Gait Analysis, Metabolic Parameters and Adherence to the Mediterranean Diet in Patients with Type 2 Diabetes Mellitus Compared with Healthy Controls: A Pilot Study.

BACKGROUND AND PURPOSE: Patients with type 2 diabetes mellitus (T2DM) are prone to developing diabetic peripheral neuropathy (DPN) with an increased risk of injuries while walking, potentially leading to plantar ulcers. We aimed to assess the early gait changes in T2DM patients without clinical signs of DPN in comparison to age-matched healthy controls (HC). SUBJECTS AND METHODS: One hundred T2DM patients (78 women, mean age: 66.4 ± 11.5 years) and 50 age-matched HC (34 women, mean age 62.1 ± 7.9 years) were evaluated with the PODOSmart® gait analysis device. Anthropometric and biochemical data, as well as dietary habits were collected for all participants. T2DM patients also completed the Diabetes Distress (DS) self-report validated questionnaire. RESULTS: One patient was excluded from the study due to lack of recent biochemical data. Among the T2DM patients, 88.9% reported little or no DS and 11.1% moderate DS. The T2DM group had higher body mass index, waist circumference, systolic blood pressure, glycated hemoglobin A1c, sodium, white blood cell count, triglycerides and low-density lipoprotein cholesterol, but lower high-density lipoprotein cholesterol than HC (p < 0.05 for all comparisons). The MedDiet score was satisfactory in both groups (p > 0.05). Significant differences were found between the two study groups in gaitline heel off, propulsion speed, foot progression angle, time taligrade phase, stride length, walking speed, angle attack, oscillation speed, pronation-supination toe off and clearance. CONCLUSIONS: The T2DM patients without self-reported DS or clinical signs of DPN may exhibit significant differences in several gait parameters analyzed with PODOSmart®. Whether gait analysis can be used as an early diagnostic tool of T2DM complications should be further explored.

VEGF-A-related genetic variants protect against Alzheimer's disease.

The Apolipoprotein E (APOE) genotype has been shown to be the strongest genetic risk factor for Alzheimer's disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of APOE, LSR and VEGF-A-related variants. The population consisted of 323 individuals (143 AD cases and 180 controls). Genotyping was performed for: the APOE common polymorphism (rs429358 and rs7412), two LSR variants (rs34259399 and rs916147) and 10 VEGF-A-related SNPs (rs6921438, rs7043199, rs6993770, rs2375981, rs34528081, rs4782371, rs2639990, rs10761741, rs114694170, rs1740073), previously identified as genetic determinants of VEGF-A levels in GWAS studies. The prediction model included direct and epistatic interaction effects, age and sex and was developed using the elastic net machine learning methodology. An optimal model including the direct effect of the APOE e4 allele, age and eight epistatic interactions between APOE and LSR, APOE and VEGF-A-related variants was developed with an accuracy of 72%. Two epistatic interactions (rs7043199*rs6993770 and rs2375981*rs34528081) were the strongest protective factors against AD together with the absence of ε4 APOE allele. Based on pathway analysis, the involved variants and related genes are implicated in neurological diseases. In conclusion, this study demonstrated links between APOE, LSR and VEGF-A-related variants and the development of AD and proposed a model of nine genetic variants which appears to strongly influence the risk for AD.

Gait Alterations in the Prediction of Metabolic Syndrome in Patients With Schizophrenia: A Pilot Study With PODOSmart ® Insoles.

BACKGROUND: Second-generation antipsychotics (APs) are associated with metabolic syndrome (MetS), characterized by abnormal pro-inflammatory cytokine production and oxidative stress due to the reduced antioxidant systems, and neurological effects, including mobility impairment. This pilot study investigated relationships between inflammatory-metabolic biomarkers, MetS and gait alterations in patients with psychosis treated with APs. METHODS: Patients with psychosis treated with APs, 20 with MetS (MPS group) and 20 without MetS (PS group) were studied, usinganthropometric data, blood measurements and gait analysis performed with the PODOSmart ® gait analysis device. RESULTS AND DISCUSSION: The MPS group had significantly higher mean body mass index (BMI) and arterial blood pressure (BP) than the PS group. PODOSmart ® gait analysis recorded significant differences between groups in pronation-supination at Heel Off (HO), gaitline HO and gaitline Toe Off (TO). Multifactorial elastic net regression models demonstrated significant association with MetS of inflammatory markers, specific AP2 treatment, gender, age; BMI; BP and smoking (accuracy λ = 0.08), and in relation to gait parameters (accuracy λ = 0.750), the three pronation- supination variables, i.e., at HO, flat foot in (AP2 related) and TO, and propulsion speed. The gait parameters were at the edges of the model, thus indicating a more significant role of these parameters compared to the other clinical variables. Early diagnosis of MetS in patients with schizophrenia via identification of gait alterations can be a screening measure for serious cardiovascular complications related to psychosis and APs, to enable timely dietary intervention that can control the pro-inflammatory state and reduce oxidative stress.

