Novel Timothy Syndrome Mutation Leading to Increase in CACNA1C Window Current

Background Timothy syndrome (TS) is a rare multisystem genetic disorder characterized by a myriad of abnormalities, including QT prolongation, syndactyly, and neurologic symptoms. The predominant genetic causes are recurrent de novo missense mutations in exon 8/8A of the CACNA1C-encoded L-type calcium channel; however, some cases remain genetically elusive. Objective The purpose of this study was to identify the genetic cause of TS in a patient who did not harbor a CACNA1C mutation in exon 8/A, and was negative for all other plausible genetic substrates. Methods Diagnostic exome sequencing was used to identify the genetic substrate responsible for our case of TS. The identified mutation was characterized using whole-cell patch-clamp technique, and the results of these analyses were modeled using a modified Luo–Rudy dynamic model to determine the effects on the cardiac action potential. Results Whole exome sequencing revealed a novel CACNA1C mutation, p.Ile1166Thr, in a young male with diagnosed TS. Functional electrophysiologic analysis identified a novel mechanism of TS-mediated disease, with an overall loss of current density and a gain-of-function shift in activation, leading to an increased window current. Modeling studies of this variant predicted prolongation of the action potential as well as the development of spontaneous early afterdepolarizations. Conclusion Through expanded whole exome sequencing, we identified a novel genetic substrate for TS, p.Ile1166Thr-CACNA1C. Electrophysiologic experiments combined with modeling studies have identified a novel TS mechanism through increased window current. Therefore, expanded genetic testing in cases of TS to the entire CACNA1C coding region, if initial targeted testing is negative, may be warranted

Retraining walking adaptability following incomplete spinal cord injury

Functional walking requires the ability to modify one's gait pattern to environmental demands and task goals-gait adaptability. Following incomplete spinal cord injury (ISCI), gait rehabilitation such as locomotor training (Basic-LT) emphasizes intense, repetitive stepping practice. Rehabilitation approaches focusing on practice of gait adaptability tasks have not been established for individuals with ISCIs but may promote recovery of higher level walking skills. The primary purpose of this case series was to describe and determine the feasibility of administering a gait adaptability retraining approach-Adapt-LT-by comparing the dose and intensity of Adapt-LT to Basic-LT

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Long-term facilitation of ventilation in humans with chronic spinal cord injury

RATIONALE: Intermittent stimulation of the respiratory system with hypoxia causes persistent increases in respiratory motor output (i.e., long-term facilitation) in animals with spinal cord injury. This paradigm, therefore, has been touted as a potential respiratory rehabilitation strategy. OBJECTIVES: To determine whether acute (daily) exposure to intermittent hypoxia can also evoke long-term facilitation of ventilation after chronic spinal cord injury in humans, and whether repeated daily exposure to intermittent hypoxia enhances the magnitude of this response. METHODS: Eight individuals with incomplete spinal cord injury (>1 yr; cervical [n = 6], thoracic [n = 2]) were exposed to intermittent hypoxia (eight 2-min intervals of 8% oxygen) for 10 days. During all exposures, end-tidal carbon dioxide levels were maintained, on average, 2 mm Hg above resting values. Minute ventilation, tidal volume, and breathing frequency were measured before (baseline), during, and 30 minutes after intermittent hypoxia. Sham protocols consisted of exposure to room air and were administered to a subset of the participants (n = 4). MEASUREMENTS AND MAIN RESULTS: Minute ventilation increased significantly for 30 minutes after acute exposure to intermittent hypoxia (P < 0.001), but not after sham exposure. However, the magnitude of ventilatory long-term facilitation was not enhanced over 10 days of intermittent hypoxia exposures. CONCLUSIONS: Ventilatory long-term facilitation can be evoked by brief periods of hypoxia in humans with chronic spinal cord injury. Thus, intermittent hypoxia may represent a strategy for inducing respiratory neuroplasticity after declines in respiratory function that are related to neurological impairment. Clinical trial registered with www.clinicaltrials.gov (NCT01272011)

