Individual and family-based approaches to increase physical activity in adolescents with intellectual and developmental disabilities: Rationale and design for an 18 month randomized trial.

Adolescents with intellectual and developmental disabilities (IDD) are less physically active and have lower cardiovascular fitness compared with their typically developing peers. This population faces additional barriers to participation in moderate-to-vigorous physical activity (MVPA) such as reliance on parents, lack of peer-support, and lack of inclusive physical activity opportunities. Previous interventions to increase MVPA in adolescents with IDD have met with limited success, at least in part due to requiring parents to transport their adolescent to an exercise facility. We recently developed a remote system to deliver MVPA to groups of adolescents with IDD in their homes via video conferencing on a tablet computer. This approach eliminates the need for transportation and provides social interaction and support from both a health coach and other participants. We will conduct a 18-mo. trial (6 mos. active, 6 mos. maintenance, 6 mos. no-contact follow-up) to compare changes in objectively assessed MVPA in 114 adolescents with IDD randomized to a single level intervention delivered only to the adolescent (AO) or a multi-level intervention delivered to both the adolescent and a parent (A + P). Our primary aim is to compare increases in MVPA (min/d) between the AO and A + P groups from 0 to 6 mos. Secondarily we will compare changes in MVPA, sedentary time, cardiovascular fitness, muscular strength, motor ability, quality of life, and the percentage of adolescents achieving the US recommendation of 60 min. MVPA/d across 18 mos. We will also explore the influence of process variables/participant characteristics on changes in MVPA across 18 mos. NCT registration: NCT03684512.

Testing hypotheses for maternal effects in Daphnia magna.

Maternal effects are widely observed, but their adaptive nature remains difficult to describe and interpret. We investigated adaptive maternal effects in a clone of the crustacean Daphnia magna, experimentally varying both maternal age and maternal food and subsequently varying food available to offspring. We had two main predictions: that offspring in a food environment matched to their mothers should fare better than offspring in unmatched environments, and that offspring of older mothers would fare better in low food environments. We detected numerous maternal effects, for example offspring of poorly fed mothers were large, whereas offspring of older mothers were both large and showed an earlier age at first reproduction. However, these maternal effects did not clearly translate into the predicted differences in reproduction. Thus, our predictions about adaptive maternal effects in response to food variation were not met in this genotype of Daphnia magna.

Lipid stimulation of fatty acid sensors in the human duodenum: relationship with gastrointestinal hormones, BMI and diet.

BACKGROUND AND AIMS: The small intestinal free fatty acid (FFA) sensors, FFA receptor 1 (FFAR1), FFAR4, G-protein receptor 119 (GPR119) and cluster of differentiation-36 (CD36), mediate the fat-induced release of gastrointestinal (GI) hormones. We investigated whether expression of duodenal FFA sensors in humans was (i) altered by intraduodenal (ID) lipid infusion, (ii) disordered in overweight or obese individuals, (iii) related to lipid-induced GI hormone secretion or (iv) affected by habitual dietary patterns. METHODS: Endoscopic duodenal biopsies were collected from 20 lean (body mass index (BMI): 22±1 kg m-2), 18 overweight (BMI: 27±1 kg m-2) and 19 obese (BMI: 35±1 kg m-2) participants at baseline, and following a 30 min ID Intralipid infusion (2 kcal min-1); FFA sensor expression was quantified by reverse transcription-PCR. On a separate day, participants underwent ID Intralipid infusion (2 kcal min-1) for 120 min, to assess GI hormone responses. Habitual diet was evaluated using food frequency questionnaires. RESULTS: Baseline FFAR1 and FFAR4 expression were lower, and CD36 was higher, in obese participants compared with lean participants. ID lipid increased GPR119 and FFAR1 expression equally across study groups, but did not alter FFAR4 or CD36 expression. Increased FFAR1 expression correlated positively with glucose-dependent insulinotropic polypeptide (GIP) secretion (r=0.3, P<0.05), whereas there was no relationship between habitual diet with the expression of FFA sensors. CONCLUSIONS: Obesity is associated with altered duodenal expression of FFAR1, FFAR4 and CD36, suggesting altered capacity for the sensing, absorption and metabolism, of dietary lipids. GPR119 and FFAR1 are early transcriptional responders to the presence of ID lipid, whereas FFAR1 may be an important trigger for lipid-induced GIP release in humans.

