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This study examined the measurement of the contralateral acoustic stapedius reflex in six-week-old infants and adults using wideband shifts in admittance and energy reflectance (YR). The reflex activator was bandpass noise from 2,500 to 11,000 Hz presented at a maximum spectrum level of 51 dB SPL measured in the ear canal. Reflexes were detected by calculating a cross-correlation between one-twelfth-octave measurements of YR for the highest activator level and responses to lower levels. The reflex-induced shifts in YR for the infant ears were similar in pattern to adult responses but were noisy at frequencies below 1000 Hz. Infant reflexes were more successfully detected when the cross-correlation was calculated from 1000 to 8000 Hz, whereas adult reflexes were more successfully detected for a cross-correlation from 250 to 2000 Hz. This method may be useful in capturing the most robust frequency region for acoustic reflex detection across postnatal middle ear development. [ABSTRACT FROM AUTHOR]

Purpose: Power absorbance measures recorded over a wide range of frequencies allow for clinical inferences about the outer/middle ears' acoustic mechanics. A frequency-dependent feature in the newborn wideband absorbance response, the prominent mid-frequency absorbance peak, has been linked to middle-ear resonance. However, current normative methods were not designed to assess subtle changes in such features. This work aims to develop and validate an absorbance peak template (APT) for assessment of absorbance peaks in newborns. Additional objectives are to compare test performance of absorbance peaks and APTs to existing normative methods, to demonstrate APT-based methods for categorization of abnormal absorbance peaks, and to describe absorbance peak test-retest variability., Method: Peak absorbance and peak frequency were analyzed in a training data set (490 measurements in 84 newborn ears who passed transient evoked otoacoustic emissions [TEOAEs] screenings), and an APT was developed by computing normal limits on these two absorbance peak variables. Split-set analysis evaluated the reproducibility of APT, and test-retest analysis was performed. Test performance analysis, conveyed by area under the receiver operating characteristic curve (AROC) and 95% confidence intervals (CIs), compared absorbance peak variables to absorbance area indices (AAIs) in a validation data set (359 ears that passed distortion-product OAE [DPOAE] screening and 64 ears that failed). APT-based assessment paradigms for normal and abnormal ears were compared to the common absorbance normative range paradigm., Results: Split-set analysis demonstrated a good reproducibility of APT, and test-retest of absorbance peak variables showed that they were stable measures for clinical assessment. Test performance of peak absorbance (AROC = 0.83; 95% CI [0.77, 0.88]) was comparable to the top-performing AAI variables (AROC = 0.85; 95% CI [0.80, 0.90]). APT-based assessment categorized measurements based on their peak absorbance and peak frequency and enhanced the detection of subtle frequency changes that were missed by the normative range method., Conclusion: Analysis of absorbance peaks guided by APT has the potential to simplify and improve assessments of sound conduction pathways in newborn ears and can be used together with or in-place of current methods for analysis of wideband absorbance data.

Clinical assessment of middle ear function has undergone multiple transformations and developments since the first acoustic impedance measurements were made in human ears nearly a century ago. The decades following the development of the first acoustic impedance bridge by Metz in 1946 witnessed a series of technological advancements leading to the widespread use of single-frequency admittance tympanometry in the 1960s. In the 1970s, multi-frequency and multi-component tympanometry (MFT) emerged for clinical use, allowing for a better understanding of the middle ear acoustic-mechanical response at frequencies between 200 and 2,000 Hz. MFT has not gained widespread clinical adoption despite its advantages over single-frequency tympanometry. More recent technological developments enabled assessment for frequencies greater than 2,000 Hz, leading to the advent of wideband acoustic immittance measures with capabilities for comprehensive assessment of middle ear acoustic mechanics, and a great potential for use of acoustic immittance testing in various diagnostic practices. This article reviews important historical markers in the development and operation of middle ear assessment tools and analysis methods. Technical and clinical factors underlying the emergence and adoption of different acoustic immittance tests as a standard of clinical practice are described. In addition, we discuss the likelihood for widespread adoption of wideband acoustic immittance and wideband tympanometry in future clinical practice., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

