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1.  Detection of chronic laryngitis due to laryngopharyngeal reflux using color and texture analysis of laryngoscopic images 
To determine if pattern recognition of hue and textural parameters can be used to identify laryngopharyngeal reflux (LPR).
Laryngoscopic images from 20 subjects with LPR and 42 control subjects without LPR were obtained. LPR status was determined using the Reflux Finding Score. Color and texture features were quantified using hue calculation and 2D Gabor filtering. Five regions were analyzed: true vocal folds, false vocal folds, epiglottis, interarytenoid space, and arytenoid mucosae. A multilayer perceptron artificial neural network with varying numbers of hidden nodes was used to classify images according to pattern recognition. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic utility and intraclass correlation coefficient analysis was performed to determine to gauge interrater reliability.
Classification accuracy when including all parameters was 80.5 ± 1.2% with an area under the ROC curve of 0.887. Classification accuracy decreased when including only hue (73.1±3.5%; area under the curve = 0.834) or texture (74.9±3.6%; area under the curve = 0.852) parameters. Interrater reliability was 0.97±0.03 for hue parameters and 0.85±0.11 for texture parameters.
This preliminary study suggests that a combination of hue and texture features can be used to detect chronic laryngitis due to LPR. A simple, minimally invasive assessment would be a valuable addition to the currently invasive and somewhat unreliable methods currently used for diagnosis. Including more data will likely improve classification accuracy. Additional investigations will be performed to determine if results are in accordance with those provided by pH probe monitoring.
PMCID: PMC3910322  PMID: 24314831
laryngopharyngeal reflux; hue; Gabor filter; artificial neural network; laryngitis
2.  Effect of Variations to a Simulated System of Straw Phonation Therapy on Aerodynamic Parameters Using Excised Canine Larynges 
Summary: Objectives/Hypothesis
Resonance tubes are commonly used in voice therapy. These devices modify supraglottal impedance, potentially decreasing the aerodynamic power necessary for phonation. We modeled phonation with resonance tubes in excised larynges and evaluated the effects of varying tube width, tube length, and flow input on phonation threshold pressure (PTP) and phonation threshold flow (PTF). We hypothesized that the increased vocal economy observed in human subjects and several other models would be observed in excised larynges.
Study Design
Repeated measures excised canine larynx bench experiment with each larynx serving as own control.
Nine conditions were evaluated, namely control, two tube diameters (17.5 and 6.5 mm), three tube lengths (7.8, 15.0, and 30.0 cm), and three levels of flow input (80, 114, and 200 mL/s). Aerodynamic data were collected for 11 excised canine larynges attached to an artificial vocal tract, and results from each experimental configuration were compared with control.
A significant decrease in average PTP occurred compared with control for the 114- and 200-mL/s flow inputs, 30-cm extension, and 17.5- and 6.5-mm constrictions. Average PTF decreased compared with control for every configuration, although statistically significant changes were only observed for 200-mL/s flow and 6.5-mm constriction.
Knowledge regarding the effect of vocal tract alterations could be clinically useful in determining the optimal “straw” configuration for voice therapy. Further exploration of the relationships among width, length, and flow input could provide theoretical support for the development of new therapies and resonance tube devices.
PMCID: PMC3951877  PMID: 24286626
Resonance tube; Straw phonation therapy; Phonation threshold flow; Phonation threshold pressure; Excised larynx
3.  Salivary Gland Development: A Template for Regeneration 
The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review will focus on research on mouse submandibular gland development and the translation of this basic research towards therapy for patients suffering from salivary hypofunction. Here we review the most recent literature that has enabled a better understanding of the mechanisms of salivary gland development. Additionally, we discuss approaches proposed to restore salivary function using gene and cell-based therapy. Increasing our understanding of the developmental mechanisms involved during development is critical to design effective therapies for regeneration and repair of damaged glands.
PMCID: PMC3988231  PMID: 24333774
Salivary gland development; submandibular gland; branching morphogenesis; stem cells; progenitor cells; regeneration; parasympathetic innervation
4.  Excised Larynx Evaluation of Wedge-Shaped Adjustable Balloon Implant for Minimally Invasive Type I Thyroplasty 
The Laryngoscope  2013;124(4):942-949.
To describe the method of inserting a wedge-shaped adjustable balloon implant (wABI) via a minithyrotomy for medialization thyroplasty and evaluate its effect on a range of phonatory parameters using the excised larynx bench apparatus.
Study Design
Repeated measures with each larynx serving as its own control.
A prototype wABI was deployed in six excised canine larynges of various sizes through a minithyrotomy and then filled with saline. Mucosal wave, aerodynamic, and acoustic parameters were measured for three conditions: normal, vocal fold paralysis, and paralysis with the wABI.
Phonation threshold pressure (P <.001), flow (P <.001), and power (P =.002) were significantly lower for wABI compared to paralysis trials; values did not differ significantly from normal trials. Percent jitter (P =.002) and percent shimmer (P =.007) were also significantly decreased compared to the paralysis condition, and values were not significantly different compared to normal. The mucosal wave was preserved after insertion of the wABI.
Effective vocal fold medialization with preservation of the mucosal wave was observed with the wABI in this preliminary excised larynx experiment. The wABI offers the potential for a minimally invasive insertion in addition to postoperative adjustability. Further studies in living animals and humans are warranted to evaluate clinical utility.
PMCID: PMC4235617  PMID: 24115091
Adjustable balloon implant; medialization thyroplasty; vocal fold paralysis; glottic insufficiency
5.  Reliability of an Automated High-Resolution Manometry Analysis Program Across Expert Users, Novice Users, and Speech-Language Pathologists 
The purpose of this study was to investigate inter- and intra-rater reliability among expert users, novice users, and speech-language pathologists with a semi-automated high-resolution manometry analysis program. We hypothesized that all users would have high intra-rater reliability and high inter-rater reliability.
Three expert users, 15 novice users, and 5 speech-language pathologists participated in this study. Following a 20-minute training session, users analyzed 30 high-resolution manometry plots using an automated analysis program. Output parameters included two- and three-dimensional pressure integrals over 5 anatomical regions of interest. Intraclass correlations were used to examine inter- and intra-rater reliability. Analysis of variance was also performed to determine any differences in mean output parameter values.
Within-group inter-rater reliability ranged from 0.54-0.99 and inter-group reliability ranged from 0.92-0.99. Intra-rater reliability ranged from 0.67-1.00 across all groups. There were no significant differences of output parameters between groups.
The high reliability observed after a short training session demonstrate that individuals with little to no prior knowledge of swallowing physiology can perform at a similar level as those with expertise. Given the quickness and ease of training in the use of this program, it has the potential for research and clinical utility.
PMCID: PMC4167385  PMID: 24686522
High-resolution manometry; reproducibility of results; speech-language pathologist; swallowing; dysphagia
6.  Gestational Weight Gain and Obesity: Is 20 Pounds Too Much? 
American journal of obstetrics and gynecology  2013;209(3):214.e1-214.e11.
To compare maternal and neonatal outcomes in obese women according to weight change and obesity class.
Study design
Cohort study from the Consortium on Safe Labor of 20,950 obese women with a singleton, term, livebirth from 2002–2008. Risk for adverse outcomes was calculated by multiple logistic regression analysis for weight change categories [weight loss (<0kg), low (0−4.9kg), normal (5.0−9.0kg), high weight gain (>9.0 kg)] in each obesity class (I 30.0−34.9kg/m2, II 35.0−39.9kg/m2, and III ≥40 kg/m2) and by predicted probabilities with weight change as a continuous variable.
Weight loss was associated with decreased cesareans for class I women (nulliparas OR 0.21, 95%CI 0.11−0.42; multiparas OR 0.61, 95%CI 0.45−.83) and increased small for gestational age (SGA) infants (class I OR 1.8, 95%CI 1.3−2.5; class II OR 2.2, 95%CI 1.5−3.2; class III OR 1.7, 95%CI 1.1−2.6). High weight gain was associated with increased large for gestational age (LGA) infants (class I OR 2.4, 95%CI 1.9−2.9; class II OR 1.7, 95% CI 1.3−2.1; class III OR 1.6, 95%CI 1.3−2.1). As weight change increased, the predicted probability for cesareans and LGA infants increased. The predicted probability of low birth weight never exceeded 4% for all obesity classes, but SGA increased with decreased weight change. The lowest average predicted probability of adverse outcomes (cesarean, postpartum hemorrhage, SGA, LGA, NICU admission) occurred when women (class I,II,III) lost weight.
Optimal maternal and neonatal outcomes appear to occur when weight gain is less than current IOM recommendations for obese women. Further study of long-term outcomes is needed with respect to gestational weight changes.
PMCID: PMC3757121  PMID: 23635421
obesity; pregnancy; gestational weight gain; maternal and neonatal outcomes
7.  Differentiating arytenoid dislocation and recurrent laryngeal nerve paralysis by arytenoid movement in laryngoscopic video 
To present a new method of quantifying arytenoid movement during inspiration and determine if it can be used to distinguish arytenoid dislocation from vocal fold paralysis.
Study Design
Case series with chart review.
Retrospective study conducted in university laboratory based on university hospital data.
Subjects and Methods
Endoscopic videos from eight patients with dislocation and five patients with vocal fold paralysis diagnosed by electromyography were included. Vector analysis measured cuneiform movement, an indirect measurement of arytenoid movement, during one inspiration. Measurements normalized and not normalized to vocal fold length were evaluated. Interrater reliability (2 raters) and intrarater reliability (1 rater performing analysis twice) were evaluated using intraclass correlation coefficient (ICC) analysis. Raters were blinded to subject group during analysis.
Pixel-valued cuneiform movement was 81.16±25.62 for dislocation and 30.22±23.60 for paralysis (p=0.019). Unitless cuneiform movement was 0.58±0.17 for dislocation and 0.24±0.18 for paralysis (p=0.030). Interrater ICC was 0.942 for pixel-valued measurements and 0.962 for unitless measurements. Intrarater ICC was 0.909 for pixel-valued measurements and 0.881 for unitless measurements.
