Xeroderma pigmentosum (XP) patients with inherited defects in nucleotide excision repair (NER) are unable to excise from their DNA bulky photoproducts induced by UV radiation and therefore develop accelerated actinic damage, including cancer, on sun-exposed tissue. Some XP patients also develop a characteristic neurodegeneration believed to result from their inability to repair neuronal DNA damaged by endogenous metabolites since the harmful UV radiation in sunlight does not reach neurons. Free radicals, which are abundant in neurons, induce DNA lesions that, if unrepaired, might cause the XP neurodegeneration. Searching for such a lesion, we developed a synthesis for 8,5-(S)-cyclo-2-deoxyadenosine (cyclo-dA), a free radical-induced bulky lesion, and incorporated it into DNA to test its repair in mammalian cell extracts and living cells. Using extracts of normal and mutant Chinese hamster ovary (CHO) cells to test for NER and adult rat brain extracts to test for base excision repair, we found that cyclo-dA is repaired by NER and not by base excision repair. We measured host cell reactivation, which reflects a cell's capacity for NER, by transfecting CHO and XP cells with DNA constructs containing a single cyclo-dA or a cyclobutane thymine dimer at a specific site on the transcribed strand of a luciferase reporter gene. We found that, like the cyclobutane thymine dimer, cyclo-dA is a strong block to gene expression in CHO and human cells. Cyclo-dA was repaired extremely poorly in NER-deficient CHO cells and in cells from patients in XP complementation group A with neurodegeneration. Based on these findings, we propose that cyclo-dA is a candidate for an endogenous DNA lesion that might contribute to neurodegeneration in XP.

A finite-element model of the vocal fold is developed from basic laws of continuum mechanics to obtain the oscillatory characteristics of the vocal folds. The model is capable of accommodating inhomogeneous, anisotropic material properties and irregular geometry of the boundaries. It has provisions for asymmetry across the midplane, both from the geometric and tension point of view, which enables one to simulate certain kinds of voice disorders due to vocal-fold paralysis. It employs the measured viscoelastic properties of the vocal-fold tissues. The detailed construction of the matrix differential equations of motion is presented followed by the solution scheme. Finally, typical results are presented and validated using an eigenvalue method and a commercial finite-element package (ABAQUS).

Empirical orthogonal eigenfunctions are extracted from biomechanical simulations of normal and chaotic vocal fold oscillations. For normal phonation, two dominant empirical eigenfunctions capture the vibration patterns of the folds and exhibit a 1:1 entrainment. The eigenfunctions show some correspondence to theoretical low-order normal modes of a simplified, three-dimensional elastic continuum, and to the normal modes of a linearized two-mass model. The eigenfunctions also facilitate a physical interpretation of energy transfer mechanisms in vocal fold dynamics. Subharmonic regimes and chaotic oscillations are observed during simulations of a lax cover, in which case at least three empirical eigenfunctions are necessary to capture the resulting vocal fold oscillations. These chaotic oscillations might be understood in terms of a desynchronization of a few of the low-order modes, and may be related to mechanisms of creaky voice or vocal fry. Furthermore, some of the empirical eigenfunctions captured during complex oscillations correspond to higher-order normal modes described in earlier theoretical work. The empirical eigenfunctions may also be useful in the design of lower-order models (valid over the range for which the empirical eigenfunctions remain more or less constant), and may help facilitate bifurcation analyses of the biomechanical simulation.

High-speed digital imaging of the medial surface of the vocal folds was performed in excised canine larynx experiments. Building on the excised larynx investigations of Baer [Ph.D. dissertation, MIT, Boston, MA (1975)] and hemilarynx investigations of Jiang and Titze [Laryngoscope 103, 872-882 (1993)], nine vocal fold fleshpoints were tracked simultaneously along the medial surface of one coronal plane of the left vocal fold using a Kodak EktaPro 4540 high-speed digital imaging system. By imaging from two distinct views, 3D reconstructions of fleshpoint trajectories were performed with a sampling frequency of 4.5 kHz and a spatial resolution of approximately 0.08 mm. Quantitative results were derived from a typical example of periodic chestlike vibrations. Furthermore, these data were decomposed into empirical eigenfunctions, the building blocks of vocal fold vibration, illuminating basic mechanisms of self-sustained oscillation. Previously, such mechanisms have only been explored theoretically using computer models of vocal fold vibration [Berry et al., J. Acoust. Soc. Am. 95, 3595-3604 (1994)]. Similar to the theoretical studies, two eigenfunctions captured 98% of the variance of the data. Because this investigation utilized high-speed technology, the methodology may also be used to examine complex, aperiodic vibrations. Thus, this technique allows mechanisms of regular and irregular vocal fold vibration to be explored using direct observations of vibrating tissues in the laboratory.

Many previous laboratory investigations of phonation involving physical models, excised larynges, and in vivo canine larynges have failed to fully specify the subglottal system. Many of these same studies have reported a variety of nonlinear phenomena, including bifurcations (e.g., various classes of phonation onset and offset, register changes, frequency jumps), subharmonics, and chaos, and attributed such phenomena to the biomechanical properties of the larynx. However, such nonlinear phenomena may also be indicative of strong coupling between the voice source and the subglottal tract. Consequently, in such studies, it has not been clear whether the underlying mechanisms of such nonlinear phenomena were acoustical, biomechanical, or a coupling of the acoustical and biomechanical systems. Using a physical model of vocal fold vibration, and tracheal tube lengths which have been commonly reported in the literature, it is hypothesized and subsequently shown that such nonlinear phenomena may be replicated solely on the basis of laryngeal interactions with the acoustical resonances of the subglottal system. Recommendations are given for ruling out acoustical resonances as the source of nonlinear phenomena in future laboratory studies of phonation.

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Several authors have recently demonstrated the intimate relationship between nonlinear dynamics and observations in vocal fold vibration (Herzel, 1993; Mende, Herzel, & Wermke, 1990; Titze, Baken, & Herzel, 1993). The aim of this paper is to analyze vocal disorders from a nonlinear dynamics point of view. Basic concepts and analysis techniques from nonlinear dynamics are reviewed and related to voice. The voices of several patients with vocal disorders are analyzed using traditional voice analysis techniques and methods from nonlinear dynamics. The two methods are shown to complement each other in many ways. Likely physiological mechanisms of the observed nonlinear phenomena are presented, and it is shown how much of the terminology in the literature describing rough voice can be unified within the framework of nonlinear dynamics.

The laryngeal neuromuscular mechanisms for modulating glottal posture and fundamental frequency are of interest in understanding normal laryngeal physiology and treating vocal pathology. The intrinsic laryngeal muscles in an in vivo canine model were electrically activated in a graded fashion to investigate their effects on onset frequency, phonation onset pressure, vocal fold strain, and glottal distance at the vocal processes. Muscle activation plots for these laryngeal parameters were evaluated for the interaction of following pairs of muscle activation conditions: (1) cricothyroid (CT) versus all laryngeal adductors (TA/LCA/IA), (2) CT versus LCA/IA, (3) CT versus thyroarytenoid (TA) and, (4) TA versus LCA/IA (LCA: lateral cricoarytenoid muscle, IA: interarytenoid). Increases in onset frequency and strain were primarily affected by CT activation. Onset pressure correlated with activation of all adductors in activation condition 1, but primarily with CT activation in conditions 2 and 3. TA and CT were antagonistic for strain. LCA/IA activation primarily closed the cartilaginous glottis while TA activation closed the mid-membranous glottis.