A number of studies have produced normative and developmental data and examples of wideband acoustic immittance (WAI) obtained in ears with pathologies and or dysfunction. However, incorporation of this tool into clinical audiology and otolaryngology practice has been slower than expected, potentially due to challenges with interpretation, integration into existing test batteries, and confidence in practical application. This article presents information aimed at helping clinicians increase their confidence in using this new tool by becoming more familiar and making connections with the ways that WAI outcomes both align with and add to standard immittance, audiometric and otologic diagnostic test outcomes. This article presents several case studies to demonstrate the use of WAI in realistic clinical settings. Each case presents a brief background, case history, audiologic/otologic findings, and initial recommendations, followed by a discussion on how the inclusion of WAI test outcomes aids in diagnostic decisions. The overall aim of this work is to identify the relationships among different diagnostic test outcomes, to demonstrate basic WAI interpretation principles, and encourage the reader to engage with this diagnostic tool in clinical practice., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Neuromedin-U (NMU) mediates several physiological functions via its two cognate receptors, NMUR1 and NMUR2. Disentangling the individual roles of each receptor has largely been undertaken through the use of transgenic mice bearing a deletion in one of the two receptors or by testing native molecules (NMU or its truncated version NMU-8) in a tissue-specific manner, in effect, taking advantage of the distinct receptor expression profiles. These strategies have proved quite useful despite the inherent limitations of overlapping receptor roles and potential compensatory influences of germline gene deletion. With these considerations in mind, the availability of potent, selective NMU compounds with appropriate pharmacokinetic profiles would advance the capabilities of investigators undertaking such efforts. Here, we evaluate a recently reported NMUR2-selective peptide (compound 17 ) for its in vitro potency (mouse and human), binding affinity, murine pharmacokinetic properties, and in vivo effects. Despite being designed as an NMUR2 agonist, our results show compound 17 unexpectedly binds but does not have functional activity on NMUR1, thereby acting as an R1 antagonist while simultaneously being a potent NMUR2 agonist. Furthermore, evaluation of compound 17 across all known and orphan G-protein-coupled receptors demonstrates multiple receptor partners beyond NMUR2/R1 binding. These properties need to be appreciated for accurate interpretation of results generated using this molecule and may limit the broader ability of this particular entity in disentangling the physiological role of NMU receptor biology., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. In mice, FGF21 is thought to cause weight loss by stimulating thermogenesis, but whether FGF21 increases energy expenditure (EE) in primates is unclear. Here, we explore the transcriptional response and gene networks active in adipose tissue of rhesus macaques following FGF21-induced weight loss. Genes related to thermogenesis responded inconsistently to FGF21 treatment and weight loss. However, expression of gene modules involved in triglyceride (TG) synthesis and adipogenesis decreased, and this was associated with greater weight loss. Conversely, expression of innate immune cell markers was increased post-treatment and was associated with greater weight loss. A lipogenesis gene module associated with weight loss was evaluated by testing the function of member genes in mice. Overexpression of NRG4 reduced weight gain in diet-induced obese mice, while overexpression of ANGPTL8 resulted in elevated TG levels in lean mice. These observations provide evidence for a shifting balance of lipid storage and metabolism due to FGF21-induced weight loss in the non-human primate model, and do not fully recapitulate increased EE seen in rodent and in vitro studies. These discrepancies may reflect inter-species differences or complex interplay of FGF21 activity and counter-regulatory mechanisms.

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.

This study aimed to explore the feasible gender differences and similarities in cerebral activity response to the acupuncture at local acupoints around knee.Fifteen male and 15 female healthy adults were recruited and included in this study. Functional magnetic resonance imaging (fMRI) was applied to measure cerebral activity response to acupuncture at Liangqiu (ST34), Xuehai (SP-10), Neixiyan (EX-LE4), and Dubi (ST-35).Acupuncture activated the postcentral gyrus, precuneus, temporal, posterior lobe, and occipital lobe in both males and females. When compared with females, males showed brain activation in the right middle frontal gyrus, inferior frontal gyrus, right precuneus, right superior parietal lobule, left cerebellum anterior lobe; and brain deactivation in the right frontal. When compared with males, females were observed brain activation in the right frontal lobe, right parietal lobe, and right middle temporal gyrus; and brain deactivation in the left and right medial frontal gyrus.The results of this study demonstrated that the neural effects of local acupoints around knee might be different between male and female subjects. Further clinical trials should take this gender effect into account in their design of studies.

Transient-evoked otoacoustic emission (TEOAE) responses were measured in normal-hearing adult ears over frequencies from 0.7 to 8 kHz, and analyzed with reflectance/admittance data to measure absorbed sound power and the tympanometric peak pressure (TPP). The mean TPP was close to ambient. TEOAEs were measured in the ear canal at ambient pressure, TPP, and fixed air pressures from 150 to -200 daPa. Both click and chirp stimuli were used to elicit TEOAEs, in which the incident sound pressure level was constant across frequency. TEOAE levels were similar at ambient and TPP, and for frequencies from 0.7 to 2.8 kHz decreased with increasing positive and negative pressures. At 4-8 kHz, TEOAE levels were larger at positive pressures. This asymmetry is possibly related to changes in mechanical transmission through the ossicular chain. The mean TEOAE group delay did not change with pressure, although small changes were observed in the mean instantaneous frequency and group spread. Chirp TEOAEs measured in an adult ear with Eustachian tube dysfunction and TPP of -165 daPa were more robust at TPP than at ambient. Overall, results demonstrate the feasibility and clinical potential of measuring TEOAEs at fixed pressures in the ear canal, which provide additional information relative to TEOAEs measured at ambient pressure.

Annual increases in global travel have resulted in more individuals being exposed to varying environmental conditions abroad and, thereby, subject to air pollution related health risks. Individuals who travel abroad may be exposed to varying levels of air pollution within a matter of hours. We wish to consider whether exposure to air pollution could be a significant contributor to the risk of illness and death in travelers, particularly those who travel to highly polluted cities. We report the findings of a study in which the peak expiratory flow (PEF) of a traveler decreased in Shanghai relative to baseline in New York City; the decline in PEF correlated to concentration of particulate matter (PM2.5). We discuss the health implication of these results on global travel.