Colestyramine slows gastric emptying of liquids and reduces appetite in healthy subjects.

BACKGROUND: There is evidence to suggest that the particulate resin colestyramine, a bile acid sequestrant formerly used as a cholesterol-lowering agent, enhances secretion of the gut hormone cholecystokinin (CCK). Established physiological actions of CCK include inhibition of gastric emptying and induction of satiation. This study evaluated the hypothesis that colestyramine, which is luminally retained, would slow gastric emptying of liquids and suppress appetite in humans. METHODS: Nine healthy volunteers consumed 500 mL liquid test meals containing 4 g colestyramine, 12 g colestyramine, or control (water alone), on three occasions, in a randomized order. The effect of colestyramine on gastric emptying was determined non-invasively using the (13) C-acetate breath test, and appetite and other gut-centered sensations were rated using visual analog scale questionnaires. KEY RESULTS: Colestyramine dose dependently slowed liquid gastric emptying compared with control (water) (4 g vs control, ∼20% reduction, P < 0.05; 12 g vs control, ∼35% reduction, P < 0.01). Colestyramine also significantly reduced hunger (4 g vs control, ∼20% reduction, P < 0.01), and the amount of food participants felt able to eat (12 g vs control, ∼32% reduction, P < 0.001), but increased bloating (both doses, P < 0.05), with no effect on ratings of nausea. CONCLUSIONS & INFERENCES: This study provides the first evidence that colestyramine significantly slows liquid gastric emptying and reduces appetite in healthy humans. Colestyramine therefore presents an attractive gut-brain signaling research tool in that it is not absorbed and thus lacks potentially confounding postabsorptive effects. Furthermore, with clear effects on gastric emptying and appetite, colestyramine now merits consideration as a trial therapeutic strategy for appetite suppression and weight loss.

Fecundity compensation and tolerance to a sterilizing pathogen in Daphnia.

Hosts are armed with several lines of defence in the battle against parasites: they may prevent the establishment of infection, reduce parasite growth once infected or persevere through mechanisms that reduce the damage caused by infection, called tolerance. Studies on tolerance in animals have focused on mortality, and sterility tolerance has not been investigated experimentally. Here, we tested for genetic variation in the multiple steps of defence when the invertebrate Daphnia magna is infected with the sterilizing bacterial pathogen Pasteuria ramosa: anti-infection resistance, anti-growth resistance and the ability to tolerate sterilization once infected. When exposed to nine doses of a genetically diverse pathogen inoculum, six host genotypes varied in their average susceptibility to infection and in their parasite loads once infected. How host fecundity changed with increasing parasite loads did not vary between genotypes, indicating that there was no genetic variation for this measure of fecundity tolerance. However, genotypes differed in their level of fecundity compensation under infection, and we discuss how, by increasing host fitness without targeting parasite densities, fecundity compensation is consistent with the functional definition of tolerance. Such infection-induced life-history shifts are not traditionally considered to be part of the immune response, but may crucially reduce harm (in terms of fitness loss) caused by disease, and are a distinct source of selection on pathogens.

Genetic variation for maternal effects on parasite susceptibility.

