A novel approach to simulate gene-environment interactions in complex diseases

Background: Complex diseases are multifactorial traits caused by both genetic and environmental factors. They represent the major part of human diseases and include those with largest prevalence and mortality (cancer, heart disease, obesity, etc.). Despite a large amount of information that has been collected about both genetic and environmental risk factors, there are few examples of studies on their interactions in epidemiological literature. One reason can be the incomplete knowledge of the power of statistical methods designed to search for risk factors and their interactions in these data sets. An improvement in this direction would lead to a better understanding and description of gene-environment interactions. To this aim, a possible strategy is to challenge the different statistical methods against data sets where the underlying phenomenon is completely known and fully controllable, for example simulated ones. Results: We present a mathematical approach that models gene-environment interactions. By this method it is possible to generate simulated populations having gene-environment interactions of any form, involving any number of genetic and environmental factors and also allowing non-linear interactions as epistasis. In particular, we implemented a simple version of this model in a Gene-Environment iNteraction Simulator (GENS), a tool designed to simulate case-control data sets where a one gene-one environment interaction influences the disease risk. The main aim has been to allow the input of population characteristics by using standard epidemiological measures and to implement constraints to make the simulator behaviour biologically meaningful. Conclusions: By the multi-logistic model implemented in GENS it is possible to simulate case-control samples of complex disease where gene-environment interactions influence the disease risk. The user has full control of the main characteristics of the simulated population and a Monte Carlo process allows random variability. A knowledge-based approach reduces the complexity of the mathematical model by using reasonable biological constraints and makes the simulation more understandable in biological terms. Simulated data sets can be used for the assessment of novel statistical methods or for the evaluation of the statistical power when designing a study

Ewing sarcoma of the mandible mimicking an odontogenic abscess – a case report

Ewing sarcoma (ES) of the mandible is rare and can be mistaken for inflammation of dental origin. We present a 24-year old male patient which underwent radical tumour surgery and primary reconstruction with a microvascular osteoseptocutaneous free fibular flap as well as postoperative adjuvant chemotherapy. Incomplete osseous tumour resection required a second intervention. This case report recapitulates the clinical and histopathological findings in oral ES, demonstrates its sometimes difficult diagnosis and discusses the (dis-)advantages of primary osseous reconstruction in ablative tumour surgery

A rapidly spinning supermassive black hole at the centre of NGC 1365

Broad X-ray emission lines from neutral and partially ionized iron observed in active galaxies have been interpreted as fluorescence produced by the reflection of hard X-rays off the inner edge of an accretion disk. In this model, line broadening and distortion result from rapid rotation and relativistic effects near the black hole, the line shape being sensitive to its spin. Alternative models in which the distortions result from absorption by intervening structures provide an equally good description of the data, and there has been no general agreement on which is correct. Recent claims that the black hole (2 × 10^6 solar masses) at the centre of the galaxy NGC 1365 is rotating at close to its maximum possible speed rest on the assumption of relativistic reflection. Here we report X-ray observations of NGC 1365 that reveal the relativistic disk features through broadened Fe-line emission and an associated Compton scattering excess of 10–30 kiloelectronvolts. Using temporal and spectral analyses, we disentangle continuum changes due to time-variable absorption from reflection, which we find arises from a region within 2.5 gravitational radii of the rapidly spinning black hole. Absorption-dominated models that do not include relativistic disk reflection can be ruled out both statistically and on physical grounds

Reduced functional measure of cardiovascular reserve predicts admission to critical care unit following kidney transplantation

