Fluid-structure interaction in abdominal aortic aneurysms: effects of asymmetry and wall thickness

BACKGROUND: Abdominal aortic aneurysm (AAA) is a prevalent disease which is of significant concern because of the morbidity associated with the continuing expansion of the abdominal aorta and its ultimate rupture. The transient interaction between blood flow and the wall contributes to wall stress which, if it exceeds the failure strength of the dilated arterial wall, will lead to aneurysm rupture. Utilizing a computational approach, the biomechanical environment of virtual AAAs can be evaluated to study the affects of asymmetry and wall thickness on this stress, two parameters that contribute to increased risk of aneurysm rupture. METHODS: Ten virtual aneurysm models were created with five different asymmetry parameters ranging from β = 0.2 to 1.0 and either a uniform or variable wall thickness to study the flow and wall dynamics by means of fully coupled fluid-structure interaction (FSI) analyses. The AAA wall was designed to have a (i) uniform 1.5 mm thickness or (ii) variable thickness ranging from 0.5 – 1.5 mm extruded normally from the boundary surface of the lumen. These models were meshed with linear hexahedral elements, imported into a commercial finite element code and analyzed under transient flow conditions. The method proposed was then compared with traditional computational solid stress techniques on the basis of peak wall stress predictions and cost of computational effort. RESULTS: The results provide quantitative predictions of flow patterns and wall mechanics as well as the effects of aneurysm asymmetry and wall thickness heterogeneity on the estimation of peak wall stress. These parameters affect the magnitude and distribution of Von Mises stresses; varying wall thickness increases the maximum Von Mises stress by 4 times its uniform thickness counterpart. A pre-peak systole retrograde flow was observed in the AAA sac for all models, which is due to the elastic energy stored in the compliant arterial wall and the expansion force of the artery during systole. CONCLUSION: Both wall thickness and geometry asymmetry affect the stress exhibited by a virtual AAA. Our results suggest that an asymmetric AAA with regional variations in wall thickness would be exposed to higher mechanical stresses and an increased risk of rupture than a more fusiform AAA with uniform wall thickness. Therefore, it is important to accurately reproduce vessel geometry and wall thickness in computational predictions of AAA biomechanics

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

A bi-directional relationship between obesity and health-related quality of life : evidence from the longitudinal AusDiab study

Objective: To assess the prospective relationship between obesity and health-related quality of life, including a novel assessment of the impact of health-related quality of life on weight gain.Design and setting: Longitudinal, national, population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study, with surveys conducted in 1999/2000 and 2004/2005.Participants: A total of 5985 men and women aged 25 years at study entry.Main outcome measure(s): At both time points, height, weight and waist circumference were measured and self-report data on health-related quality of life from the SF-36 questionnaire were obtained. Cross-sectional and bi-directional, prospective associations between obesity categories and health-related quality of life were assessed.Results: Higher body mass index (BMI) at baseline was associated with deterioration in health-related quality of life over 5 years for seven of the eight health-related quality of life domains in women (all P0.01, with the exception of mental health, P&gt;0.05), and six out of eight in men (all P&lt;0.05, with the exception of role-emotional, P=0.055, and mental health, P&gt;0.05). Each of the quality-of-life domains related to mental health as well as the mental component summary were inversely associated with BMI change (all P&lt;0.0001 for women and P0.01 for men), with the exception of vitality, which was significant in women only (P=0.008). For the physical domains, change in BMI was inversely associated with baseline general health in women only (P=0.023).Conclusions: Obesity was associated with a deterioration in health-related quality of life (including both physical and mental health domains) in this cohort of Australian adults followed over 5 years. Health-related quality of life was also a predictor of weight gain over 5 years, indicating a bi-directional association between obesity and health-related quality of life. The identification of those with poor health-related quality of life may be important in assessing the risk of future weight gain, and a focus on health-related quality of life may be beneficial in weight management strategies.<br /

Versatile Aggressive Mimicry of Cicadas by an Australian Predatory Katydid

Background: In aggressive mimicry, a predator or parasite imitates a signal of another species in order to exploit the recipient of the signal. Some of the most remarkable examples of aggressive mimicry involve exploitation of a complex signal-response system by an unrelated predator species. Methodology/Principal Findings: We have found that predatory Chlorobalius leucoviridis katydids (Orthoptera: Tettigoniidae) can attract male cicadas (Hemiptera: Cicadidae) by imitating the species-specific wing-flick replies of sexually receptive female cicadas. This aggressive mimicry is accomplished both acoustically, with tegminal clicks, and visually, with synchronized body jerks. Remarkably, the katydids respond effectively to a variety of complex, species-specific Cicadettini songs, including songs of many cicada species that the predator has never encountered. Conclusions/Significance: We propose that the versatility of aggressive mimicry in C. leucoviridis is accomplished by exploiting general design elements common to the songs of many acoustically signaling insects that use duets in pairformation. Consideration of the mechanism of versatile mimicry in C. leucoviridis may illuminate processes driving the evolution of insect acoustic signals, which play a central role in reproductive isolation of populations and the formation of species

