Methodological aspects of the assessment of gene-nutrient interactions at the population level

Nutritional-related diseases are the result of complex interactions between genes and diet. The understanding of these interactions will provide the rationale for dietary interventions based on the individual's genetic constitution. However, the approach to this kind of study is not easy, the complexity of the interactions increasing exponentially the dimensionality of the problem. The aim of this review is to analyze the major problems that arise in approaching complex interactions at the population level. Furthermore, several statistical tools available for this type of analysis are discussed. In conclusion, although analytic techniques able to reduce the dimensionality of the problem are suggested, sample size requirement seems to remain an inescapable challenge for the researcher. A synergy between traditional and nontraditional statistical approaches could be useful.     

Identification of the main arterial branches by whole-body contrast-enhanced MRA in elderly subjects using limited user interaction and fast marching

PURPOSE: To extract a graph model corresponding to a predefined set of arterial branches from whole-body contrast-enhanced magnetic resonance angiography (CE-MRA) data sets in elderly asymptomatic subjects, a high-incidence group. MATERIALS AND METHODS: Maximum intensity projections (MIPs) were used as an interface to place landmarks in the three-dimensional (3D) data sets. These landmarks were linked together using fast marching to form a graph model of the arterial tree. Only vessels of interest were identified. RESULTS: We tested our method on 10 subjects. We were able to build a graph model of the main arterial branches that performed well in the presence of vascular pathologies, such as stenosis and aneurysm. The results were rated by an experienced radiologist, with an overall success rate of 80%. CONCLUSION: We were able to extract chosen arterial branches in 3D whole-body CE-MRA images with a moderate amount of interaction using a single MIP projection.     

Interacting genes in lithium prophylaxis: Preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients

Lithium represents the first-choice and most effective drug in the treatment of bipolar disorder (BD). While its mechanism of action is far from being totally understood, a large amount of evidence pointed to a role of second messengers mediated pathways and elements of the circadian system in modulating its mood stabilizing effect. In the present paper, we tested the possible association and interaction effect of the nuclear receptor subfamily 1, group D, member 1 (NR1D1) gene and the Diacylglycerol kinase eta (DGKH) gene with the therapeutic response to lithium prophylaxis. Single nucleotide polymorphisms (SNPs) rs12941497 and rs939347 at NR1D1 gene and SNPs rs9315885, rs1012053 and rs1170191 at DGKH gene were genotyped in a sample of 199 Sardinian BD patients characterized for the response to lithium therapy. Genotype and allele frequency distributions did not differ significantly between groups of patients Full Responders and partial/not responders to lithium prophylaxis. Moreover, no significant differences were identified between groups of patients when divided considering the improvement in symptoms after lithium treatment. The interaction analysis did not show a significant effect on these outcomes. While negative, our findings do not exclude an involvement of DGKH and NR1D1 in lithium prophylaxis. Moreover, the lack of statistic interaction might not necessarily correspond to a lack of biologic interaction between the genes studied.     

Structure and regulation of cytoplasmic adapter proteins involved in innate immune signaling

Summary:  Initiation of the innate immune response requires agonist recognition by a pathogen recognition receptor. Following ligand binding, conformational rearrangement of the receptor creates a molecular scaffold from which signal transduction is propagated via complex cellular signaling pathways. This in turn leads to the induction of a pro-inflammatory immune response. A critical component of these signaling pathways is the homotypic interaction of receptor and adapter proteins via specific protein interaction domains. Within the innate immune signaling cascade, homotypic interactions between members of the death domain family and the Toll/interleukin-1 receptor domain are particularly important. Here we discuss the current understanding of the molecular basis of these homotypic receptor:adapter interactions and their role in innate immune signal transduction.     

Aging defined by a chronologic-replicative protein network in Saccharomyces cerevisiae: An interactome analysis

Aging is a multifactorial condition that results in the loss of an organism's fitness over time. Different theories have been formulated to explain the mechanisms of aging, but a synthesis of these theories has not been possible until now. In addition, the increase in molecular data gathered by proteomics projects utilizing different organisms has permitted a better picture of proteins that function in aging. In this sense, the yeast Saccharomyces cerevisiae is a biological model for aging, and it shows two distinct aging states: a replicative state termed the replicative lifespan (RLS) and a quiescent state known as the chronological lifespan (CLS). Interestingly, both RLS and CLS appear to share common groups of proteins, but a combined model of both aging mechanisms has not been defined. Thus, by applying systems biology tools that allow mining of the yeast proteins associated with aging, it was possible to obtain an interactome network in which both RLS and CLS are represented. In addition, four subgraphs comprising ubiquitin-dependent proteasome/regulation of cell growth, nucleic acid metabolism, carbohydrate metabolism/RNA metabolism, and carbohydrate-organic acid-amino acid/DNA metabolism were found within the interactome, defining a new model of aging for yeast termed the chronologic-replicative protein network (CRPN).     