Background: There is currently no effective preoperative assessment for patients undergoing kidney transplantation that is able to identify those at high perioperative risk requiring admission to critical care unit (CCU). We sought to determine if functional measures of cardiovascular reserve, in particular the anaerobic threshold (VO2AT) could identify these patients. Methods: Adult patients were assessed within 4 weeks prior to kidney transplantation in a University hospital with a 37-bed CCU, between April 2010 and June 2012. Cardiopulmonary exercise testing (CPET), echocardiography and arterial applanation tonometry were performed. Results: There were 70 participants (age 41.7614.5 years, 60% male, 91.4% living donor kidney recipients, 23.4% were desensitized). 14 patients (20%) required escalation of care from the ward to CCU following transplantation. Reduced anaerobic threshold (VO2AT) was the most significant predictor, independently (OR = 0.43; 95% CI 0.27–0.68; p,0.001) and in the multivariate logistic regression analysis (adjusted OR = 0.26; 95% CI 0.12–0.59; p = 0.001). The area under the receiveroperating- characteristic curve was 0.93, based on a risk prediction model that incorporated VO2AT, body mass index and desensitization status. Neither echocardiographic nor measures of aortic compliance were significantly associated with CCU admission. Conclusions: To our knowledge, this is the first prospective observational study to demonstrate the usefulness of CPET as a preoperative risk stratification tool for patients undergoing kidney transplantation. The study suggests that VO2AT has the potential to predict perioperative morbidity in kidney transplant recipients

Improving the Efficiency of Physical Examination Services

The objective of our project was to improve the efficiency of the physical examination screening service of a large hospital system. We began with a detailed simulation model to explore the relationships between four performance measures and three decision factors. We then attempted to identify the optimal physician inquiry starting time by solving a goal-programming problem, where the objective function includes multiple goals. One of our simulation results shows that the proposed optimal physician inquiry starting time decreased patient wait times by 50% without increasing overall physician utilization

Aerobic capacity, activity levels and daily energy expenditure in male and female adolescents of the kenyan nandi sub-group

The relative importance of genetic and socio-cultural influences contributing to the success of east Africans in endurance athletics remains unknown in part because the pre-training phenotype of this population remains incompletely assessed. Here cardiopulmonary fitness, physical activity levels, distance travelled to school and daily energy expenditure in 15 habitually active male (13.9±1.6 years) and 15 habitually active female (13.9±1.2) adolescents from a rural Nandi primary school are assessed. Aerobic capacity ([Formula: see text]) was evaluated during two maximal discontinuous incremental exercise tests; physical activity using accelerometry combined with a global positioning system; and energy expenditure using the doubly labelled water method. The [Formula: see text] of the male and female adolescents were 73.9±5.7 ml(.) kg(-1.) min(-1) and 61.5±6.3 ml(.) kg(-1.) min(-1), respectively. Total time spent in sedentary, light, moderate and vigorous physical activities per day was 406±63 min (50% of total monitored time), 244±56 min (30%), 75±18 min (9%) and 82±30 min (10%). Average total daily distance travelled to and from school was 7.5±3.0 km (0.8-13.4 km). Mean daily energy expenditure, activity-induced energy expenditure and physical activity level was 12.2±3.4 MJ(.) day(-1), 5.4±3.0 MJ(.) day(-1) and 2.2±0.6. 70.6% of the variation in [Formula: see text] was explained by sex (partial R(2) = 54.7%) and body mass index (partial R(2) = 15.9%). Energy expenditure and physical activity variables did not predict variation in [Formula: see text] once sex had been accounted for. The highly active and energy-demanding lifestyle of rural Kenyan adolescents may account for their exceptional aerobic fitness and collectively prime them for later training and athletic success

Female Resistance to Invading Males Increases Infanticide in Langurs

BACKGROUND: Infanticide by adult male occurs in many mammalian species under natural conditions, and it is often assumed to be a goal-directed action and explained predominately by sexual selection. Motivation of this behavior in mammals is limitedly involved. METHODOLOGY AND PRINCIPAL FINDINGS: We used long-term reproductive records and direct observation in captivity and in the field of two snub-nosed langur species on the basis of individual identification to investigate how infanticide happened and to be avoided in nonhuman primates. Our observations suggested that infanticide by invading males might be more accidental than goal-directed. The invading male seemed to monopolize all the females including lactating mothers during takeovers. Multiparous mothers who accepted the invading male shortly after takeovers avoided infanticide in most cases. Our results conjectured primiparous mothers would decrease infanticidal possibility if they sexually accepted the invading male during or immediately after takeovers. In the studied langur species, voluntary abortion or mating with the invading male was evidently adopted by females to limit or avoid infanticide by takeover males. CONCLUSIONS AND SIGNIFICANCE: The objective of the invading male was to monopolize all adult females after his takeover. It appeared that the mother's resistance to accepting the new male as a mating partner was the primary incentive for infanticide. Motivation analysis might be helpful to further understand why infanticide occurs in primate species