The expression of infectious disease is increasingly recognized to be impacted by maternal effects, where the environmental conditions experienced by mothers alter resistance to infection in offspring, independent of heritability. Here, we studied how maternal effects (high or low food availability to mothers) mediated the resistance of the crustacean Daphnia magna to its bacterial parasite Pasteuria ramosa. We sought to disentangle maternal effects from the effects of host genetic background by studying how maternal effects varied across 24 host genotypes sampled from a natural population. Under low-food conditions, females produced offspring that were relatively resistant, but this maternal effect varied strikingly between host genotypes, i.e. there were genotype by maternal environment interactions. As infection with P. ramosa causes a substantial reduction in host fecundity, this maternal effect had a large effect on host fitness. Maternal effects were also shown to impact parasite fitness, both because they prevented the establishment of the parasites and because even when parasites did establish in the offspring of poorly fed mothers, and they tended to grow more slowly. These effects indicate that food stress in the maternal generation can greatly influence parasite susceptibility and thus perhaps the evolution and coevolution of host-parasite interactions.

Identifying energy constraints to parasite resistance.

Life-history theory suggests that energetically expensive traits may trade off against each other, resulting in costs associated with the development or maintenance of a particular phenotype. The deployment of resistance mechanisms during parasite exposure is one such trait, and thus their potential benefit in fighting off parasites may be offset by costs to other fitness-related traits. In this study, we used trade-off theory as a basis to test whether stimulating an increased development rate in juvenile Daphnia would reveal energetic constraints to its ability to resist infection upon subsequent exposure to the castrating parasite, Pasteuria ramosa. We show that the presumably energetically expensive process of increased development rate does result in more infected hosts, suggesting that parasite resistance requires the allocation of resources from a limited source, and thus has the potential to be costly.

Gastric emptying of hexose sugars: role of osmolality, molecular structure and the CCK1 receptor.

BACKGROUND: It is widely reported that hexose sugars slow gastric emptying (GE) via osmoreceptor stimulation but this remains uncertain. We evaluated the effects of a panel of hexoses of differing molecular structure, assessing the effects of osmolality, intra-individual reproducibility and the role of the CCK(1) receptor, in the regulation of GE by hexoses. METHODS: Thirty one healthy non-obese male and female subjects were studied in a series of protocols, using a (13) C-acetate breath test to evaluate GE of varying concentrations of glucose, galactose, fructose and tagatose, with water, NaCl and lactulose as controls. GE was further evaluated following the administration of a CCK(1) receptor antagonist. Three subjects underwent repeated studies to evaluate intra-individual reproducibility. KEY RESULTS: At 250 mOsmol, a hexose-specific effect was apparent: tagatose slowed GE more potently than water, glucose and fructose (P < 0.05). Fructose (P < 0.05) also slowed GE, but with substantial inter-, but not intra-, individual differences. As osmolality increased further the hexose-specific differences were lost. At 500 mOsmol, all hexoses slowed GE compared with water (P < 0.05), whereas lactulose and saline did not. The slowing of GE by hexose sugars appeared to be CCK(1) receptor-dependent. CONCLUSIONS & INFERENCES: The effects of hexose sugars on GE appear related to their molecular structure rather than osmolality per se, and are, at least in part, CCK(1) receptor-dependent.

Exploring the molecular landscape of host-parasite coevolution.

Host-parasite coevolution is a dynamic process that can be studied at the phenotypic, genetic, and molecular levels. Although much of what we currently know about coevolution has been learned through phenotypic measures, recent advances in molecular techniques have provided tools to greatly deepen this research. Both the availability of full-genome sequences and the increasing feasibility of high-throughput gene expression profiling are leading to the discovery of genes that have a key role in antagonistic interactions between naturally coevolving species. Identification of such genes can enable direct observation, rather than inference, of the host-parasite coevolutionary dynamic. The Daphnia magna-Pasteuria ramosa host-parasite model is a prime example of an interaction that has been well studied at the population and whole-organism levels, and much is known about genotype- and environment-specific interactions from a phenotypic perspective. Now, with the recent completion of genome sequences for two Daphnia species, and a transcriptomics project under way, coevolution between these two enemies is being investigated directly at the level of interacting genes.

