Opportunism: a panacea for implementation of whole-genome sequencing studies in nutrigenomics research?

Observational studies have consistently shown associations between mild deficiencies in folate and vitamin B₁₂ with increased risk of a myriad of common diseases. These findings have invariably translated into null outcomes in intervention trials due in part to our ignorance of the specific genomic and environmental factors that underpin population variability in requirements to these B-vitamins. Although genome-wide association studies have shed initial light on the genetic architecture of variability in status of these vitamins, particularly vitamin B₁₂, the causal mechanisms remain uncharacterised. A recent study by Grarup et al. (PLoS Genet 9(6):e1003530, 2013) used next-generation whole-genome sequencing to gain further insight into the genetic architecture of vitamin B₁₂ and folate status in the general population. Their study represents the analysis of approximately ten times greater number of genetic variants and nearly four times the number of individuals compared to the largest previous GWAS study of these B-vitamins. In light of this, we purport that although the study may be viewed as the state of the art in the roadmap to personalised or precision nutrition, the lack of insight provided by the study serves as a cautionary reminder of the importance of study design, particularly when leveraging large-scale data, such as those from whole-genome sequences. We believe that the precedent set by such large-scale “proof of principle” type projects will wrongly enforce a negative outlook for nutrigenomics research and present alternative study designs, which although less opportunistic are far more likely to be informative and yield novel results.     

Rheumatoid Arthritis Susceptibility Is Associated with the KIR2DS4-Full of Killer-Cell Immunoglobulin-Like Receptor Genes in the Lur Population of Iran

Background:The pathophysiology underlying the progression and development of autoimmune conditions, such as Rheumatoid Arthritis (RA), is a result of dysregulations of the immune system. Research has explored the genetic alterations present in RA; however, limited studies have examined the role of Killer cell Immunoglobulin-like Receptors (KIR) and Human Leukocyte Antigen (HLA) molecules in RA. Therefore, the aim of this study was to examine KIR genes, their HLA ligands, and KIR-HLA compounds in patients with RA.Methods:In this case-control study, a total of 50 patients with RA and 100 healthy individuals were enrolled. DNA samples were evaluated using PCR with sequence specific Primers (PCR-SSP). Odds ratio (OR) with a 95% confidence interval (CI) were reported.Results:Among the KIR genes examined, KIR2DLA (p= 0.0255, OR= 0.389, 95% CI= 0.210-0.722) and KIR2DS4-full (p< 0.0001, OR= 6.163, 95% CI= 3.174-11.968) were observed to have a statistically significant correlation with disease susceptibility to RA. As an inhibitory gene, KIR2DLA was observed to have a protective effect against RA while KIR2DS4-full as an activating gene, was found to increase risk for RA. No significant associations were found between any of the other KIR genotypes, HLA ligands, or KIR-HLA compounds examined in this study to RA susceptibility. Conclusion:In this study of RA in the Lur population of Iran, KIR2DS4-full was observed to increase susceptibility to RA, while KIR2DL5A was found to act as a protecting factor based on both the cross Table and regression analyses. Further research should focus on repeating this study in additional populations.Key Words: HLA, KIR, NK cells, Rheumatoid Arthritis     

Exercise-induced changes of MCT1 in cardiac and skeletal muscles of diabetic rats induced by high-fat diet and STZ

We hypothesized that a part of therapeutic effects of endurance training on insulin resistance is mediated by increase in cardiac and skeletal muscle mitochondrial lactate transporter, monocarboxylate transporter 1 (MCT1). Therefore, we examined the effect of 7 weeks endurance training on the mRNA and protein expression of MCT1 and MCT4 and their chaperon, CD147, on both sarcolemmal and mitochondrial membrane, separately, in healthy and type 2 diabetic rats. Diabetes was induced by injection of low dose of streptozotocin and feeding with high-fat diet. Insulin resistance was confirmed by homeostasis model assessment-estimated insulin resistance index and accuracy of two membranes separation was confirmed by negative control markers (glucose transporter 1 and cytochrome c oxidase. Real-time PCR and western blotting were used for mRNA and protein expression, respectively. Diabetes dramatically reduced MCT1 and MCT4 mRNA and their expression on sarcolemmal membrane whereas the reduction in MCT1 expression was less in mitochondrial membrane. Training increased the MCT1 mRNA and protein expression in both membranes and decreased insulin resistance as an adaptive consequence. In both tissues increase in CD147 mRNA was only parallel to MCT1 expression. The response of MCT1 on sarcolemmal and mitochondrial membranes was different between cardiac and skeletal muscles which indicate that intracellular lactate kinetic is tissue specific that allows a tissue to coordinate whole organism metabolism.     

