide range of V̇O2 during graded exercise and sustained exercise in the heat.
PMCID: PMC4620538  PMID: 23175181
physiological monitoring; portable metabolic system; reliability
13.  Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons 
Physiological Genomics  2015;48(1):1-11.
Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20–104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.
PMCID: PMC4757025  PMID: 26487704
gene-expression; muscle; strength; blood; human; leukocyte
14.  Routes of Acquisition of the Gut Microbiota of the Honey Bee Apis mellifera 
Applied and Environmental Microbiology  2014;80(23):7378-7387.
Studies of newly emerged Apis mellifera worker bees have demonstrated that their guts are colonized by a consistent core microbiota within several days of eclosure. We conducted experiments aimed at illuminating the transmission routes and spatiotemporal colonization dynamics of this microbiota. Experimental groups of newly emerged workers were maintained in cup cages and exposed to different potential transmission sources. Colonization patterns were evaluated using quantitative real-time PCR (qPCR) to assess community sizes and using deep sequencing of 16S rRNA gene amplicons to assess community composition. In addition, we monitored the establishment of the ileum and rectum communities within workers sampled over time from natural hive conditions. The study verified that workers initially lack gut bacteria and gain large characteristic communities in the ileum and rectum within 4 to 6 days within hives. Typical communities, resembling those of workers within hives, were established in the presence of nurse workers or nurse worker fecal material, and atypical communities of noncore or highly skewed compositions were established when workers were exposed only to oral trophallaxis or hive components (comb, honey, bee bread). The core species of Gram-negative bacteria, Snodgrassella alvi, Gilliamella apicola, and Frischella perrara, were dependent on the presence of nurses or hindgut material, whereas some Gram-positive species were more often transferred through exposure to hive components. These results indicate aspects of the colony life cycle and behavior that are key to the propagation of the characteristic honey bee gut microbiota.
PMCID: PMC4249178  PMID: 25239900
15.  Salivary and serum cortisol levels during recovery from intense exercise and prolonged, moderate exercise 
Biology of Sport  2015;32(2):91-95.
The aim of this study was to compare serum (SERc) and salivary cortisol (SALc) responses during recovery from two different exhaustive exercises to determine peak cortisol sampling time and the agreement between SERc and SALc levels. Twelve healthy men underwent a maximal treadmill graded exercise to exhaustion (MEx) and a prolonged, submaximal cycle exercise in the heat for 90 min (PEx) while SERc and SALc samples were taken in parallel at baseline, end of exercise, and 15 min intervals over one hour of recovery. MEx and PEx significantly increased SERc and SALc levels (p < 0.01) while absolute SERc levels were approximately 7-10 folds higher than SALc. SERc and SALc showed highly positive correlation (R = 0.667-0.910, p < 0.05) at most sampling times and only a few individual values were out of 95% limit of agreement when analyzed by Bland-Altman plots. However, peak SERc levels (MEx: 784.0±147, PEx: 705.5±212.0 nmol · L−1) occurred at 15 min of recovery, whereas peak SALc levels (MEx: 102.7±46.4, PEx: 95.7±40.9 nmol · L−1) were achieved at the end of exercise in MEx and PEx. The recovery trend of SERc and SALc also differed following MEx and PEx. Activity of 11β-hydroxysteroid dehydrogenase type 2 enzymes may be suppressed following MEx compared to PEx. In conclusion, sampling for peak SERc and SALc levels should take into account their evolution and clearance characteristics as well as type of exercise performed, whereas SALc appeared to be a more sensitive marker than SERc for the measurement of cortisol responses during exercise recovery.
PMCID: PMC4296213  PMID: 26028807
cortisol; saliva; hormonal marker; heat stress; recovery; exercise; young adults; male
16.  Positive association between serum silicon levels and bone mineral density in female rats following oral silicon supplementation with monomethylsilanetriol 
Osteoporosis International  2015;26(4):1405-1415.
Observational (epidemiological) studies suggest the positive association between dietary silicon intake and bone mineral density may be mediated by circulating estradiol level. Here, we report the results of a silicon supplementation study in rats that strongly support these observations and suggest an interaction between silicon and estradiol.
Epidemiological studies report strong positive associations between dietary silicon (Si) intake and bone mineral density (BMD) in premenopausal women and indicate that the association may be mediated by estradiol. We have tested this possibility in a mixed-gender rodent intervention study.
Tissue samples were obtained from three groups of 20-week-old Sprague Dawley rats (five males and five females per group) that had been supplemented ad libitum for 90 days in their drinking water with (i) <0.1 mg Si/L (vehicle control), (ii) 115 mg Si/L (moderate dose) or (iii) 575 mg Si/L (high dose). All rats received conventional laboratory feed, whilst supplemental Si was in the form of monomethylsilanetriol, increasing dietary Si intakes by 18 and 99 %, for the moderate- and high-dose groups, respectively.
Fasting serum and tissue Si concentrations were increased with Si supplementation (p < 0.05), regardless of gender. However, only for female rats was there (i) a trend for a dose-responsive increase in serum osteocalcin concentration with Si intervention and (ii) strong significant associations between serum Si concentrations and measures of bone quality (p < 0.01). Correlations were weaker or insignificant for tibia Si levels and absent for other serum or tibia elemental concentrations and bone quality measures.
Our findings support the epidemiological observations that dietary Si positively impacts BMD in younger females, and this may be due to a Si-estradiol interaction. Moreover, these data suggest that the Si effect is mediated systemically, rather than through its incorporation into bone.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-014-3016-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4357649  PMID: 25572052
Animal study; Bone μCT; Estradiol; Matrix mineralisation; Nutrition; Silicon
17.  Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease 
Translational Psychiatry  2015;5(1):e494-.
There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10–0.48, P=4.19E−04; ChE 34:0, OR=0.152, 95% CI=0.05–0.37, P=2.90E−04; ChE 34:6, OR=0.126, 95% CI=0.03–0.35, P=5.40E−04; ChE 32:4, OR=0.056, 95% CI=0.01–0.24, P=6.56E−04 and ChE 33:6, OR=0.205, 95% CI=0.06–0.50, P=2.21E−03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.
PMCID: PMC4312824  PMID: 25585166
18.  A Dose Finding Study of Temsirolimus and Liposomal Doxorubicin for Patients with Recurrent and Refractory Bone and Soft Tissue Sarcoma 
There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mTOR inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose-finding portion of this study. Adult and pediatrics patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose-limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m2 monthly with temsirolimus 20 mg/m2 weekly. Hematologic toxicity was common but manageable. Dose-limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Coadministration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.
PMCID: PMC3681832  PMID: 23382028
mTOR; cancer stem cell; chemoresistance; sarcoma; clinical trial
19.  Genomics and Successful Aging: Grounds for Renewed Optimism? 
Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer’s disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned.
Here, we review age-related disease associated single-nucleotide polymorphisms and identify key underlying pathways including lipid handling, specific immune processes, early tissue development, and cell cycle control.
Most age-related disease associated single-nucleotide polymorphisms do not affect coding regions of genes or protein makeup but instead influence regulation of gene expression. Recent evidence indicates that evolution of gene regulatory sites is fundamental to interspecies differences. Animal models relevant to human aging may therefore need to focus more on gene regulation rather than testing major disruptions to fundamental pathway genes. Recent larger scale human studies of in vivo genome-wide expression (notably from the InCHIANTI aging study) have identified changes in splicing, the “fine tuning” of protein sequences, as a potentially important factor in decline of cellular function with age. Studies of expression with muscle strength and cognition have shown striking concordance with certain mice models of muscle repair and beta-amyloid phagocytosis respectively.
The emerging clearer picture of the genetic architecture of age-related diseases in humans is providing new insights into the underlying pathophysiological pathways involved. Translation of genomics into new approaches to prevention, tests and treatments to extend successful aging is therefore likely in the coming decades.
PMCID: PMC3326244  PMID: 22454374
Longevity; Genetics; Public health
20.  Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma 
British Journal of Pharmacology  2012;166(1):177-193.