Measuring parasite fitness under genetic and thermal variation.

Accurate measures of parasite fitness are essential to study host-parasite evolution. Parasite fitness depends on several traits involved in establishing infection, growth and transmission. Individually, these traits provide a reasonable approximation of fitness, but they may also be under the shared control of both host and parasite genetics (G(H) x G(P) interactions), or be differentially sensitive to environmental variation. Using the natural host-parasite system Daphnia magna-Pasteuria ramosa, we performed experimental infections that incorporated host and parasite genetic variation at three different temperatures, and compared the measures of parasite fitness based only on growth rate, or incorporating the ability to infect. We found that infectivity was most important for parasite fitness and depended mainly on the combination of host and parasite genotypes. Variation in post-infection parasite growth and killing time depended on the parasite genotype and its interaction with temperature. These results highlight the merits of studies that can incorporate natural infection routes and emphasize that accurate measures of parasite fitness require knowledge of the genetic control and environmental sensitivity of more than one trait. In addition, no G(H) x G(P) x E interactions were present, suggesting that the potential for genetic specificities to drive frequency-dependent coevolution in this system is robust to thermal variation.

Temperature-dependent costs of parasitism and maintenance of polymorphism under genotype-by-environment interactions.

The maintenance of genetic variation for infection-related traits is often attributed to coevolution between hosts and parasites, but it can also be maintained by environmental variation if the relative fitness of different genotypes changes with environmental variation. To gain insight into how infection-related traits are sensitive to environmental variation, we exposed a single host genotype of the freshwater crustacean Daphnia magna to four parasite isolates (which we assume to represent different genotypes) of its naturally co-occurring parasite Pasteuria ramosa at 15, 20 and 25 degrees C. We found that the cost to the host of becoming infected varied with temperature, but the magnitude of this cost did not depend on the parasite isolate. Temperature influenced parasite fitness traits; we found parasite genotype-by-environment (G x E) interactions for parasite transmission stage production, suggesting the potential for temperature variation to maintain genetic variation in this trait. Finally, we tested for temperature-dependent relationships between host and parasite fitness traits that form a key component of models of virulence evolution, and we found them to be stable across temperatures.

Hormone profiles of mares affected by the mare reproductive loss syndrome.

While searching for the cause of the Mare Reproductive Loss syndrome (MRLS), we postulated that 1 of 3 tissues in 40-120 D pregnant mares was the likely primary target of the noxious factor that caused early abortions: The corpora lutea (CL), the endometrium or the fetus and/or its membranes. At this stage of gestation, progesterone (P4) is solely produced by luteal tissue, eCG by endometrial cups in the endometrium and oestrogens by the feto-placental unit. We determined whether concentrations of P4, eCG and/or total conjugated oestrogens (CE) would indicate which tissue was targeted during the MRLS. P4, eCG and CE were measured in single serum samples collected from 216 mares, 60-110 D after ovulation during the 2001 MRLS outbreak. All mares had previously been confirmed pregnant by ultrasonography. The following data was obtained from each mare: Interval from ovulation, pregnancy status and normalcy of fetal fluids at the time of sampling, and pregnancy status 3 weeks after sampling and at term. There were no meaningful differences in hormone concentrations between pregnant mares that had normal and excessively echogenic fetal fluids at the time of sampling. CE were lower (p < 0.05) in mares that aborted after sample collection than in mares the carried to term. In 8 mares from which multiple samples were obtained, CE consistently decreased prior to any decreases in P4 or eCG. Arguments are presented that lead to the hypothesis that the fetal trophoblast was the primary target of the MRLS agent.

Bayesian hypothesis testing-use in interpretation of measurements.

Bayesian hypothesis testing may be used to qualitatively interpret a dataset as indicating something "detected" or not. Hypothesis testing is shown to be equivalent to testing the posterior distribution for positive true amounts by redefining the prior to be a mixture of the original prior and a delta-function component at 0 representing the null hypothesis that nothing is truly present. The hypothesis-testing interpretation of the data is based on the posterior probability of the usual modeling hypothesis relative to the null hypothesis. Real numerical examples are given and discussed, including the distribution of the non-null hypothesis probability over 4,000 internal dosimetry cases. Currently used comparable methods based on classical statistics are discussed.

Parasite variation and the evolution of virulence in a Daphnia-microparasite system.

Understanding genetic relationships amongst the life-history traits of parasites is crucial for testing hypotheses on the evolution of virulence. This study therefore examined variation between parasite isolates (the bacterium Pasteuria ramosa) from the crustacean Daphnia magna. From a single wild-caught infected host we obtained 2 P. ramosa isolates that differed substantially in the mortality they caused. Surprisingly, the isolate causing higher early mortality was, on average, less successful at establishing infections and had a slower growth rate within hosts. The observation that within-host replication rate was negatively correlated with mortality could violate a central assumption of the trade-off hypothesis for the evolution of virulence, but we discuss a number of caveats which caution against premature rejection of the trade-off hypothesis. We sought to test if the characteristics of these parasite isolates were constant across host genotypes in a second experiment that included 2 Daphnia host clones. The relative growth rates of the two parasite isolates did indeed depend on the host genotype (although the rank order did not change). We suggest that testing evolutionary hypotheses for virulence may require substantial sampling of both host and parasite genetic variation, and discuss how selection for virulence may change with the epidemiological state of natural populations and how this can promote genetic variation for virulence.

Low back pain associated with internal snapping hip syndrome in a competitive cyclist.

Low back pain is a common complaint among cyclists. Here we present the case of a competitive master cyclist with low back pain and whose symptoms ultimately resolved when he was treated for internal snapping hip syndrome. Internal snapping hip syndrome is a painful lesion of the iliopsoas caused by snapping of the tendon over the iliopectineal eminence or anterior femoral head when the femur is extended from a flexed position. This is the first published report that we are aware of that describes this syndrome as a potential cause of low back pain in a competitive cyclist.

Comparison of dose estimation from occupational exposure to 239Pu using different modelling approaches.

Several approaches are available for bioassay interpretation when assigning Pu doses to Mayak workers. First, a conventional approach is to apply ICRP models per se. An alternative method involves individualised fitting of bioassay data using Bayesian statistical methods. A third approach is to develop an independent dosimetry system for Mayak workers by adapting ICRP models using a dataset of available bioassay measurements for this population. Thus, a dataset of 42 former Mayak workers, who died of non-radiation effects, with both urine bioassay and post-mortem tissue data was used to test these three approaches. All three approaches proved to be adequate for bioassay and tissue interpretation, and thus for Pu dose reconstruction purposes. However, large discrepancies are observed in the resulting quantitative dose estimates. These discrepancies can, in large part, be explained by differences in the interpretation of Pu behaviour in the lungs in the context of ICRP lung model. Thus, a careful validation of Pu lung dosimetry model is needed in Mayak worker dosimetry systems.

Internal dose assessment data management system for a large population of Pu workers.

This paper describes the design and implementation of the Los Alamos National Laboratory (LANL) dose assessment (DA) data system. Dose calculations for the most important radionuclides at LANL, namely plutonium, americium, uranium and tritium, are performed through the Microsoft Access DA database. DA includes specially developed forms and macros that perform a variety of tasks, such as retrieving bioassay data, launching the FORTRAN internal dosimetry applications and displaying dose results in the form of text summaries and plots. The DA software involves the following major processes: (1) downloading of bioassay data from a remote data source, (2) editing local and remote databases, (3) setting up and carrying out internal dose calculations using the UF code or the ID code, (3) importing results of the dose calculations into local results databases, (4) producing a secondary database of 'official results' and (5) automatically creating and e-mailing reports. The software also provides summary status and reports of the pending DAs, which are useful for managing the cases in process.