Mechanism of and Threshold Biomechanical Conditions for Falsetto Voice Onset

The sound source of a voice is produced by the self-excited oscillation of the vocal folds. In modal voice production, a drastic increase in transglottal pressure after vocal fold closure works as a driving force that develops self-excitation. Another type of vocal fold oscillation with less pronounced glottal closure observed in falsetto voice production has been accounted for by the mucosal wave theory. The classical theory assumes a quasi-steady flow, and the expected driving force onto the vocal folds under wavelike motion is derived from the Bernoulli effect. However, wavelike motion is not always observed during falsetto voice production. More importantly, the application of the quasi-steady assumption to a falsetto voice with a fundamental frequency of several hundred hertz is unsupported by experiments. These considerations suggested that the mechanism of falsetto voice onset may be essentially different from that explained by the mucosal wave theory. In this paper, an alternative mechanism is submitted that explains how self-excitation reminiscent of the falsetto voice could be produced independent of the glottal closure and wavelike motion. This new explanation is derived through analytical procedures by employing only general unsteady equations of motion for flow and solids. The analysis demonstrated that a convective acceleration of a flow induced by rapid wall movement functions as a negative damping force, leading to the self-excitation of the vocal folds. The critical subglottal pressure and volume flow are expressed as functions of vocal fold biomechanical properties, geometry, and voice fundamental frequency. The analytically derived conditions are qualitatively and quantitatively reasonable in view of reported measurement data of the thresholds required for falsetto voice onset. Understanding of the voice onset mechanism and the explicit mathematical descriptions of thresholds would be beneficial for the diagnosis and treatment of voice diseases and the development of artificial vocal folds

Anti-nerve growth factor in pain management: current evidence

David S Chang,1 Eugene Hsu,2 Daniel G Hottinger,1 Steven P Cohen1,3–5 1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 2Clinical Excellence Research Center, Stanford University School of Medicine, Stanford, CA, 3Department of Anesthesiology, 4Department of Physical Medicine and Rehabilitation, Uniformed Services University of the Health Sciences, Bethesda 5Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract: There continues to be an unmet need for safe and effective pain medications. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) dominate the clinical landscape despite limited effectiveness and considerable side-effect profiles. Although significant advancements have identified myriad potential pain targets over the past several decades, the majority of new pain pharmacotherapies have failed to come to market. The discovery of nerve growth factor (NGF) and its interaction with tropomyosin receptor kinase A (trkA) have been well characterized as important mediators of pain initiation and maintenance, and pharmacotherapies targeting this pathway have the potential to be considered promising methods in the treatment of a variety of nociceptive and neuropathic pain conditions. Several methodologic approaches, including sequestration of free NGF, prevention of NGF binding and trkA activation, and inhibition of trkA function, have been investigated in the development of new pharmacotherapies. Among these, NGF-sequestering antibodies have exhibited the most promise in clinical trials. However, in 2010, reports of rapid joint destruction leading to joint replacement prompted the Food and Drug Administration (FDA) to place a hold on all clinical trials involving anti-NGF antibodies. Although the FDA has since lifted this hold and a number of new trials are under way, the long-term efficacy and safety profile of anti-NGF antibodies are yet to be established. Keywords: nociceptive pain, neuropathic pain, drug discovery, tanezumab, fulranumab, fasinuma