Both pixel-valued and unitless measures of arytenoid movement were significantly greater in arytenoid dislocation than vocal fold paralysis. Pixel-valued measurements were included to demonstrate the ability to make quantitative comparisons across subjects without precise knowledge of camera precision provided position is approximately stable, as each measurement is inherently normalized by vocal tract length. Future studies will apply this new method of evaluating vocal fold immobility disorders on a larger scale and incorporate a more diverse group of etiologies.
PMCID: PMC3770460  PMID: 23719396
arytenoid dislocation; vocal fold paralysis; videolaryngoscopy; endoscopy
8.  Female-specific hypertension loci on rat chromosome 13 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01708.
A 3.7 Mb region of rat chromosome 13 (45.2–49.0 Mb) affects blood pressure (BP) in females only, indicating the presence of gender-specific BP loci in close proximity to the Renin locus. In the present study, we used a series of Dahl salt-sensitive/Mcwi (SS)-13 Brown Norway (BN) congenic rat strains to further resolve BP loci within this region. We identified 3 BP loci affecting female rats only, of which the 2 smaller loci (line9BP3 and line9BP4) were functionally characterized by sequence and expression analysis. Compared with SS, the presence of a 591 Kb region of BN chromosome 13 (line9BP3) significantly lowered BP by 21 mmHg on an 8% NaCl diet (153±7 vs 174±5 mmHg, P<0.001). Unexpectedly, the addition of 23 Kb of BN chromosome 13 (line9BP4) completely erased the female-specific BP protection on 8% NaCl diet, suggesting that BN hypertensive allele(s) reside in this region. The congenic interval of the protective line 9F strain contains 3 genes (Optc, Prelp, and Fmod) and the hypertensive line 9E contains 1 additional gene (Btg2). Sequence analysis of the 2 BP loci revealed a total of 282 intergenic variants, with no coding variants. Analysis of gene expression by RT-qPCR revealed strain- and gender-specific differences in Prelp, Fmod, and Btg2 expression, implicating these as novel candidate genes for female-specific hypertension.
PMCID: PMC3870583  PMID: 23817491
Hypertension; Genetics; Gender; Blood Pressure; Kidney
9.  Respiratory Morbidity in Late Preterm Births 
Late preterm births (LPTB, 34 0/7-36 6/7 weeks) account for a growing proportion of prematurity-associated short term morbidities, particularly respiratory, that require specialized care and prolonged neonatal hospital stays.
To assess short-term respiratory morbidity in LPTB compared to term births in a contemporary cohort of deliveries in the United States.
Design, Setting, and Participants
Retrospective collection of electronic data from 12 institutions (19 hospitals) across the United States on 233,844 deliveries between 2002 and 2008. Charts were abstracted for all neonates with respiratory compromise admitted to a neonatal intensive care unit (NICU) and LPTB were compared to term births in regard to resuscitation, respiratory support and respiratory diagnoses. A multivariate logistic regression analysis compared infants at each gestational week controlling for factors that influence respiratory outcomes.
Main outcome measures
Respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), pneumonia, respiratory failure, standard and oscillatory ventilator support.
Of 19,334 LPTB, 7,055 were admitted to a NICU and 2,032 had respiratory compromise. Of 165,993 term infants, 11,980 were admitted to a NICU, 1,874 with respiratory morbidity.
Respiratory distress syndrome decreased from 10.5% (390/3700) at 34 weeks to 0.3% (140/41,764) at 38 weeks. Similarly, TTN decreased from 6.4% (n=236) to 0.4% (n=155), pneumonia from 1.5% (n=55) to 0.1% (n=62), and respiratory failure from 1.6% (n=61) to 0.2% (n=63). Standard and oscillatory ventilator support had similar patterns. Odds of RDS decreased with each advancing week until 38 weeks compared to 39-40 weeks (adjusted OR at 34 weeks 40.1 [95% CI 32.0-50.3] and at 38 weeks 1.1 [95% CI, 0.9-1.4]). At 37 weeks odds for RDS were greater than 39-40 weeks (3.1 [95% CI, 2.5-3.7]), but the odds at 38 weeks did not differ from 39-40 weeks. Similar patterns were noted for TTN (adjusted OR at 34 weeks 14.7 [95% CI, 11.7-18.4] and at 38 weeks 1.0 [95% CI 0.8-1.2]); pneumonia (adjusted OR at 34 weeks 7.6 [95% CI, 5.2-11.2] and at 38 weeks 0.9 [95% CI, 0.6-1.2]), and respiratory failure (adjusted OR at 34 weeks 10.5 [95% CI, 6.9-16.1] and at 38 weeks 1.4 [95% CI, 1.0-1.9]).
In a contemporary cohort, late preterm birth, compared with term delivery, was associated with increased risk for respiratory distress syndrome and other respiratory morbidity.
PMCID: PMC4146396  PMID: 20664042
10.  Quantifying Contributions of the Cricopharyngeus to Upper Esophageal Sphincter Pressure Changes by Means of Intramuscular Electromyography and High-Resolution Manometry 
We sought to determine whether the association between cricopharyngeus muscle activity and upper esophageal sphincter pressure may change in a task-dependent fashion. We hypothesized that more automated tasks related to swallow or airway protection would yield a stronger association than would more volitional tasks related to tidal breathing or voice production.
Six healthy adult subjects underwent simultaneous intramuscular electromyography of the cricopharyngeus muscle and high-resolution manometry of the upper esophageal sphincter. Correlation coefficients were calculated to characterize the association between the time-linked series.
Cricopharyngeus muscle activity was most strongly associated with upper esophageal sphincter pressure during swallow and effortful exhalation tasks (r = 0.77 and 0.79, respectively; P < .01). The association was also less variable during swallow and effortful exhalation.
These findings suggest a greater coupling for the more automatic tasks, and may suggest less coupling and more flexibility for the more volitional, voice-related tasks. These findings support the important role of central patterning for respiratory- and swallow-related tasks.
PMCID: PMC4128397  PMID: 24633943
cricopharyngeus; deglutition; electromyography; high-resolution manometry; upper esophageal sphincter
11.  Three-dimensional analysis of pharyngeal high-resolution manometry data 
The Laryngoscope  2013;123(7):1746-1753.
High-resolution manometry (HRM) represents a critical advance in the quantification of swallow-related pressure events in the pharynx. Previous analyses of the pressures measured by HRM, though, have been largely two-dimensional, focusing on a single sensor in a given region. We present a method a three-dimensional approach which combines information from adjacent sensors in a region. Two- and three-dimensional approaches were compared for their ability to classify data correctly as normal or disordered.
Study Design
Case series evaluating new method of data analysis.
1,324 total swallows from 16 normal subjects and 61 subjects with dysphagia were included. Two-dimensional single sensor integrals of the area under the curves created by rises in pressure in the velopharynx, tongue base, and UES were calculated. Three-dimensional multi-sensor integrals of the volume under all curves corresponding to the same regions were also computed. The two sets of measurements were compared for their ability to classify data correctly as normal or disordered using an artificial neural network (ANN).
Three-dimensional parameters yielded a maximal classification accuracy of 86.71±1.47%, while two-dimensional parameters achieved a maximum accuracy of 83.36±1.42%. When combining two- and three-dimensional parameters with all other variables, including three-dimensional parameters yielded a classification accuracy of 96.99±0.51%, and including 2-dimensional parameters yielded a classification accuracy of 96.32±1.05%.
Three-dimensional analysis led to improved classification of swallows based on pharyngeal HRM. Artificial neural network performance with both two-dimensional and three-dimensional analyses was effective, classifying a large percentage of swallows correctly, thus demonstrating its potential clinical utility.
PMCID: PMC3774539  PMID: 23417441
high-resolution manometry; swallowing; pharynx; dysphagia
12.  Classification of high-resolution manometry data according to videofluoroscopic parameters using pattern recognition 
To determine if pattern recognition techniques applied to high-resolution manometry (HRM) spatiotemporal plots of the pharyngeal swallow can identify features of disordered swallowing reported on the Modified Barium Swallow Impairment Profile (MBSImP).
Study Design
Case series evaluating new method of data analysis.
University hospital.
Subjects and Methods
Simultaneous HRM and videofluoroscopy was performed on 30 subjects (335 swallows) with dysphagia. Videofluoroscopic studies were scored according to the MBSImP guidelines while HRM plots were analyzed using a novel program. Pattern recognition using a multilayer perceptron artificial neural network (ANN) was performed to determine if seven pharyngeal components of the MBSImP as well as penetration/aspiration status could be identified from the HRM plot alone. Receiver operating characteristic (ROC) analysis was also performed.
MBSImP parameters were identified correctly as normal or disordered at an average rate of approximately 91% (area under the ROC curve ranged from 0.902 to 0.981). Classifications incorporating two MBSImP parameters resulted in classification accuracies over 93% (area under the ROC curve ranged from 0.963 to 0.989).
Pattern recognition coupled with multiparameter quantitative analysis of HRM spatiotemporal plots can be used to identify swallowing abnormalities which are currently assessed using videofluoroscopy. The ability to provide quantitative, functional data at the bedside while avoiding radiation exposure make HRM an appealing tool to supplement and, at times, replace traditional videofluoroscopic studies.
PMCID: PMC3823556  PMID: 23728150
High-resolution manometry; pharyngeal swallow; MBSImP; videofluoroscopy
13.  Micro-patterned surfaces reduce bacterial colonization and biofilm formation in vitro: Potential for enhancing endotracheal tube designs 
Ventilator-associated pneumonia (VAP) is a leading hospital acquired infection in intensive care units despite improved patient care practices and advancements in endotracheal tube (ETT) designs. The ETT provides a conduit for bacterial access to the lower respiratory tract and a substratum for biofilm formation, both of which lead to VAP. A novel microscopic ordered surface topography, the Sharklet micro-pattern, has been shown to decrease surface attachment of numerous microorganisms, and may provide an alternative strategy for VAP prevention if included on the surface of an ETT. To evaluate the feasibility of this micro-pattern for this application, the microbial range of performance was investigated in addition to biofilm studies with and without a mucin-rich medium to simulate the tracheal environment in vitro.
