Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5′-triphosphate (ATP) turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

IMPORTANCE Auricular reconstruction is a unique blend of cosmesis and functionality. The choice of the optimal framework material to use is an important decision for the patient with microtia.OBJECTIVE To evaluate and compare the outcomes of reconstruction of microtia using porous polyethylene implants and rib cartilage grafts.

Cochlear nerve deficiency is not an uncommon cause for profound sensorineural hearing loss and presents a challenge in the decision-making process regarding whether to proceed with a cochlear implant. Children with a deficient but visible cochlear nerve on magnetic resonance image can expect to show some speech understanding after cochlear implantation; however, these children do not develop speech understanding to the level of implanted children with normal cochlear nerves. Children with an absent cochlear nerve determined by magnetic resonance imaging can be expected to have limited postimplantation sound and speech awareness.

Hair cells are sensory cells that transduce motion into neural signals. In the cochlea, they are used to detect sound waves in the environment and turn them into auditory signals that can be processed in the brain. Hair cells in the cochlea of birds and mammals were thought to be produced only during embryogenesis and, once made, they were expected to last throughout the lifetime of the animal. Thus, any loss of hair cells due to trauma or disease was thought to lead to permanent impairment of auditory function. Recently, however, studies from a number of laboratories have shown that hair cells in the avian cochlea can be regenerated after acoustic trauma or ototoxic drug damage. This regeneration is accompanied by a repair of the sensory organ and associated tissues and results in a recovery of auditory function. In this review, we examine and compare the structural events that lead to hair cell loss after noise damage and ototoxic drug damage as well as the processes involved in the recovery of the epithelium and the regeneration of the hair cells. Moreover, we examine functional recovery and how it relates to the structural recovery. Finally, we investigate the evidence for the hypothesis that supporting cells in the basilar papilla act as the progenitor cells for the regenerated hair cells and examine the cellular events required to stimulate the progenitor cells to leave the quiescent state, re-enter the cell cycle, and divide.

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Crosslinks, when added to short-segment posterior fixation, improve stiffness and decrease motion in axial rotation, but do not restore baseline stability in this corpectomy model. Short-segment posterior fixation is also inadequate in restoring stability in flexion with injuries of this severity. Short-segment posterior instrumentation alone can achieve baseline stability in lateral bending, and crosslinks provide even greater stiffness.

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