Identification of <Emphasis Type="Italic">I</Emphasis><Subscript>Kr</Subscript> Kinetics and Drug Binding in Native Myocytes

Determining the effect of a compound on I _Kr is a standard screen for drug safety. Often the effect is described using a single IC₅₀ value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of I _Kr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on I _Kr. I _Kr was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from −70 to −20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published I _Kr Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on I _Kr I–V relation and I _Kr inactivation. The method produced models that quantitatively reproduce both the control I _Kr kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC₅₀ method. Although the method was developed for I _Kr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A Simulation of Vessel–Clamp Interaction: Transient Closure Dynamics

Cross-clamping of aorta is routinely performed in cardiac surgery. The objective of this study was to simulate cross-clamping of the aorta to elucidate the perturbation of stresses in the wall (solid mechanics) and lumen of the vessel (fluid mechanics). Models of the aorta and clamp were created in Computer Assisted Design and Finite Element Analysis packages. The vessel wall was considered as a non-linear anisotropic material while the fluid was simulated as Newtonian with pulsatile flow. The clamp was applied to produce total occlusion in approximately 1 s. A cylindrical and rectangular geometry for the clamp were considered. High jet speed and flow reversal were demonstrated during clamping. It was found that the clamp design and vessel wall anisotropy affected both the fluid wall shear stress (WSS) and solid stresses in vessel wall. The maximum wall stresses increased by about 170 and 220% during closure in the cases of plate and cylindrical clamps, respectively. The plate clamp design was superior for reduction of both solid stresses as well as fluid shear stresses. The cylindrical clamp causes much larger stresses than the plate clamp in each of the stress components; e.g., radial compression of −180 vs. −50 kPa. Vibrations, flow and WSS oscillations were detected immediately before total vessel occlusion. The present findings provide valuable insights into the mode of tissue injury during clamping and may also be useful for improving surgical clamp designs.     

Perceptions of participation: child patients with a disability in the doctor-parent-child partnership

Objective

To explore how the doctor–parent–child partnership is experienced and if the child patient is considered a contributor.

Methods

Qualitative methodology using semi-structured interviews with 33 participants (9 paediatricians, 14 parents, and 10 children aged 8–12 with cerebral palsy) from a paediatric teaching hospital in Victoria, Australia.

Results

Children were reported to participate in the doctor–parent–child partnership. The child was not perceived to be an ‘equal’ or ‘regular’ partner as there were reports of variability in the involvement between children, as well as variability in the progressive involvement of each child. Three categories emerged in relation to the child's position in the partnership: creating a space for the child's involvement; acknowledging the variability of child preferences to be involved; and negotiating the child's age and development.

Conclusion

The doctor–parent–child partnership was perceived not necessarily to be dyadic, shared exclusively by the parent and paediatrician. Children were reported to contribute to the partnership, although there were limitations to the child's involvement.

Practice implications

Previous understandings of partnership are not sufficient to explain the complexities involved in a doctor–parent–child partnership, and a social-model approach to care is highlighted as an important factor for enabling the development of a triadic partnership.     

The effect of physician–patient collaboration on patient adherence in non-psychiatric medicine

Objective

Factors contributing to treatment adherence are poorly understood but the physician–patient interaction is one factor that is known to affect patient adherence.

Methods

This meta-analysis systematically reviewed the published literature to determine the magnitude of the relationships between physician–patient collaboration and patient adherence.

Results

A statistically significant weighted mean effect size of M_d = 0.145 from 48 published studies indicated better physician–patient collaboration is associated with better patient adherence. The relationship between collaboration and adherence was sustained for pediatric and adult populations, chronic and acute conditions, and primary physician and specialists.

Conclusion

These results emphasize the need for physician–patient collaboration within the medical consultation.

Practice implications

The inclusion of the patient's perspective during the consultation is essential to obtaining cooperation once the patient has left the physician's office.