The top five pathogens associated with ETT-related pneumonia, Methicillin-Resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter baumannii, and Escherichia coli, were evaluated for attachment to micro-patterned and un-patterned silicone surfaces in a short-term colonization assay. Two key pathogens, MRSA and Pseudomonas aeruginosa, were evaluated for biofilm formation in a nutrient rich broth for four days and minimal media for 24 hours, respectively, on each surface type. P. aeruginosa was further evaluated for biofilm formation on each surface type in a mucin-modified medium mimicking tracheal mucosal secretions. Results are reported as percent reductions and significance is based on t-tests and ANOVA models of log reductions. All experiments were replicated at least three times.
Micro-patterned surfaces demonstrated reductions in microbial colonization for a broad range of species, with up to 99.9% (p < 0.05) reduction compared to un-patterned controls. Biofilm formation was also reduced, with 67% (p = 0.12) and 52% (p = 0.05) reductions in MRSA and P. aeruginosa biofilm formation, respectively. Further, a 58% (p < 0.01) reduction was demonstrated on micro-patterned surfaces for P. aeruginosa biofilms under clinically-simulated conditions when compared to un-patterned controls.
This engineered micro-pattern reduces the colonization and biofilm formation of key VAP-associated pathogens in vitro. Future application of this micro-pattern on endotracheal tubes may prevent or prolong the onset of VAP without the need for antimicrobial agents.
PMCID: PMC3996152  PMID: 24739529
Micro-pattern; Sharklet; VAP; Endotracheal tube; Biofilm inhibition
14.  Congenic mapping and sequence analysis of the Renin locus 
Hypertension  2013;61(4):850-856.
Renin was the first blood pressure (BP) quantitative trait locus (QTL) mapped by linkage analysis in the rat. Subsequent BP linkage and congenic studies capturing different portions of the renin region have returned conflicting results, suggesting that multiple interdependent BP loci may be residing in the chromosome 13 BP QTL that includes Renin. We used SS-13BN congenic strains to map 2 BP loci in the Renin region (chr13:45.2–49.0 Mb). We identified a 1.1 Mb protective Brown Norway (BN) region around Renin (chr13:46.1–47.2 Mb) that significantly decreased BP by 32 mmHg. The Renin protective BP locus was offset by an adjacent hypertensive locus (chr13:47.2–49.0 Mb) that significantly increased BP by 29 mmHg. Sequence analysis of the protective and hypertensive BP loci revealed 1,433 and 2,063 variants between Dahl salt-sensitive/Mcwi (SS) and BN rats, respectively. To further reduce the list of candidate variants, we re-genotyped an overlapping SS-13SR congenic strain (S/renrr) with a previously reported BP phenotype. Sequence comparison between SS, Dahl R (SR), and BN reduced the number of candidate variants in the 2 BP loci by 42% for further study. Combined with previous studies, these data suggest that at least 4 BP loci reside within the 30 cM chromosome 13 BP QTL that includes Renin.
PMCID: PMC3770301  PMID: 23460292
hypertension; genetic; congenic; Dahl salt-sensitive rat; Brown Norway
15.  Artificial neural network classification of pharyngeal high-resolution manometry with impedance data 
The Laryngoscope  2012;123(3):713-720.
To use classification algorithms to classify swallows as safe, penetration, or aspiration based on measurements obtained from pharyngeal high-resolution manometry (HRM) with impedance.
Study design
Case series evaluating new method of data analysis.
Multilayer perceptron (MLP), an artificial neural network (ANN), was evaluated for its ability to classify swallows as safe, penetration, or aspiration. Data were collected from 25 disordered subjects swallowing 5 or 10 ml boluses. Following extraction of relevant parameters, a subset of the data was used to train the models and the remaining swallows were then independently classified by the ANN.
A classification accuracy of 89.4±2.4% was achieved when including all parameters. Including only manometry-related parameters yielded a classification accuracy of 85.0±6.0% while including only impedance-related parameters yielded a classification accuracy of 76.0±4.9%. Receiver operating characteristic (ROC) analysis yielded areas under the curve (AUC) of 0.8912 for safe, 0.8187 for aspiration, and 0.8014 for penetration.
Classification models show high accuracy in classifying swallows from dysphagic patients as safe or unsafe. HRM-impedance with ANN represents one method which could be used clinically to screen for patients at risk for penetration or aspiration.
PMCID: PMC3648989  PMID: 23070810
artificial neural network; classification model; high-resolution manometry; impedance; aspiration; dysphagia
16.  Evaluation of auditory and visual feedback for airflow interruption 
Clinical application of mechanical interruption methods for measuring aerodynamic parameters has been hindered by relatively high intrasubject variability. To improve intrasubject reliability, we evaluated the effect of auditory and visual feedback on subject performance when measuring aerodynamic parameters with the airflow interrupter.