The maintenance of excitatory and inhibitory balance in the brain is essential for its function. Here we find that the developmental axon guidance receptor Roundabout 2 (Robo2) is critical for the maintenance of inhibitory synapses in the adult ventral tegmental area (VTA), a brain region important for the production of the neurotransmitter dopamine. Following selective genetic inactivation of Robo2 in the adult VTA of mice, reduced inhibitory control results in altered neural activity patterns, enhanced phasic dopamine release, behavioral hyperactivity, associative learning deficits, and a paradoxical inversion of psychostimulant responses. These behavioral phenotypes could be phenocopied by selective inactivation of synaptic transmission from local GABAergic neurons of the VTA, demonstrating an important function for Robo2 in regulating the excitatory and inhibitory balance of the adult brain.

Fear is a graded central motive state ranging from mild to intense. As threat intensity increases, fear transitions from discriminative to generalized. The circuit mechanisms that process threats of different intensity are not well resolved. Here, we isolate a unique population of locally projecting neurons in the central nucleus of the amygdala (CeA) that produce the neuropeptide corticotropin-releasing factor (CRF). CRF-producing neurons and CRF in the CeA are required for discriminative fear, but both are dispensable for generalized fear at high US intensities. Consistent with a role in discriminative fear, CRF neurons undergo plasticity following threat conditioning and selectively respond to threat-predictive cues. We further show that excitability of genetically isolated CRF-receptive (CRFR1) neurons in the CeA is potently enhanced by CRF and that CRFR1 signaling in the CeA is critical for discriminative fear. These findings demonstrate a novel CRF gain-control circuit and show separable pathways for graded fear processing., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Protein Kinase A (PKA) mediates synaptic plasticity and is widely implicated in learning and memory. The hippocampal dentate gyrus (DG) is thought to be responsible for processing and encoding distinct contextual associations in response to highly similar inputs. The mossy fiber (MF) axons of the dentate granule cells convey strong excitatory drive to CA3 pyramidal neurons and express presynaptic, PKA-dependent forms of plasticity. Here, we demonstrate an essential role for the PKA anchoring protein, AKAP7, in mouse MF axons and terminals. Genetic ablation of AKAP7 specifically from dentate granule cells results in disruption of MF-CA3 LTP directly initiated by cAMP, and the AKAP7 mutant mice are selectively deficient in pattern separation behaviors. Our results suggest that the AKAP7/PKA complex in the MF projections plays an essential role in synaptic plasticity and contextual memory formation., Competing Interests: The authors declare that no competing interests exist.

Vaccinations are a cornerstone of the pretravel consultation. The pretravel provider should assess a traveler's past medical history, planned itinerary, activities, mode of travel, and duration of stay and make appropriate vaccine recommendations. Given that domestic vaccine-preventable illnesses are more common in international travelers than are exotic or low-income nation-associated vaccine-preventable illnesses, clinicians should first ensure that travelers are current regarding routine immunizations. Additional immunizations may be indicated in some travelers. Familiarity with geographic distribution and seasonality of infectious diseases is essential. Clinicians should be cognizant of which vaccines are live, as there exist contraindications for live vaccines., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Given the ever-changing nature of travel medicine, practitioners who provide pretravel and posttravel care are obligatorily students for the duration of their professional careers. A large variety of resources are available for medical practitioners. Providers should join at least one travel or tropical medicine professional association, attend its annual meeting, and read its journal. The largest general travel medicine association is the International Society of Travel Medicine., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Familiarity with the distribution, mode of transmission, and risk factors for acquisition of illnesses commonly transmitted to travelers to low-income nations can help guide clinicians in their work-up of an ill returned traveler. The 3 most common categories of illness in returned international travelers are gastrointestinal illness, fever, and dermatoses. Diarrhea is the most common illness reported in returned international travelers. Fever is a marker of a potentially significant illness; work-up of the ill febrile returned traveler should be conducted promptly., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Wideband acoustic immittance (WAI) measures provide information about middle-ear function across the traditional audiometric frequency range from 0.25 to 8.0 kHz. Recent studies have found that WAI is effective in predicting the presence of conductive hearing loss (CHL). It is not known whether WAI can accurately estimate the degree of threshold shift caused by CHL., Purpose: The purpose of the present study was to evaluate the relationship between changes in pure-tone threshold and changes in wideband absorbance and acoustic conductance levels induced by positive and negative ear-canal static pressure., Study Sample: Twenty young adult subjects with normal hearing and a negative history of middle-ear disorders participated in the study., Data Collection and Analysis: Experimental pure-tone thresholds at 0.5 and 2.0 kHz were estimated by using a three-interval, three-alternative forced-choice adaptive psychometric procedure under three conditions: ambient ear-canal pressure, +200 daPa static pressure, and -200 daPa static pressure. Wideband absorbance and conductance were obtained in the same subjects by using a Welch Allyn prototype diagnostic middle ear analyzer. Changes in pure-tone threshold from the ambient pressure condition to the static pressure condition were evaluated by using a paired-samples t test and Pearson product-moment correlation., Results: Wideband middle-ear absorbance and conductance at ambient pressure in this study were consistent with published data in adults with normal hearing. The mean change in threshold at 0.5 and 2.0 kHz with +200 daPa or -200 daPa ear-canal static pressure was similar to the mean change in absorbance and conductance levels in the same conditions. However, there was one statistically significant difference between the shift in pure-tone threshold and the change in conductance level for the +200 daPa pressure condition for 2.0 kHz, with the change in threshold being 1.5 dB greater than the change in conductance level (t = 2.39, p = 0.03). In contrast to the good performance of WAI measures in predicting mean threshold shifts caused by ear-canal pressure, the shifts in WAI were not correlated with threshold shifts. Thus WAI was not well suited to predict individual threshold changes caused by ear-canal static pressure., Conclusions: For the conditions of this study, results suggest that mean change in absorbance or conductance level caused by ear-canal static pressure of +200 daPa or -200 daPa provides a good estimate of the change in pure-tone threshold in the same conditions. However, individual threshold change was not accurately predicted by the change in absorbance or conductance level., (American Academy of Audiology.)

Background: Wideband acoustic immittance (WAI) measurements are a relatively new class of aural acoustic tests that have shown promise as useful tools for evaluating middle-ear status. A growing body of work has described WAI for infants, children, and adults with normal middle-ear function, but a relatively limited number of studies have investigated the influence of specific middle-ear disorders on WAI. Although emerging WAI research data show promising results, additional measurements from ears of patients with a variety of middle-ear disorders are needed., Purpose: The aims of the present study were to (1) obtain WAI data from patients with a variety of middle-ear conditions, (2) examine relationships between WAI data relative to standard audiometric tests, and (3) identify patterns or profiles in WAI data within and among patients with different middle-ear conditions., Research Design: A descriptive study., Study Sample: Participants included 30 children and two adults with a variety of middle-ear disorders who were recruited from clinical audiology settings., Data Collection/analysis: Experimental ambient and tympanometric WAI data were gathered along with standard audiometric test data as part of clinical audiology appointments. Single-subject and small-group data sets for ears of patients with suspected otitis media with effusion (sOME), pressure equalization (PE) tubes, negative tympanometric peak pressure (TPP), tympanoplasty, and cerumen impaction were obtained. Qualitative analysis and descriptive statistics (means and percentiles) were used to characterize the data., Results: Group mean absorbance for ears in the sOME group was reduced across the majority of frequencies; absorbance for ears with negative TPP was also reduced, although to a lesser degree. Absorbance patterns for ears with PE tubes show even greater differences because of the effects of the tube and open middle-ear cavity. WAI from ears with a tympanoplasty and cerumen impaction was suggestive of middle-ear dysfunction in the presence of normal single-frequency tympanometry. Percentile (5th, 50th, and 95th) plots for absorbance and other WAI quantities of admittance level, admittance phase, and equivalent ear-canal volume calculated for the sOME, negative TPP, and PE tube groups showed distinctive profiles that might be useful for discrimination of different middle-ear pathologies. Quantities from wideband tympanometry, including 250- and 1000-Hz single-frequency admittance tympanometric data were also derived., Conclusions: WAI measurements for some middle-ear conditions were consistent with patterns and profiles previously reported in the literature. WAI profiles for other middle-ear conditions, which had not been previously reported in the literature, were presented. Relationships between WAI data and results of standard audiometric tests were generally consistent with expectations. However, in some cases, WAI measurements were suggestive of middle-ear dysfunction despite normal 226-Hz admittance tympanometric findings., (American Academy of Audiology.)

The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Rapid developmental changes of the peripheral auditory system in normal infants occur in the first year of life. Specifically, the postnatal development of the external and middle ear affects all measures of external and middle ear function including wideband acoustic immittance(WAI). This article provides an overview of WAI studies in newborns and infants from a developmental perspective. Normative WAI data in newborns are fairly consistent across studies. However, there are discrepancies in some WAI measures between studies, possibly due to differences in sampling, methodology, and instrumentation. Accuracy of WAI measurements is compromised when a good probe seal cannot be maintained during testing or an inaccurate estimate of the cross-sectional area of the ear canal of newborns occurs. Comparison of WAI data between age groups from 0 to 12 months reveals maturation effects. Additional age-specific longitudinal and cross-sectional normative WAI data for infants from birth to 12 months are required to validate and consolidate existing data.

Middle ear muscle reflex (MEMR) measurements have been a part of the standard clinical immittance test battery for decades as a cross-check with the behavioral audiogram and as a way to separate cochlear from retrocochlear pathologies. MEMR responses are measured in the ear canal by using a probe stimulus (e.g., single frequency or broadband noise) to monitor admittance changes elicited by a reflex-activating stimulus. In the clinical MEMR procedures, one test yields changes in a single measurement (i.e., admittance) at a single pure tone (e.g., 226 or 1000 Hz). In contrast, for the wideband acoustic immittance (WAI) procedure,one test yields information about multiple measurements (e.g., admittance, power reflectance, absorbance) across a wide frequency range (e.g., 250 to 8000 Hz analysis bandwidth of the probe). One benefit of the WAI method is that the MEMR can be identified in a single test regardless of the frequency at which the maximum shift in the immittance measurement occurs; this is beneficial because maximal shifts in immittance vary as a function of age and other factors. Another benefit is that the wideband response analysis yields lower MEMR thresholds than with the clinical procedures. Lower MEMR thresholds would allow for MEMR decay tests in ears in which the activator levels could not be safely presented. Finally, the WAI procedures can be automated with objective identification of the MEMR, which would allow for use in newborn and other screening programs in which the tests are completed by nonaudiological personnel.

As hospitals and healthcare have become specialized, so has nursing. Orthopaedic nurse certification is an example of this specialization. The purpose of this article is to describe the outcomes of one specialty hospital's implemented plan designed to encourage and support nurses seeking to demonstrate expertise in orthopaedic nursing practice. A review course was developed with attention to potential barriers and concerns that were identified in the review of literature. Successful resolution of problems encountered with staff nurses becoming orthopaedic nurse certified are described. Participants in the first 2 sessions passed the examination on the first attempt at a rate of 100% and 88%, which exceeds the national rate of 86.5% (Orthopaedic Nurse Certification Board, 2011, retrieved from http://oncb.org/certification-statistics). Since initiation of the program, the number of "orthopaedic nurse certification" nurses has nearly tripled in this orthopaedic specialty hospital.

Wideband acoustic immittance (WAI) measures have potential capability to improve newborn hearing screening outcomes and middle ear diagnosis for infants and children. To fully capitalize on these immittance measures for pediatric hearing care, developmental and pathologic effects need to be fully understood. Published literature on wideband immittance (reflectance, absorbance, tympanometry, and acoustic reflexes) is reviewed in this article to determine pathologic effects in newborns, infants, and children relative to standard audiologic tests such as otoacoustic emissions (OAEs), standard tympanometry, air and bone conduction auditory brainstem response, and otoscopy. Infants and children with surgically confirmed otitis media with effusion have lower absorbance in the mid-frequency range (1 to 3 kHz) for the affected ear(s). Newborns that do not pass OAE screening at birth also have lower absorbance for frequencies from 1 to 3 kHz, suggesting that nonpass results are frequently associated with middle ear issues at birth. In Newborn Hearing Screening Programs, WAI may help to interpret hearing screening results. Conclusions are limited by the fact that the true status of the middle ear and cochlea are not known for newborns and infants in studies that use OAE or tympanometry as the reference standard. Likelihood ratios for reflectance against surgery gold standards range from diagnostically suggestive to informative. Although some of the results are promising, limited evidence and methodological considerations restrict the conclusions that can be drawn regarding the diagnostic accuracy of WAI technologies in infants and children. Additional investigations using stronger gold standard comparisons are needed to determine which tools can most accurately predict middle ear status in the pediatric population.

Wideband tympanometry (WT) measurements provide a view of the acoustic response properties of the middle ear over a broad range of frequencies and ear-canal pressures. These measurements show sensitivity to trends in ear-canal/middle ear maturation and changes in middle ear status as a result of different types of dysfunction. While results from early WT work showed improvements over ambient wideband tests in terms of test performance for identifying middle ear dysfunction and conductive hearing loss (CHL), more recent studies have shown high, but similar test performance for both ambient and tympanometric wideband tests. Case study and group results presented in this article, demonstrating the sensitivity of WT to middle ear dysfunction, CHL, and maturational changes in the middle ear, are promising and suggest the need for additional investigations in individual subjects and large subject populations. Future research should focus on identifying key predictors of developmental trends, middle ear dysfunction, and CHL in an effort to develop middle ear tests with high sensitivity and specificity. Technological advances, more accessibility to equipment, and evolving data analysis techniques should encourage progress in the areas of WT research and clinical application.

The participants in the Eriksholm Workshop on Wideband Absorbance Measures of the Middle Ear developed statements for this consensus article on the final morning of the Workshop. The presentations of the first 2 days of the Workshop motivated the discussion on that day. The article is divided into three general areas: terminology; research needs; and clinical application. The varied terminology in the area was seen as potentially confusing, and there was consensus on adopting an organizational structure that grouped the family of measures into the term wideband acoustic immittance (WAI), and dropped the term transmittance in favor of absorbance. There is clearly still a need to conduct research on WAI measurements. Several areas of research were emphasized, including the establishment of a greater WAI normative database, especially developmental norms, and more data on a variety of disorders; increased research on the temporal aspects of WAI; and methods to ensure the validity of test data. The area of clinical application will require training of clinicians in WAI technology. The clinical implementation of WAI would be facilitated by developing feature detectors for various pathologies that, for example, might combine data across ear-canal pressures or probe frequencies.

Dopamine is highly implicated both as a teaching signal in reinforcement learning and in motivating actions to obtain rewards. However, theoretical disconnects remain between the temporal encoding properties of dopamine neurons and the behavioral consequences of its release. Here, we demonstrate in rats that dopamine evoked by Pavlovian cues increases during acquisition, but dissociates from stable conditioned appetitive behavior as this signal returns to preconditioning levels with extended training. Experimental manipulation of the statistical parameters of the behavioral paradigm revealed that this attenuation of cue-evoked dopamine release during the postasymptotic period was attributable to acquired knowledge of the temporal structure of the task. In parallel, conditioned behavior became less dopamine dependent after extended training. Thus, the current work demonstrates that as the presentation of reward-predictive stimuli becomes anticipated through the acquisition of task information, there is a shift in the neurobiological substrates that mediate the motivational properties of these incentive stimuli.

The interplay between redox-active transition metal ions and redox-active ligands in metalloenzyme sites is an area of considerable research interest. Galactose oxidase (GO) is the archetypical example, catalyzing the aerobic oxidation of primary alcohols to aldehydes via two one-electron cofactors: a copper atom and a cysteine-modified tyrosine residue. The electronic structure of the oxidized form of the enzyme (GO(ox)) has been investigated extensively through small molecule analogues including metal-salen phenoxyl radical complexes. Similar to GO(ox), one-electron oxidized metal-salen complexes are mixed-valent species, in which molecular orbitals (MOs) with predominantly phenolate and phenoxyl π-character act as redox-active centers bridged by mixing with metal d-orbitals. A detailed evaluation of the electronic distribution in these odd electron species using a variety of spectroscopic, electrochemical, and theoretical techniques has led to keen insights into the electronic structure of GO(ox).

Objective: This study tested the hypothesis that wideband aural absorbance predicts conductive hearing loss (CHL) in children medically classified as having otitis media with effusion., Design: Absorbance was measured in the ear canal over frequencies from 0.25 to 8 kHz at ambient pressure or as a swept tympanogram. CHL was defined using criterion air-bone gaps of 20, 25, and 30 dB at octaves from 0.25 to 4 kHz. A likelihood-ratio predictor of CHL was constructed across frequency for ambient absorbance, and across frequency and pressure for absorbance tympanometry. Performance was evaluated at individual frequencies and for any frequency at which a CHL was present., Study Sample: Absorbance and conventional 0.226-kHz tympanograms were measured in children of age three to eight years with CHL and with normal hearing., Results: Absorbance was smaller at frequencies above 0.7 kHz in the CHL group than the control group. Based on the area under the receiver operating characteristic curve, wideband absorbance in ambient and tympanometric tests were significantly better predictors of CHL than tympanometric width, the best 0.226-kHz predictor. Accuracies of ambient and tympanometric wideband absorbance did not differ., Conclusions: Absorbance accurately predicted CHL in children and was more accurate than conventional 0.226-kHz tympanometry.

Purpose: To conduct an evidence-based systematic review on the state of the evidence and the diagnostic accuracy of multifrequency tympanometry (MFT), 1000 Hz tympanometry, and wideband acoustic transfer functions in determining the presence or absence of middle ear disorders., Method: A systematic search of the literature published between 1975 and 2011 was conducted. Articles meeting the selection criteria were appraised by 2 reviewers and vetted by a 3rd for methodological quality., Results: Ten studies were included and focused on participants with otosclerosis or otitis media. Two studies investigated 1000 Hz tympanometry, 7 examined MFT, and 2 addressed wideband reflectance (WBR). Methodological quality varied. Positive likelihood ratios (LR+) were predominantly uninformative for MFT and were mixed for 1000 Hz tympanometry. LR+ values for WBR ranged from diagnostically suggestive to informative. Negative likelihood ratios (LR-) for 1000 Hz tympanometry and WBR were at least diagnostically suggestive. LR- values for MFT were mixed, with half considered clinically uninformative and half considered diagnostically suggestive., Conclusions: Although some of the results are promising, limited evidence and methodological considerations restrict the conclusions that can be drawn regarding the diagnostic accuracy of these technologies. Additional investigations are needed to determine which tools can most accurately predict middle ear status.

Objectives/hypothesis: Compare the accuracy of wideband acoustic transfer functions (WATFs) measured in the ear canal at ambient pressure to methods currently recommended by clinical guidelines for predicting middle-ear effusion (MEE)., Study Design: Cross-sectional validating diagnostic study among young children with and without MEE to investigate the ability of WATFs to predict MEE., Methods: WATF measures were obtained in an MEE group of 44 children (53 ears; median age, 1.3 years) scheduled for middle-ear ventilation tube placement and a normal age-matched control group of 44 children (59 ears; median age, 1.2 years) with normal pneumatic otoscopic findings and no history of ear disease or middle-ear surgery. An otolaryngologist judged whether MEE was present or absent and rated tympanic-membrane (TM) mobility via pneumatic otoscopy. A likelihood-ratio classifier reduced WATF data (absorbance, admittance magnitude and phase) from 0.25 to 8 kHz to a single predictor of MEE status. Absorbance was compared to pneumatic otoscopy classifications of TM mobility., Results: Absorbance was reduced in ears with MEE compared to ears from the control group. Absorbance and admittance magnitude were the best single WATF predictors of MEE, but a predictor combining absorbance, admittance magnitude, and phase was the most accurate. Absorbance varied systematically with TM mobility based on data from pneumatic otoscopy., Conclusions: Results showed that absorbance is sensitive to middle-ear stiffness and MEE, and WATF predictions of MEE in young children are as accurate as those reported for methods recommended by the clinical guidelines., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