Test-Retest Reliability of PODOSmart® Gait Analysis Insoles.

It is recognized that gait analysis is a powerful tool used to capture human locomotion and quantify the related parameters. PODOSmart® insoles have been designed to provide accurate measurements for gait analysis. PODOSmart® insoles are lightweight, slim and cost-effective. A recent publication presented the characteristics and data concerning the validity of PODOSmart® insoles in gait analysis. In literature, there is still no evidence about the repeatability of PODOSmart® gait analysis system. Such evidence is essential in order to use this device in both research and clinical settings. The aim of the present study was to assess the repeatability of PODOSmart® system. In this context, it was hypothesized that the parameters of gait analysis captured by PODOSmart® would be repeatable. In a sample consisting of 22 healthy male adults, participants performed two walking trials on a six-meter walkway. The ICC values for 28 gait variables provided by PODOSmart® indicated good to excellent test-retest reliability, ranging from 0.802 to 0.997. The present findings confirm that PODOSmart® gait analysis insoles present excellent repeatability in gait analysis parameters. These results offer additional evidence regarding the reliability of this gait analysis tool.

A genetic determinant of VEGF-A levels is associated with telomere attrition.

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, ß=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.

A Novel Tool for Gait Analysis: Validation Study of the Smart Insole PODOSmart®.

The new smart insole PODOSmart®, is introduced as a new tool for gait analysis against high cost laboratory based equipment. PODOSmart® system measures walking profile and gait variables in real life conditions. PODOSmart® insoles consists of wireless sensors, can be fitted into any shoe and offer the ability to measure spatial, temporal, and kinematic gait parameters. The intelligent insoles feature several sensors that detect and capture foot movements and a microprocessor that calculates gait related biomechanical data. Gait analysis results are presented in PODOSmart® platform. This study aims to present the characteristics of this tool and to validate it comparing with a stereophotogrammetry-based system. Validation was performed by gait analysis for eleven healthy individuals on a six-meters walkway using both PODOSmart® and Vicon system. Intraclass correlation coefficients (ICC) were calculated for gait parameters. ICC for the validation ranged from 0.313 to 0.990 in gait parameters. The highest ICC was observed in cadence, circumduction, walking speed, stride length and stride duration. PODOSmart® is a valid tool for gait analysis compared to the gold standard Vicon. As PODOSmart®, is a portable gait analysis tool with an affordable cost it can be a useful novel tool for gait analysis in healthy and pathological population.

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

Telomere length determinants in childhood.

Telomere length (TL) is a dynamic marker that reflects genetic predispositions together with the environmental conditions of an individual. It is closely related to longevity and a number of pathological conditions. Even though the extent of telomere research in children is limited compared to that of adults, there have been a substantial number of studies providing first insights into child telomere biology and determinants. Recent discoveries revealed evidence that TL is, to a great extent, determined already in childhood and that environmental conditions in adulthood have less impact than first believed. Studies have demonstrated that large inter-individual differences in TL are present among newborns and are determined by diverse factors that influence intrauterine development. The first years of child growth are associated with high cellular turnover, which results in fast shortening of telomeres. The rate of telomere loss becomes stable in early adulthood. In this review article we summarise the existing knowledge on telomere dynamics during the first years of childhood, highlighting the conditions that affect newborn TL. We also warn about the knowledge gaps that should be filled to fully understand the regulation of telomeres, in order to implement them as biomarkers for use in diagnostics or treatment.

Correction: Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: Associations with inflammatory molecules in a healthy population.

[This corrects the article DOI: 10.1371/journal.pone.0220902.].