Eleven subjects performed four sets of ten trials with the airflow interrupter: no feedback (control); auditory feedback (tone matching subject’s F0 played over headphones); visual feedback (real-time feedback of sound pressure level, frequency, and airflow); and combined auditory and visual feedback. Task order was varied across subjects. The effect of each feedback method on mean and coefficient of variation (CV) of subglottal pressure (Ps), mean flow rate (MFR), and laryngeal airway resistance (RL; Ps/MFR) compared to control trials was determined using paired t-tests. Feedback methods were compared against each other using one-way repeated measures analysis of variance.
Each feedback method significantly decreased the CV of RL compared to control trials (auditory: p=0.005; visual: p=0.008; combined: p<0.001). Auditory (p=0.011) and combined feedback (p=0.026) also decreased the CV of MFR. Mean MFR was significantly higher during trials with visual feedback compared to auditory feedback.
Each feedback method improved intrasubject consistency when measuring RL. Feedback appeared to have a greater effect on MFR than Ps. While there is no clear optimal feedback method, each is preferable to not providing any feedback during trials. Evaluating new methods of visual feedback to further improve MFR and thus RL measurement would be valuable.
PMCID: PMC3595395  PMID: 23280384
airflow interruption; mechanical interruption; auditory feedback; visual feedback; subglottal pressure; aerodynamics
17.  Refractive change in the adult rabbit eye after corneal relaxation with the femtosecond laser 
BMC Ophthalmology  2014;14:8.
A new procedure to correct myopia that does not disturb the cornea in the optical zone and avoids injuring the corneal epithelium could be a key advance in corneal refractive surgery. The aim of this study is to observe the refractive change in the adult rabbits undergoing femtosecond laser-assisted multilayer intrastromal ablation in the mid-periphery of the cornea without injury of epithelium.
The right eyes of 8 New Zealand White adult rabbits were used for the experiments. A 60-kHz femtosecond laser delivery system was used, and three lamellar layers of laser pulses were focused starting at a corneal depth of 180 μm and ending at 90 μm from the surface, with each successive layer placed 45 μm anterior to the previous layer. In the interface of the applanation contact lens cone, a 6-mm diameter aluminum circle was placed at the center to block the laser, limiting ablation to the mid-periphery of the cornea. The laser settings were as follows: spot/line separation, 10 μm; diameter, 8.0 mm; energy for ablating the stroma, 1.3 μJ. An authorefractor was used to assess the manifest refraction.
Mean spherical equivalent (SE) (mean ± SD, SD: standard deviation) was significantly increased at postoperative week 1 (1.67 ± 0.26 D, p < 0.0001), month 1 (1.65 ± 0.23 D, p < 0.0001), and month 3 (1.60 ± 0.22 D, p < 0.0001) compared to baseline (0.68 ± 0.27 D). Mean spherical equivalent showed no significant change between postoperative week 1 and month 3 (p = 0.1168).
Femtosecond laser-assisted multilayer corneal intrastromal ablation in the mid-periphery may cause a consequent hyperopic shift with no refractive regression.
PMCID: PMC3917590  PMID: 24447397
18.  Identification of Hypertension Susceptibility Loci on Rat Chromosome 12 
Hypertension  2012;60(4):10.1161/HYPERTENSIONAHA.112.198200.
Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed blood pressure loci using a series of overlapping SS-12BN congenic lines. We found that transferring 6.1Mb of SS chromosome 12 (13.4-19.5Mb) onto the consomic SS-12BN background significantly elevated blood pressure on 1% NaCl (146±6 vs. 127±1 mmHg, P<0.01) and 8% NaCl diets (178±7 vs. 144±2 mmHg, P<0.05). Compared with the SS-12BN consomic, these animals also had significantly elevated albumin (218±31 vs. 104±8 mg/day, P<0.01) and protein excretion (347±41 vs. 195±12 mg/day, P<0.01) on 1% NaCl diet. Elevated blood pressure, albuminuria, and proteinuria coincided with greater renal and cardiac damage, demonstrating that SS allele(s) within the 6.1Mb congenic interval are associated with strong cardiovascular disease phenotypes. Sequence analysis of the 6.1Mb congenic region revealed 12,675 single nucleotide polymorphisms between SS and BN. Of these polymorphisms, 295 lie within coding regions and 20 resulted in nonsynonymous changes in conserved genes, of which 5 were predicted to be potentially damaging to protein function. Syntenic regions in human chromosome 7 have also been identified in multiple linkage and association studies of cardiovascular disease, suggesting that genetic variants underlying cardiovascular phenotypes in this congenic strain can likely be translated to a better understanding of human hypertension.
PMCID: PMC3873777  PMID: 22868394
Hypertension; Genetic; Dahl Salt-Sensitive Rat; Brown Norway; Congenic
19.  Combined KIT and FGFR2b Signaling Regulates Epithelial Progenitor Expansion during Organogenesis 
Stem Cell Reports  2013;1(6):604-619.
