Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis

An extended complementary filter (ECF) for full-body MARG orientation estimation

Inertial sensing suites now permeate all forms of smart automation, yet a plateau exists in real-world derivation of global orientation. Magnetic field fluctuations and inefficient sensor fusion still inhibit deployment. We introduce a new algorithm, an Extended Complementary Filter (ECF), to derive 3D rigid body orientation from inertial sensing suites addressing these challenges. The ECF combines computational efficiency of classic complementary filters with improved accuracy compared to popular optimization filters. We present a complete formulation of the algorithm, including an extension to address the challenge of orientation accuracy in the presence of fluctuating magnetic fields. Performance is tested under a variety of conditions and benchmarked against the commonly used gradient decent (GDA) inertial sensor fusion algorithm. Results demonstrate improved efficiency, with the ECF achieving convergence 30% faster than standard alternatives. We further demonstrate an improved robustness to sources of magnetic interference in pitch and roll and to fast changes of orientation in the yaw direction. The ECF has been implemented at the core of a wearable rehabilitation system tracking movement of stroke patients for home telehealth. The ECF and accompanying magnetic disturbance rejection algorithm enables previously unachievable real-time patient movement feedback in the form of a full virtual human (avatar), even in the presence of magnetic disturbance. Algorithm efficiency and accuracy have also spawned an entire commercial product line released by the company x-io. We believe the ECF and accompanying magnetic disturbance routines are key enablers for future widespread use of wearable systems with the capacity for global orientation trackin

Measurements of the interface pressure between the stump and the socket and its relevance to the prosthetic socket design

Paper concerned with measurements of the interface pressure between the stump and the socket and its relevance to the prosthetic socket design

CREBH Couples Circadian Clock With Hepatic Lipid Metabolism

The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)–tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II transport vesicle and thus controls the ER-to-Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglyceride (TG) and fatty acid (FA) metabolism and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates and interacts with the hepatic nuclear receptors peroxisome proliferator–activated receptor α and liver X receptor α as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm