Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Neuromuscular properties of the thigh muscles in patients with Ehlers-Danlos syndrome

Item does not contain fulltextINTRODUCTION: Ehlers-Danlos syndrome (EDS), a connective tissue disorder, may lead to impaired contractile function of lower limb muscles. METHODS: To test this hypothesis and to understand the possible mechanisms involved, isometric function of the thigh muscles was investigated at different joint angles (30 degrees , 60 degrees , and 90 degrees of knee flexion) in 7 tenascin-X (TNX)-deficient EDS patients. RESULTS: There was reduced maximal voluntary torque of the knee extensors (but not knee flexors) across all joint angles in the patients. Time to reach maximal rate of torque development was delayed, and voluntary activation capacity was reduced in patients compared with controls, particularly at 30 degrees . CONCLUSIONS: EDS is associated with muscle weakness, most likely due to increased compliance of the series-elastic component of muscle tissue and failure of maximal voluntary muscle activation. Further research is required to understand the influence of reduced voluntary activation on the severe fatigue reported by EDS patients

Strength, size and activation of knee extensors followed during 8 weeks of horizontal bed rest and the influence of a countermeasure.

Contains fulltext : 49690.pdf (publisher's version ) (Closed access)Changes in the quadriceps femoris muscle with respect to anatomical cross sectional area (CSA), neural activation level and muscle strength were determined in 18 healthy men subjected to 8 weeks of horizontal bed rest (BR) with (n = 9) and without (n = 9) resistive vibration exercise (RVE). CSA of the knee extensor muscle group was measured with magnetic resonance imaging every 2 weeks during bed rest. In the control subjects (Ctrl), quadriceps femoris CSA decreased linearly over the 8 weeks of bed rest to -14.1 +/- 5.2% (P < 0.05). This reduction was significantly (P < 0.001) mitigated by the exercise paradigm (-3.5 +/- 4.2%; P < 0.05). Prior to and seven times during bed rest, maximal unilateral voluntary torque (MVT) values of the right leg were measured together with neural activation levels by means of a superimposed stimulation technique. For Ctrl, MVT decreased also linearly over time to -16.8 +/- 7.4% after 8 weeks of bed rest (P < 0.01), whereas the exercise paradigm fully maintained MVT during bed rest. In contrast to previous reports, the maximal voluntary activation remained unaltered for both groups throughout the study. For Ctrl, the absence of deterioration of the activation level might have been related to the repeated testing of muscle function during the bed rest. This notion was supported by the observation that for a subset of Ctrl subjects (n = 5) the MVT of the left leg, which was not tested during BR, was reduced by 20.5 +/- 10.1%, (P < 0.01) which was for those five subjects significantly (P < 0.05) more than the 11.1 +/- 9.2% (P < 0.01) reduction for the right, regularly tested leg

Skin autofluorescence - A tool to identify type 2 diabetic patients at risk for developing microvascular complications

Abstract: OBJECTIVE - Skin auto fluorescence is a noninvasive measure of the level of tissue accumulation of advanced glycation end products, representing cumulative glycemic and oxidative stress. Recent studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as the predictive value of skin autofluorescence for total and cardiovascular mortality in type 2 diabetes. Our aim was to investigate the predictive value of skin autofluorescence for the development of microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS - At baseline, skin autofluorescence of 973 type 2 diabetic patients with well-controlled diabetes was noninvasively measured with an autofluorescence reader. The aggregate clinical outcome was defined as the development of any diabetes-associated microvascular complication of 881 surviving patients, which was assesse at baseline and at the end of follow-up. Single end points were the development of diabetes-sassociated retinopathy, neuropathy, and (micro)albuminuria. RESULTS - After a mean follow-up period of 3.1 years, baseline skin autofluorescence was significantly higher in patients who developed any microvascular complication, neuropathy, or (micro) albuminuria but not in those who developed retinopathy. Multivariate analyses showed skin auto fluorescence as a predictor for development of any microvascular complication along with AlC, for development of neuropathy along with smoking, and for development of (micro)albuminuria together with sex, AlC, and diabetes duration. Skin autofluorescence did not have predictive value for the development of retinopathy, albeit diabetes duration did. CONCLUSIONS - Our study is the first observation of skin autofluorescence measurement as an independent predictor of development of microvascular complications in type 2 diabetes.

Upcycling food leftovers and grass resources through livestock: Impact of livestock system and productivity

Consumption of animal-source food is criticised, among other reasons, for its relatively high environmental impact. It is, however, increasingly acknowledged that livestock can contribute to nutrition security if they upcycle low-opportunity-cost feed (LCF) – food waste, food processing by-products and grass resources – into nutritious animal-source food. So far, however, no study explored the allocation question “to which livestock should we feed what LCF to maximise livestock's contribution to human nutrition”. Here we optimise the use of the LCF available in the EU, using a model that assigns LCF to those livestock systems that maximise animal protein production. We included the five most common livestock systems in the EU – pigs, laying hens, broilers, dairy cattle and beef cattle – considering their nutrient requirements under three productivity levels (low, mid and high). LCF availability is based on current food supply combined with food wastage and food processing data, and current grassland productivity. Our results showed that optimal conversion of LCF available in the EU, could supply 31 g animal protein per EU capita per day. We confirmed that this optimal conversion requires a variety of both livestock systems and productivity levels. Dominant livestock systems were those that have a high conversion efficiency (laying hens, dairy cattle), were best able to valorise specific LCF (dairy cattle for grass; pigs for food waste), and could valorise low quality LCF because of their low productivity. Limiting the model to use only conventional, high productive, livestock reduced animal protein supply by 16% to 26 g/(cap*d). Besides the efficiency with which livestock used the available LCF, the estimated protein supply from livestock fed solely on LCF, was sensitive to assumptions regarding the availability and quality of LCF, especially grass resources. Our model provides valuable insights into how livestock can efficiently use LCF, which is essential for a transition towards a circular food system.</p