Organ formation and regeneration require epithelial progenitor expansion to engineer, maintain, and repair the branched tissue architecture. Identifying the mechanisms that control progenitor expansion will inform therapeutic organ (re)generation. Here, we discover that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling specifically increases distal progenitor expansion during salivary gland organogenesis. FGFR2b signaling upregulates the epithelial KIT pathway so that combined KIT/FGFR2b signaling, via separate AKT and mitogen-activated protein kinase (MAPK) pathways, amplifies FGFR2b-dependent transcription. Combined KIT/FGFR2b signaling selectively expands the number of KIT+K14+SOX10+ distal progenitors, and a genetic loss of KIT signaling depletes the distal progenitors but also unexpectedly depletes the K5+ proximal progenitors. This occurs because the distal progenitors produce neurotrophic factors that support gland innervation, which maintains the proximal progenitors. Furthermore, a rare population of KIT+FGFR2b+ cells is present in adult glands, in which KIT signaling also regulates epithelial-neuronal communication during homeostasis. Our findings provide a framework to direct regeneration of branched epithelial organs.
•Combined KIT and FGFR2b signaling amplifies FGFR2b-dependent transcription•KIT/FGFR2b signaling during organogenesis expands distal KIT+ epithelial progenitors•Distal progenitors communicate with proximal progenitors via the neuronal niche•KIT+ progenitors maintain epithelial-neuronal communication during adult homeostasis
Hoffman and colleagues demonstrate that combined KIT and fibroblast growth factor receptor 2b (FGFR2b) signaling expands the distal KIT+FGFR2b+ progenitor population in branching organs. This is important for continued branching morphogenesis because the KIT+FGFR2b+ progenitors produce neurotrophic factors to communicate with the neuronal niche to direct the ductal differentiation of proximal Keratin 5+ progenitors.
PMCID: PMC3871401  PMID: 24371813
20.  Classification of glottic insufficiency and tension asymmetry using a multilayer perceptron 
The Laryngoscope  2012;122(12):2773-2780.
Laryngeal function can be evaluated from multiple perspectives, including aerodynamic input, acoustic output, and mucosal wave vibratory characteristics. To determine the classifying power of each of these, we used a multilayer perceptron artificial neural network (ANN) to classify data as normal, glottic insufficiency, or tension asymmetry.
Study design
Case series analyzing data obtained from excised larynges simulating different conditions.
Aerodynamic, acoustic, and videokymographic data were collected from excised canine larynges simulating normal, glottic insufficiency, and tension asymmetry. Classification of samples was performed using a multilayer perceptron ANN.
A classification accuracy of 84% was achieved when including all parameters. Classification accuracy dropped below 75% when using only aerodynamic or acoustic parameters and below 65% when using only videokymographic parameters.
Samples were classified with the greatest accuracy when using a wide range of parameters. Decreased classification accuracies for individual groups of parameters demonstrate the importance of a comprehensive voice assessment when evaluating dysphonia.
Level of evidence
Not applicable – study was performed on excised canine larynges.
PMCID: PMC3522789  PMID: 23070824
voice analysis; artificial neural network; multiparameter assessment; recurrent laryngeal nerve paralysis; superior laryngeal nerve paralysis
21.  Aerodynamic and nonlinear dynamic acoustic analysis of tension asymmetry in excised canine larynges 
To model tension asymmetry caused by superior laryngeal nerve paralysis (SLNP) in excised larynges and apply perturbation, nonlinear dynamic, and aerodynamic analyses.
SLNP was modeled in 8 excised larynges using sutures and weights to mimic cricothyroid (CT) muscle function. Weights were removed from one side to create tension asymmetry, mimicking unilateral SLNP. Two sets of weights were used, one light and one heavy. Experimental measurements were made for five conditions: no tension; symmetrical light tension; asymmetrical light tension; symmetrical heavy tension; and asymmetrical heavy tension.
Perturbation parameters were not significantly different across conditions (percent jitter: p=0.451; percent shimmer: p=0.321). Additionally, many measurements were invalid (error values > 10). Second order entropy (K2) was significantly different across conditions (p=0.002), while correlation dimension (D2) was not (p=0.428). Validity of these nonlinear dynamic parameters was demonstrated by low standard deviations. Phonation threshold pressure (p<0.001) and power (p=0.05) differed significantly across conditions, while phonation threshold flow did not (p=0.396).
Nonlinear dynamic analysis differentiated between symmetrical and asymmetrical tension conditions while traditional perturbation analysis was less useful characterizing type 2 or 3 vocal signals. Supplementing acoustic with aerodynamic parameters may help distinguish among laryngeal disorders of neuromuscular origin.
PMCID: PMC3593670  PMID: 22562826
superior laryngeal nerve paralysis; tension asymmetry; nonlinear dynamic analysis; acoustic analysis; aerodynamic analysis
22.  High resolution manometry of pharyngeal swallow pressure events associated with effortful swallow and the Mendelsohn maneuver 
Dysphagia  2012;27(3):418-426.
Effortful swallow and the Mendelsohn maneuver are two common strategies to improve disordered swallowing. We used high-resolution manometry (HRM) to quantify the effects of these maneuvers on pressure and timing characteristics. Fourteen normal subjects swallowed multiple, five ml water boluses using three techniques: normal swallow; effortful swallow; and Mendelsohn maneuver. Maximum pressure, rate, duration, area integral, and line integral were determined for the velopharynx and tongue base. Minimum pressure, duration of pressure-related change, duration of nadir pressure, maximum pre-opening and post-closure pressure, area integral, and line integral were recorded for the upper esophageal sphincter (UES). Area and line integrals of the velopharyngeal pressure curve significantly increased with the Mendelsohn maneuver; the line integral increased with the effortful swallow. Pre-opening UES pressure decreased significantly for the Mendelsohn, while post-closure pressure tended to increase insignificantly for both maneuvers. UES area and line integrals as well as nadir UES pressure duration increased with both maneuvers. Maneuver-dependent changes were observed primarily at the velopharynx and UES. These regions are critical to safe swallowing, as the velopharynx provides positive pressure at the bolus tail while the UES allows a bolus to enter the esophagus without risk of regurgitation. Integrals were more responsive than maximum pressure or duration and should be investigated further.
PMCID: PMC3717357  PMID: 22215280
pharyngeal pressure; swallowing maneuver; high-resolution manometry; deglutition; deglutition disorder
23.  Parasympathetic stimulation improves epithelial organ regeneration 
Nature communications  2013;4:1494.
Parasympathetic nerves are a vital component of the progenitor cell niche during development, maintaining a pool of progenitors for organogenesis. Injured adult organs do not regenerate after parasympathectomy, and there are few treatments to improve organ regeneration, particularly after damage by therapeutic irradiation. Here we show that restoring parasympathetic function with the neurotrophic factor neurturin increases epithelial organ regeneration after damage. We use mouse salivary gland explant culture containing fluorescently-labeled progenitors, and injure the tissue with irradiation. The progenitors survive, parasympathetic function is diminished, and epithelial apoptosis reduces expression of neurturin, which increases neuronal apoptosis. Treatment with neurturin reduces neuronal apoptosis, restores parasympathetic function, and increases epithelial regeneration. Furthermore adult human salivary glands damaged by irradiation also have reduced parasympathetic innervation. We propose that neurturin will protect the parasympathetic nerves from damage and improve organ regeneration. This concept may be applicable for other organs where parasympathetic innervation influences their function.
PMCID: PMC3582394  PMID: 23422662
24.  New insights into mechanism of Eustachian tube ventilation based on cine computed tomography images 
There is debate concerning the mechanism of Eustachian tube (ET) ventilation. While a mechanism of complete opening has been advocated previously, sequential contraction of the levator veli palatini and medial pterygoid muscles followed by the tensor veli palatini and lateral pterygoid muscles may produce a transient sequential opening mechanism, allowing an air bolus to traverse the ET. This may explain confusion surrounding sonotubometry reports that not every swallow leads to sound passage in normal subjects. We hypothesize that the ET may not need to open completely when ventilating the middle ear; rather, a discrete air bolus can pass through it.
Subjects and Methods
Five normal and five disordered subjects underwent low-radiation dose cine computed tomography (CT) scans of the ET. Sixteen contiguous 2.5 mm slice locations were chosen through a 4 cm area in the nasopharynx that were parallel to and encompassed the entire ET. Twelve images were acquired at each slice over 4.8 seconds during swallowing and other tasks. Serial images were analyzed.
An air bolus was observed passing through the ET in the normal subjects, but not the subject with ET dysfunction. Medial and lateral pterygoid contractions were also observed.
A new hypothetical mechanism of transient sequential ET ventilation is presented. This is not a definitive conclusion, as the number of scans taken and maneuvers used was limited. Improved understanding of ET ventilation may facilitate management of middle ear disease as treatment evolves from ventilatory tube placement to ET manipulation.
PMCID: PMC3679544  PMID: 22120826
Eustachian tube ventilation; Eustachian tube dysfunction; patulous Eustachian tube
25.  Interactions between developing nerves and salivary glands 
Organogenesis  2013;9(3):199-205.
Our aim is to provide a summary of the field of salivary gland development and regeneration from the perspective of what is known about the function of nerves during these processes. The primary function of adult salivary glands is to produce and secrete saliva. Neuronal control of adult salivary gland function has been a focus of research ever since Pavlov’s seminal experiments on salivation in dogs. Less is known about salivary gland innervation during development and how the developing nerves influence gland organogenesis and regeneration. Here, we will review what is known about the communication between the autonomic nervous system and the epithelium of the salivary glands during organogenesis. An important emerging theme is the instructive role of the nervous system on the epithelial stem/progenitor cells during development as well as regeneration after damage. We will provide a brief overview of the neuroanatomy of the salivary glands and discuss recent literature that begins to integrate neurobiology with epithelial organogenesis, which may provide paradigms for exploring these interactions in other organ systems.
PMCID: PMC3896591  PMID: 23974175
parasympathetic innervation; salivary gland; innervation; neurturin; epithelial progenitors; cholinergic signaling

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