Long-Term Facilitation of Ventilation in Humans with Chronic Spinal Cord Injury

RATIONALE: Intermittent stimulation of the respiratory system with hypoxia causes persistent increases in respiratory motor output (i.e., long-term facilitation) in animals with spinal cord injury. This paradigm, therefore, has been touted as a potential respiratory rehabilitation strategy. OBJECTIVES: To determine whether acute (daily) exposure to intermittent hypoxia can also evoke long-term facilitation of ventilation after chronic spinal cord injury in humans, and whether repeated daily exposure to intermittent hypoxia enhances the magnitude of this response. METHODS: Eight individuals with incomplete spinal cord injury (>1 yr; cervical [n = 6], thoracic [n = 2]) were exposed to intermittent hypoxia (eight 2-min intervals of 8% oxygen) for 10 days. During all exposures, end-tidal carbon dioxide levels were maintained, on average, 2 mm Hg above resting values. Minute ventilation, tidal volume, and breathing frequency were measured before (baseline), during, and 30 minutes after intermittent hypoxia. Sham protocols consisted of exposure to room air and were administered to a subset of the participants (n = 4). MEASUREMENTS AND MAIN RESULTS: Minute ventilation increased significantly for 30 minutes after acute exposure to intermittent hypoxia (P < 0.001), but not after sham exposure. However, the magnitude of ventilatory long-term facilitation was not enhanced over 10 days of intermittent hypoxia exposures. CONCLUSIONS: Ventilatory long-term facilitation can be evoked by brief periods of hypoxia in humans with chronic spinal cord injury. Thus, intermittent hypoxia may represent a strategy for inducing respiratory neuroplasticity after declines in respiratory function that are related to neurological impairment. Clinical trial registered with www.clinicaltrials.gov (NCT01272011)

Cough following low thoracic hemisection in the cat

Montrer, démontrer le territoire Journée d’études organisée par l’IRHiS Programme transversal « La Maîtrise du territoire » Jeudi 28 juin 2012   LIEU : Maison régionale de l’environnement et des solidarités (MRES) 23, rue Gosselet – Lille – M° République ou Grand Palais Salle Agora, 1er étage PROGRAMME Matinée : 10h-13h Jean-Marc Besse : Scènes du savoir géographique : les géoramas parisiens au XIXe siècle. Isabelle Surun : Le Sénégal sous la Tour Eifel : concevoir le pavillon du Sénégal po..

Case Study: A Bio-Inspired Control Algorithm for a Robotic Foot-Ankle Prosthesis Provides Adaptive Control of Level Walking and Stair Ascent

Powered ankle-foot prostheses assist users through plantarflexion during stance and dorsiflexion during swing. Provision of motor power permits faster preferred walking speeds than passive devices, but use of active motor power raises the issue of control. While several commercially available algorithms provide torque control for many intended activities and variations of terrain, control approaches typically exhibit no inherent adaptation. In contrast, muscles adapt instantaneously to changes in load without sensory feedback due to the intrinsic property that their stiffness changes with length and velocity. We previously developed a “winding filament” hypothesis (WFH) for muscle contraction that accounts for intrinsic muscle properties by incorporating the giant titin protein. The goals of this study were to develop a WFH-based control algorithm for a powered prosthesis and to test its robustness during level walking and stair ascent in a case study of two subjects with 4–5 years of experience using a powered prosthesis. In the WFH algorithm, ankle moments produced by virtual muscles are calculated based on muscle length and activation. Net ankle moment determines the current applied to the motor. Using this algorithm implemented in a BiOM T2 prosthesis, we tested subjects during level walking and stair ascent. During level walking at variable speeds, the WFH algorithm produced plantarflexion angles (range = −8 to −19°) and ankle moments (range = 1 to 1.5 Nm/kg) similar to those produced by the BiOM T2 stock controller and to people with no amputation. During stair ascent, the WFH algorithm produced plantarflexion angles (range −15 to −19°) that were similar to persons with no amputation and were ~5 times larger on average at 80 steps/min than those produced by the stock controller. This case study provides proof-of-concept that, by emulating muscle properties, the WFH algorithm provides robust, adaptive control of level walking at variable speed and stair ascent with minimal sensing and no change in parameters