Numerical simulation of wave propagation in a realistic model of the human external ear

In this study, a numerical investigation is performed to evaluate the effects of high-pressure sinusoidal and blast wave's propagation around and inside of a human external ear. A series of computed tomography images are used to reconstruct a realistic three-dimensional (3D) model of a human ear canal and the auricle. The airflow field is then computed by solving the governing differential equations in the time domain using a computational fluid dynamics software. An unsteady algorithm is used to obtain the high-pressure wave propagation throughout the ear canal which is validated against the available analytical and numerical data in literature. The effects of frequency, wave shape, and the auricle on pressure distribution are then evaluated and discussed. The results clearly indicate that the frequency plays a key role on pressure distribution within the ear canal. At 4 kHz frequency, the pressure magnitude is much more amplified within the ear canal than the frequencies of 2 and 6 kHz, for the incident wave angle of 90° investigated in this study, attributable to the ‘4-kHz notch’ in patients with noise-induced hearing loss. According to the results, the pressure distribution patterns at the ear canal are very similar for both sinusoidal pressure waveform with the frequency of 2 kHz and blast wave. The ratio of the peak pressure value at the eardrum to that at the canal entrance increases from about 8% to 30% as the peak pressure value of the blast wave increases from 5 to 100 kPa for the incident wave angle of 90° investigated in this study. Furthermore, incorporation of the auricle to the ear canal model is associated with centerline pressure magnitudes of about 50% and 7% more than those of the ear canal model without the auricle throughout the ear canal for sinusoidal and blast waves, respectively, without any significant effect on pressure distribution pattern along the ear canal for the incident wave angle of 90° investigated in this study.     

Prevalence of cytomegalovirus infection and its role in total immunoglobulin pattern in Iranian patients with different subtypes of multiple sclerosis

Multiple sclerosis (MS) is the most common autoimmune disease characterized by multifocal areas of inflammatory demyelination within the central nervous system. Cytomegalovirus (CMV) has a complex pathobiology and in most cases is simply asymptomatic. There is some recent controversy over the role of CMV in the pathology of MS. The aim of this study was to evaluate active CMV infection and its effect on the humoral immunity in patients with MS. Serum, plasma, peripheral blood mononuclear cells (PBMCs), saliva and urine collected from MS patients (n=78) and healthy subjects (n=123) were screened for the presence of anti-CMV antibodies and CMV-DNA by nephelometric and PCR methods. Concentrations of total antibodies in MS subtypes were measured using both nephelometric and enzyme linked fluorescent assay (ELFA) techniques. The results extend the observation of an increased frequency of CMV-DNA in patients, in contrast with controls (p<0.001). Furthermore, systemic CMV infections were found in 25.5% of patients and only 3.2% of controls (p<0.001). There was significant difference in the titers of anti-CMV IgG and total IgE in patient and controls (P<0.001). These results support the hypothesis that CMV may contribute to MS thought to establish systemic infection process and induce immune response.     

Human metabolic profiles are stably controlled by genetic and environmental variation

¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top‐down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non‐identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common‐environmental), individual‐environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual‐environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR‐detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker‐discovery studies. We provide a power‐calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR‐based biomarkers quantifying predisposition to disease.     

Optic Nerve Diffusion Tensor Imaging after Acute Optic Neuritis Predicts Axonal and Visual Outcomes

Background

Early markers of axonal and clinical outcomes are required for early phase testing of putative neuroprotective therapies for multiple sclerosis (MS).

Objectives

To assess whether early measurement of diffusion tensor imaging (DTI) parameters (axial and radial diffusivity) within the optic nerve during and after acute demyelinating optic neuritis (ON) could predict axonal (retinal nerve fibre layer thinning and multi-focal visual evoked potential amplitude reduction) or clinical (visual acuity and visual field loss) outcomes at 6 or 12 months.

Methods

Thirty-seven patients presenting with acute, unilateral ON were studied at baseline, one, three, six and 12 months using optic nerve DTI, clinical and paraclinical markers of axonal injury and clinical visual dysfunction.

Results

Affected nerve axial diffusivity (AD) was reduced at baseline, 1 and 3 months. Reduced 1-month AD correlated with retinal nerve fibre layer (RNFL) thinning at 6 (R=0.38, p=0.04) and 12 months (R=0.437, p=0.008) and VEP amplitude loss at 6 (R=0.414, p=0.019) and 12 months (R=0.484, p=0.003). AD reduction at three months correlated with high contrast visual acuity at 6 (ρ = -0.519, p = 0.001) and 12 months (ρ = -0.414, p=0.011). The time-course for AD reduction for each patient was modelled using a quadratic regression. AD normalised after a median of 18 weeks and longer normalisation times were associated with more pronounced RNFL thinning and mfVEP amplitude loss at 12 months. Affected nerve radial diffusivity (RD) was unchanged until three months, after which time it remained elevated.

Conclusions

These results demonstrate that AD reduces during acute ON. One month AD reduction correlates with the extent of axonal loss and persistent AD reduction at 3 months predicts poorer visual outcomes. This suggests that acute ON therapies that normalise optic nerve AD by 3 months could also promote axon survival and improve visual outcomes.     

Fractalkine and apoptotic/anti-apoptotic markers in granulosa cells of women with polycystic ovarian syndrome

Molecular Biology Reports - Owing to the role of fractalkine in regulating cellular apoptosis/proliferation, we investigated fractalkine effects on apoptosis/proliferation signaling of granulosa...