IL-13 is a pleiotropic Th2 cytokine considered likely to play a pivotal role in asthma. Here we describe the preclinical in vitro and in vivo characterization of CAT-354, an IL-13-neutralizing IgG4 monoclonal antibody (mAb), currently in clinical development.
In vitro the potency, specificity and species selectivity of CAT-354 was assayed in TF-1 cells, human umbilical vein endothelial cells and HDLM-2 cells. The ability of CAT-354 to modulate disease-relevant mechanisms was tested in human cells measuring bronchial smooth muscle calcium flux induced by histamine, eotaxin generation by normal lung fibroblasts, CD23 upregulation in peripheral blood mononuclear cells and IgE production by B cells. In vivo CAT-354 was tested on human IL-13-induced air pouch inflammation in mice, ovalbumin-sensitization and challenge in IL-13 humanized mice and antigen challenge in cynomolgus monkeys.
CAT-354 has a 165 pM affinity for human IL-13 and functionally neutralized human, human variant associated with asthma and atopy (R130Q) and cynomolgus monkey, but not mouse, IL-13. CAT-354 did not neutralize human IL-4. In vitro CAT-354 functionally inhibited IL-13-induced eotaxin production, an analogue of smooth muscle airways hyperresponsiveness, CD23 upregulation and IgE production. In vivo in humanized mouse and cynomolgus monkey antigen challenge models CAT-354 inhibited airways hyperresponsiveness and bronchoalveolar lavage eosinophilia.
CAT-354 is a potent and selective IL-13-neutralizing IgG4 mAb. The preclinical data presented here support the trialling of this mAb in patients with moderate to severe uncontrolled asthma.
PMCID: PMC3415647  PMID: 21895629
CAT-354; IL-13; IgG4; preclinical development for asthma; uncontrolled asthma; therapeutic antibody; asthma treatment
21.  Adenosine Receptors and Cancer 
The A1, A2A, A2B and A3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A1AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A1AR is mediated via tumor-associated microglial cells. Activation of the A2AAR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A2BAR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A2BAR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A3AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-κB, known to act as an A3AR transcription factor. Interestingly, high A3AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A3AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-κB signaling pathways. Taken together, A3ARs that are abundantly expressed in tumor cells may be targeted by specific A3AR agonists, leading to tumor growth inhibition. The unique characteristics of these A3AR agonists make them attractive as drug candidates.
PMCID: PMC3598010  PMID: 19639290
A1 adenosine receptor; A2A adenosine receptor; A2B adenosine receptor; A3 adenosine receptor; Expression; Tumor growth; Agonists; Antagonists
23.  Long-Term Exposure to Antibiotics Has Caused Accumulation of Resistance Determinants in the Gut Microbiota of Honeybees 
mBio  2012;3(6):e00377-12.
Antibiotic treatment can impact nontarget microbes, enriching the pool of resistance genes available to pathogens and altering community profiles of microbes beneficial to hosts. The gut microbiota of adult honeybees, a distinctive community dominated by eight bacterial species, provides an opportunity to examine evolutionary responses to long-term treatment with a single antibiotic. For decades, American beekeepers have routinely treated colonies with oxytetracycline for control of larval pathogens. Using a functional metagenomic screen of bacteria from Maryland bees, we detected a high incidence of tetracycline/oxytetracycline resistance. This resistance is attributable to known resistance loci for which nucleotide sequences and flanking mobility genes were nearly identical to those from human pathogens and from bacteria associated with farm animals. Surveys using diagnostic PCR and sequencing revealed that gut bacteria of honeybees from diverse localities in the United States harbor eight tetracycline resistance loci, including efflux pump genes (tetB, tetC, tetD, tetH, tetL, and tetY) and ribosome protection genes (tetM and tetW), often at high frequencies. Isolates of gut bacteria from Connecticut bees display high levels of tetracycline resistance. Resistance genes were ubiquitous in American samples, though rare in colonies unexposed for 25 years. In contrast, only three resistance loci, at low frequencies, occurred in samples from countries not using antibiotics in beekeeping and samples from wild bumblebees. Thus, long-term antibiotic treatment has caused the bee gut microbiota to accumulate resistance genes, drawn from a widespread pool of highly mobile loci characterized from pathogens and agricultural sites.