Oscillatory stimuli differentiate adapting circuit topologies

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca2+ NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.The work was supported by US National Institutes of Health grant 5RO1-GM078153-07 (F.R.C.), NRSA Training Grant CA009673-36A1 (S.J.R.), a Merck Postdoctoral Fellowship at The Rockefeller University (S.J.R.), and the Simons Foundation (S.J.R.). J.L. was supported by a fellowship from the Boehringer Ingelheim Fonds. E.D.S. was partially supported by the US Office of Naval Research (ONR N00014-13-1-0074) and the US Air Force Office of Scientific Research (AFOSR FA9550-14-1-0060)

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing

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

Mutations in protocadherin 15 and cadherin 23 affect tip links and mechanotransduction in mammalian sensory hair cells

Immunocytochemical studies have shown that protocadherin-15 (PCDH15) and cadherin-23 (CDH23) are associated with tip links, structures thought to gate the mechanotransducer channels of hair cells in the sensory epithelia of the inner ear. The present report describes functional and structural analyses of hair cells from Pcdh15av3J (av3J), Pcdh15av6J (av6J) and Cdh23v2J (v2J) mice. The av3J and v2J mice carry point mutations that are predicted to introduce premature stop codons in the transcripts for Pcdh15 and Cdh23, respectively, and av6J mice have an in-frame deletion predicted to remove most of the 9th cadherin ectodomain from PCDH15. Severe disruption of hair-bundle morphology is observed throughout the early-postnatal cochlea in av3J/av3J and v2J/v2J mice. In contrast, only mild-to-moderate bundle disruption is evident in the av6J/av6J mice. Hair cells from av3J/av3J mice are unaffected by aminoglycosides and fail to load with [3H]-gentamicin or FM1-43, compounds that permeate the hair cell's mechanotransducer channels. In contrast, hair cells from av6J/av6J mice load with both FM1-43 and [3H]-gentamicin, and are aminoglycoside sensitive. Transducer currents can be recorded from hair cells of all three mutants but are reduced in amplitude in all mutants and have abnormal directional sensitivity in the av3J/av3J and v2J/v2J mutants. Scanning electron microscopy of early postnatal cochlear hair cells reveals tip-link like links in av6J/av6J mice, substantially reduced numbers of links in the av3J/av3J mice and virtually none in the v2J/v2J mice. Analysis of mature vestibular hair bundles reveals an absence of tip links in the av3J/av3J and v2J/v2J mice and a reduction in av6J/av6J mice. These results therefore provide genetic evidence consistent with PCDH15 and CDH23 being part of the tip-link complex and necessary for normal mechanotransduction

Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)

Studying the association between musculoskeletal disorders, quality of life and mental health. A primary care pilot study in rural Crete, Greece

<p>Abstract</p> <p>Background</p> <p>The burden of musculoskeletal disorders (MSD) on the general health and well-being of the population has been documented in various studies. The objective of this study was to explore the association between MSD and the quality of life and mental health of patients and to discuss issues concerning care seeking patterns in rural Greece.</p> <p>Methods</p> <p>Patients registered at one rural Primary Care Centre (PCC) in Crete were invited to complete the Nordic Musculoskeletal Questionnaire (NMQ) for the analysis of musculoskeletal symptoms, together with validated instruments for measuring health related quality of life (SF-36) and mental distress (GHQ-28).</p> <p>Results</p> <p>The prevalence rate of MSD was found to be 71.2%, with low back and knee pain being the most common symptoms. Most conditions significantly impaired the quality of life, especially the physical dimensions of SF-36. Depression was strongly correlated to most MSD (<it>p </it>< 0.001). Multiple logistic analyses revealed that patients who consulted the PCC due to MSD were likely to have more mental distress or impaired physical functioning compared to those who did not.</p> <p>Conclusion</p> <p>Musculoskeletal disorders were common in patients attending the rural PCC of this study and were associated with a poor quality of life and mental distress that affected their consultation behaviour.</p