Cronkhite-Canada syndrome associated with rib fractures: a case report

<p>Abstract</p> <p>Background</p> <p>Cronkhite-Canada syndrome (CCS) is a rare multiple gastrointestinal polyposis. Up till now, many complications of CCS have been reported in the literature, but rib fracture is not included.</p> <p>Case Presentation</p> <p>We report a case of a 58-year-old man who was admitted to our hospital with a 6-month history of frequent diarrhea, intermittent hematochezia and a weight loss of 13 kg. On admission, physical examination revealed alopecia of the scalp, hyperpigmentation of the hands and soles, and dystrophy of the fingernails. Laboratory data revealed hypocalcaemia and hypoproteinemia. Esophagogastroduodenoscopy, video capsule endoscopy and colonoscopy revealed various sizes of generalized gastrointestinal polyps. Histological examination of the biopsy specimens obtained from the stomach and the colon showed adenomatous polyp and inflammatory polyp respectively. Thus, a diagnosis of CCS was made. After treatment with corticosteroids for 24 days and nutritional support for two months, his clinical condition improved. Two months later, he was admitted to our hospital for the second time with frequent diarrhea and weight loss. The chest radiography revealed fractures of the left sixth and seventh ribs. Examinations, including emission computed tomography, bone densitometry test, and other serum parameters, were performed, but could not identify the definite etiology of the rib fractures. One month later, the patient suffered from aggravating multiple rib fractures due to the ineffective treatment, persistent hypocalcaemia and malnutrition.</p> <p>Conclusions</p> <p>This is the first case of a CCS patient with multiple rib fractures. Although the association between CCS and multiple rib fractures in this case remains uncertain, we presume that persistent hypocalcaemia and malnutrition contribute to this situation, or at least aggravate this rare complication. Besides, since prolonged corticosteroid therapy will result in an increased risk of osteoporotic fracture, CCS patients who accept corticosteroid therapy could be potential victims of rib fracture.</p

Walks4work: Rationale and study design to investigate walking at lunchtime in the workplace setting

Background: Following recruitment of a private sector company, an 8week lunchtime walking intervention was implemented to examine the effect of the intervention on modifiable cardiovascular disease risk factors, and further to see if walking environment had any further effect on the cardiovascular disease risk factors. Methods. For phase 1 of the study participants were divided into three groups, two lunchtime walking intervention groups to walk around either an urban or natural environment twice a week during their lunch break over an 8week period. The third group was a waiting-list control who would be invited to join the walking groups after phase 1. In phase 2 all participants were encouraged to walk during their lunch break on self-selecting routes. Health checks were completed at baseline, end of phase 1 and end of phase 2 in order to measure the impact of the intervention on cardiovascular disease risk. The primary outcome variables of heart rate and heart rate variability were measured to assess autonomic function associated with cardiovascular disease. Secondary outcome variables (Body mass index, blood pressure, fitness, autonomic response to a stressor) related to cardiovascular disease were also measured. The efficacy of the intervention in increasing physical activity was objectively monitored throughout the 8-weeks using an accelerometer device. Discussion. The results of this study will help in developing interventions with low researcher input with high participant output that may be implemented in the workplace. If effective, this study will highlight the contribution that natural environments can make in the reduction of modifiable cardiovascular disease risk factors within the workplace. © 2012 Brown et al.; licensee BioMed Central Ltd

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice