Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Iterativ Lernende Regelung für eine Gang-Neuroprothese

Dieser Beitrag beschreibt den Entwurf einer linearen Iterativ Lernenden Regelung (ILR) im Zeitbereich für die automatische Anpassung einer Neuroprothese bei Schlaganfallpatienten. Eine unzureichende Fußhebung in der Schwungphase des Ganges soll durch die gezielte Stimulation des Fußhebers kompensiert werden. Für die Erfassung des Gelenkwinkels wird ein neuartiges Messverfahren verwendet, bei welchem durch Regelung ist ferner eine Gangphasenerkennung mittels Drucksensoren unter der Fußsohle notwendig, um die Stimulation exakt mit der Schwungphase zu synchronisieren. Ein erster Test des Regelungskonzepts und des neuen Ansatzes zur Winkelmessung wurde an einem gesunden Probanden durchgeführt. © Oldenbourg Wissenschaftsverla

Automatic Control of a Drop-Foot Stimulator based on Angle Measurement using Bioimpedance

The topic of this contribution is iterative learning control of a drop-foot stimulator in which a predefined angle profile during swing phase is realized. Ineffective dorsiflexion is compensated by feedback controlled stimulation of the muscle tibialis anterior. The ankle-joint measurement is based on changes in the bioimpedance caused by leg movements. A customized four-channel bioimpedance measurement system was developed. The suggested control approach and the new measurement method for the joint angle were successfully tested in preliminary experiments with a neurologically intact subject. Reference angle measurements were taken with a marker-based optical system. An almost linear relation between joint angle and bioimpedance was found for the angle range applicable during gait. The desired angle trajectory was closely tracked by the iterative learning controller after 3 gait cycles. The final root mean square tracking error was below 5 degree. © 2008 International Center for Artificial Organs and Transplantation and Blackwell Publishin

Iterative learning control for correction of drop- foot using bio-impedance as sensory information

Automatic control of ankle-joint angle for the correction of drop-foot has been investigated using Bio-Impedance (BI) for measuring the joint angle and Iterative Learning Control (ILC) for adjusting the stimulation profile. A customised four-channel measurement system (50 kHz) was used to assess bio-impedance changes caused by ankle-joint motion. Two current excitation electrodes were placed below the patella on the shank and on the dorsum of the foot. Voltage detection electrodes were attached to the posterior surface of lower leg below the calf and on the M. tibialis anterior close to its origin. A demodulation circuit determines changes in the absolute value of the BI from the measured and amplified voltage. All circuits are protected against stimulation artefacts so that the recording of BI is possible while muscle stimulation is active. Calibration of the angle measurement was performed by positioning the ankle joint at three known angles. Reference measurements were taken with a marker-based optical system. Dorsiflexion of the unconstrained ankle joint was achieved by stimulation of the M. tibialis anterior. First-order ILC was applied to realise a pre-defined angle profile in a cycle-to-cycle manner. The new stimulation intensity profile will be an update of the last profile taking tracking errors of the last cycle into account. Preliminary experiments were conducted with one able-bodied subject. An almost linear correlation between ankle-joint angle and bio-impedance was found for the angle range applicable during gait. The chosen angle trajectory (sine half-wave from the resting foot to 0 degree) was realised by the ILC within 3 cycles. The final root mean square tracking error was below 5 degree. Automatic control of ankle-joint angle by ILC is feasible when using bio-impedance as sensory information. Experiments under real walking conditions and with stroke patients must be conducted in future

Experimentelle Studie zur automatischen kutanen elektrischen Stimulation der supra-hyoidalen Muskulatur zur Kehlkopfhebung beim Schlucken

Ghost Train figure photographed August 1974