We found that 50 years of using antibiotics in beekeeping in the United States has resulted in extensive tetracycline resistance in the gut microbiota. These bacteria, which form a distinctive community present in healthy honeybees worldwide, may function in protecting bees from disease and in providing nutrition. In countries that do not use antibiotics in beekeeping, bee gut bacteria contained far fewer resistance genes. The tetracycline resistance that we observed in American samples reflects the capture of mobile resistance genes closely related to those known from human pathogens and agricultural sites. Thus, long-term treatment to control a specific pathogen resulted in the accumulation of a stockpile of resistance capabilities in the microbiota of a healthy gut. This stockpile can, in turn, provide a source of resistance genes for pathogens themselves. The use of novel antibiotics in beekeeping may disrupt bee health, adding to the threats faced by these pollinators.
PMCID: PMC3487773  PMID: 23111871
24.  Distinctive Gut Microbiota of Honey Bees Assessed Using Deep Sampling from Individual Worker Bees 
PLoS ONE  2012;7(4):e36393.
Surveys of 16S rDNA sequences from the honey bee, Apis mellifera, have revealed the presence of eight distinctive bacterial phylotypes in intestinal tracts of adult worker bees. Because previous studies have been limited to relatively few sequences from samples pooled from multiple hosts, the extent of variation in this microbiota among individuals within and between colonies and locations has been unclear. We surveyed the gut microbiota of 40 individual workers from two sites, Arizona and Maryland USA, sampling four colonies per site. Universal primers were used to amplify regions of 16S ribosomal RNA genes, and amplicons were sequenced using 454 pyrotag methods, enabling analysis of about 330,000 bacterial reads. Over 99% of these sequences belonged to clusters for which the first blastn hits in GenBank were members of the known bee phylotypes. Four phylotypes, one within Gammaproteobacteria (corresponding to “Candidatus Gilliamella apicola”) one within Betaproteobacteria (“Candidatus Snodgrassella alvi”), and two within Lactobacillus, were present in every bee, though their frequencies varied. The same typical bacterial phylotypes were present in all colonies and at both sites. Community profiles differed significantly among colonies and between sites, mostly due to the presence in some Arizona colonies of two species of Enterobacteriaceae not retrieved previously from bees. Analysis of Sanger sequences of rRNA of the Snodgrassella and Gilliamella phylotypes revealed that single bees contain numerous distinct strains of each phylotype. Strains showed some differentiation between localities, especially for the Snodgrassella phylotype.
PMCID: PMC3338667  PMID: 22558460
25.  Interaction of catechol O-methyltransferase and serotonin transporter genes modulates effective connectivity in a facial emotion-processing circuitry 
Translational Psychiatry  2012;2(1):e70-.
Imaging genetic studies showed exaggerated blood oxygenation level-dependent response in limbic structures in carriers of low activity alleles of serotonin transporter-linked promoter region (5-HTTLPR) as well as catechol O-methyltransferase (COMT) genes. This was suggested to underlie the vulnerability to mood disorders. To better understand the mechanisms of vulnerability, it is important to investigate the genetic modulation of frontal-limbic connectivity that underlies emotional regulation and control. In this study, we have examined the interaction of 5-HTTLPR and COMT genetic markers on effective connectivity within neural circuitry for emotional facial expressions. A total of 91 healthy Caucasian adults underwent functional magnetic resonance imaging experiments with a task presenting dynamic emotional facial expressions of fear, sadness, happiness and anger. The effective connectivity within the facial processing circuitry was assessed with Granger causality method. We have demonstrated that in fear processing condition, an interaction between 5-HTTLPR (S) and COMT (met) low activity alleles was associated with reduced reciprocal connectivity within the circuitry including bilateral fusiform/inferior occipital regions, right superior temporal gyrus/superior temporal sulcus, bilateral inferior/middle prefrontal cortex and right amygdala. We suggest that the epistatic effect of reduced effective connectivity may underlie an inefficient emotion regulation that places these individuals at greater risk for depressive disorders.
PMCID: PMC3309546  PMID: 22832732
COMT; effective connectivity; facial emotion processing; 5-HTTLPR

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