Peripheral blood mononuclear cells extracts VEGF protein levels and VEGF mRNA: Associations with inflammatory molecules in a healthy population.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a signal protein, implicated in various physiological and pathophysiological processes together with other common inflammatory biomarkers. However, their associations have not yet been fully elucidated. In the present study, we investigated associations between VEGF and four specific VEGF mRNA isoforms with levels of 11 inflammation molecules, derived from peripheral blood mononuclear cells (PBMCs) extracts. METHODS: Healthy participants from the STANISLAS Family Study (n = 285) were included. Levels of VEGF (four mRNA isoforms and protein levels) and inflammatory molecules (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, INF-γ, TNF-α, MCP-1, EGF) were measured in PBMCs extracts. Multiple regression analyses were performed, adjusted for age and gender. RESULTS: The analyses revealed significant associations between VEGF protein levels and levels of IL-4 (ß = 0.028, P = 0.013), MCP-1 (ß = 0.015, P<0.0001) and EGF (ß = 0.017, P<0.0001). Furthermore, mRNA isoform VEGF165 was associated with MCP-1 and IL-1α (P = 0.002 and P = 0.008, respectively); and mRNA isoform VEGF189 was associated with IL-4 and IL-6 (P = 0.019 and P = 0.034, respectively). CONCLUSIONS: To our knowledge, the present study represents the first investigation that successfully demonstrates links between VEGF protein levels and inflammatory molecules levels derived from PBMCs extracts and identifies associations between specific VEGF mRNA isoforms and inflammatory molecules. IMPACT: These findings provide novel insights that may assist in the development of new tissue and mRNA isoform specific measurements of VEGF levels, which may positively contribute to predicting the risk of common complex diseases and response of currently used anti-VEGF agents, and developing of novel targeted therapies for VEGF-related pathophysiology.

The 9th Santorini Conference: Systems Medicine, Personalised Health and Therapy. "The Odyssey from Hope to Practice", Santorini, Greece, 30 September⁻3 October 2018.

The 9th traditional biannual conference on Systems Medicine, Personalised Health & Therapy-"The Odyssey from Hope to Practice", inspired by the Greek mythology, was a call to search for practical solutions in cardio-metabolic diseases and cancer, to resolve and overcome the obstacles in modern medicine by creating more interactions among disciplines, as well as between academic and industrial research, directed towards an effective 'roadmap' for personalised health and therapy. The 9th Santorini Conference, under the Presidency of Sofia Siest, the director of the INSERM U1122; IGE-PCV (www.u1122.inserm.fr), University of Lorraine, France, offered a rich and innovative scientific program. It gathered 34 worldwide distinguished speakers, who shared their passion for personalised medicine with 160 attendees in nine specific sessions on the following topics: First day: The Odyssey from hope to practice: Personalised medicine-landmarks and challenges Second day: Diseases to therapeutics-genotype to phenotype an "-OMICS" approach: focus on personalised therapy and precision medicine Third day: Gene-environment interactions and pharmacovigilance: a pharmacogenetics approach for deciphering disease "bench to clinic to reality" Fourth day: Pharmacogenomics to drug discovery: a big data approach and focus on clinical data and clinical practice. In this article we present the topics shared among the participants of the conference and we highlight the key messages.

Genetic determinants of leucocyte telomere length in children: a neglected and challenging field.

BACKGROUND: Telomere length is associated with a large range of human diseases. Genome-wide association studies (GWAS) have identified genetic variants that are associated with leucocyte telomere length (LTL). However, these studies are limited to adult populations. Nevertheless, childhood is a crucial period for the determination of LTL, and the assessment of age-specific genetic determinants, although neglected, could be of great importance. Our aim was to provide insights and preliminary results on genetic determinants of LTL in children. METHODS: Healthy children (n = 322, age range = 6.75-17 years) with available GWAS data (Illumina Human CNV370-Duo array) were included. The LTL was measured using multiplex quantitative real-time polymerase chain reaction. Linear regression models adjusted for age, gender, parental age at child's birth, and body mass index were used to test the associations of LTL with polymorphisms identified in adult GWAS and to perform a discovery-only GWAS. RESULTS: The previously GWAS-identified variants in adults were not associated with LTL in our paediatric sample. This lack of association was not due to possible interactions with age or gene × gene interactions. Furthermore, a discovery-only GWAS approach demonstrated six novel variants that reached the level of suggestive association (P ≤ 5 × 10(-5)) and explain a high percentage of children's LTL. CONCLUSIONS: The study of genetic determinants of LTL in children may identify novel variants not previously identified in adults. Studies in large-scale children populations are needed for the confirmation of these results, possibly through a childhood consortium that could better handle the methodological challenges of LTL genetic epidemiology field.