We report the formation of solid-state nanopores using a scanning helium ion microscope. The fabrication process offers the advantage of high sample throughput along with fine control over nanopore dimensions, producing single pores with diameters below 4 nm. Electronic noise associated with ion transport through the resultant pores is found to be comparable with levels measured on devices made with the established technique of transmission electron microscope milling. We demonstrate the utility of our nanopores for biomolecular analysis by measuring the passage of double-strand DNA.

A 25 keV focused helium ion beam has been used to grow PtC nanopillars on a silicon substrate by beam-induced decomposition of a (CH(3))(3)Pt(C(P)CH(3)) precursor gas. The ion beam diameter was about 1 nm. The observed relatively high growth rates suggest that electronic excitation is the dominant mechanism in helium ion-beam-induced deposition. Pillars grown at low beam currents are narrow and have sharp tips. For a constant dose, the pillar height decreases with increasing current, pointing to depletion of precursor molecules at the beam impact site. Furthermore, the diameter increases rapidly and the total pillar volume decreases slowly with increasing current. Monte Carlo simulations have been performed with realistic values for the fundamental deposition processes. The simulation results are in good agreement with experimental observations. In particular, they reproduce the current dependences of the vertical and lateral growth rates and of the volumetric deposition efficiency. Furthermore, the simulations reveal that the vertical pillar growth is due to type-1 secondary electrons and primary ions, while the lateral outgrowth is due to type-2 secondary electrons and scattered ions.

A wideband (WB) aural acoustical test battery of middle-ear status, including acoustic-reflex thresholds (ARTs) and acoustic-transfer functions (ATFs, i.e., absorbance and admittance) was hypothesized to be more accurate than 1-kHz tympanometry in classifying ears that pass or refer on a newborn hearing screening (NHS) protocol based on otoacoustic emissions. Assessment of middle-ear status may improve NHS programs by identifying conductive dysfunction and cases in which auditory neuropathy exists. Ipsilateral ARTs were assessed with a stimulus including four broadband-noise or tonal activator pulses alternating with five clicks presented before, between and after the pulses. The reflex shift was defined as the difference between final and initial click responses. ARTs were measured using maximum likelihood both at low frequencies (0.8-2.8 kHz) and high (2.8-8 kHz). The median low-frequency ART was elevated by 24 dB in NHS refers compared to passes. An optimal combination of ATF and ART tests performed better than either test alone in predicting NHS outcomes, and WB tests performed better than 1-kHz tympanometry. Medial olivocochlear efferent shifts in cochlear function may influence ARs, but their presence would also be consistent with normal conductive function. Baseline clinical and WB ARTs were also compared in ipsilateral and contralateral measurements in adults., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Von Hippel-Lindau (VHL) inactivation develops a tumor syndrome characterized by highly vascularized tumors as a result of hypoxia inducible factors (HIF) stabilization. The most common manifestation is the development of hemangioblastomas typically located in the central nervous system and other organs including the liver. PTEN (Phosphatase and tension homologue deleted on chromosome 10) inactivation also upregulates HIF-1alpha and may take part in promoting vascular lesions in tumors. The coordinate effect of loss of these tumor suppressors on HIF levels, and the subsequent effect on vascular lesion formation would elucidate the potential for mechanisms to modify HIF dosage supplementally and impact tumor phenotype. We therefore employed models of somatic conditional inactivation of Vhl, Pten, or both tumor suppressor genes in individual cells of the liver by Cre-loxP recombination to study the cooperativity of these two tumor suppressors in preventing tumor formation. Nine months after tumor suppressor inactivation, Vhl conditional deletion (Vhl (loxP/loxP)) mice showed no abnormalities, Pten conditional deletion (Pten (loxP/loxP)) mice developed liver steatosis and focal nodular expansion of hepatocytes containing lipid droplet and fat. Vhl and Pten conditional deletion (Vhl (loxP/loxP);Pten (loxP/loxP)) mice, however, developed multiple cavernous liver lesions reminiscent of hemangioblastoma. Liver hemangioblastomas in VHL disease may, therefore, require secondary mutation in addition to VHL loss of heterozygosity which is permissive for vascular lesion development or augments levels of HIF-1alpha.

Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-alpha regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl(2B/2B)) displayed preserved physiological regulation of both HIF factors with slightly greater normoxic dysregulation of HIF-2alpha. Differentiated Vhl(2B/2B)-derived teratomas overexpressed joint HIF targets Vegf and EglN3 but not the HIF-1alpha-specific target Pfk1. Vhl(2B/2B) teratomas additionally displayed a growth advantage over Vhl(-/-)-derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1alpha and HIF-2alpha stabilization and cell growth. Vhl(2B/2B) mice displayed mid-gestational embryonic lethality, whereas adult Vhl(2B/+) mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at 12 months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development and tumor predisposition.

A system with potential for middle-ear screening and diagnostic testing was developed for the measurement of wideband energy absorbance (EA) in the ear canal as a function of air pressure, and tested on adults with normal hearing. Using a click stimulus, the EA was measured at 60 frequencies between 0.226 and 8 kHz. Ambient-pressure results were similar to past studies. To perform tympanometry, air pressure in the ear canal was controlled automatically to sweep between -300 and 200 daPa (ascending/descending directions) using sweep speeds of approximately 75, 100, 200, and 400 daPas. Thus, the measurement time for wideband tympanometry ranged from 1.5 to 7 s and was suitable for clinical applications. A bandpass tympanogram, calculated for each ear by frequency averaging EA from 0.38 to 2 kHz, had a single-peak shape; however, its tympanometric peak pressure (TPP) shifted as a function of sweep speed and direction. EA estimated at the TPP was similar across different sweep speeds, but was higher below 2 kHz than EA measured at ambient pressure. Future studies of EA on normal ears of a different age group or on impaired ears may be compared with the adult normal baseline obtained in this study.

Wideband acoustic transfer function (ATF) measurements of energy reflectance (ER) and admittance magnitude (|Y|) were obtained at varying static ear-canal pressures in 4-, 12-, and 27-week-old infants and young adults. Developmental changes in wideband ATF measurements varied as a function of frequency. For frequencies from 0.25 to 0.75 kHz there was as much as a 30% change in mean ER and mid |Y| with changes in static ear-canal pressure between 4 and 24 weeks of age. From 0.75 to 2 kHz, the effects of pressure produced a small number of significant differences in ER and mid |Y| with age, suggestive of a developmentally stable frequency range. Between 2 and 6 kHz, there were differential effects of pressure for the youngest infants; negative pressures caused increased ER and mid |Y| and positive pressures caused decreased ER and mid |Y|; the magnitude of this effect decreased with age. Findings from this study demonstrate developmental differences in wideband tympanometric ATF measurements in 4-, 12- and 24-week-old infants and provide additional insight on the effects of static ear-canal pressure in the young infant's ear. The maturational effects shown in the experimental data are discussed in light of known age-related anatomical changes in the developing outer and middle ear.

Introduction: Pulmonary embolus (PE) is a potentially devastating and fatal postoperative complication in morbidly obese patients. This study was undertaken to review the safety and efficacy of retrievable prophylactic inferior vena cava (IVC) filters in high-risk morbidly obese patients undergoing gastric bypass., Methods: Patients who underwent gastric bypass surgery and preoperative insertion of retrievable IVC filters had their records reviewed. Indications for IVC filter insertion were: history of deep venous thrombosis (DVT) or PE, long-standing sleep apnea, venous stasis disease, and/or weight > 400 pounds., Results: 24 patients underwent IVC filter placement before gastric bypass surgery. There were 10 women and 14 men with an average age of 50 +/- 6.3 years (range 39 to 59) and average body mass index (BMI) of 57 +/- 7.5 kg/m(2) (range 49 to 74). BMI greater then 50 kg/m(2) was present in 21 of 24 patients (88%). All patients had successful IVC filter placement. IVC filter retrieval postoperatively was performed in 20 of 24 patients (83%) with three left for clinical reasons and one (4%) left due to technical inability to retrieve. There was one complication directly attributable to IVC filter retrieval. There were no deaths. Five patients (21%) developed DVT or PE postoperatively. Follow-up was 16 +/- 7.6 months (range 8 to 33)., Conclusions: Prophylactic IVC filter placement and retrieval can be safely undertaken in high-risk gastric bypass patients. We recommend preoperative IVC filter placement in selected patients.

Studies that have examined age effects in the human middle ear using either admittance measures at 220 or 660 Hz or multifrequency tympanometry from 200 to 2000 Hz have had conflicting results. Several studies have suggested an increase in admittance with age, while several others have suggested a decrease in admittance with age. A third group of studies found no significant age effect. This study examined 226 Hz tympanometry and wideband energy reflectance and impedance at ambient pressure in a group of 40 young adults and a group of 30 adults with age > or = 60 years. The groups did not differ in admittance measures of the middle ear at 226 Hz. However, significant age effects were found in wideband energy reflectance and impedance. In particular, in older adults there was a comparative decrease in reflectance from 800 to 2000 Hz but an increase near 4000 Hz. The results suggest a decrease in middle-ear stiffness with age. The findings of this study hold relevance for understanding the aging process in the auditory system, for the establishment of normative data for wideband energy reflectance, for the possibility of a conductive component to presbycusis, and for the interpretation of otoacoustic emission measurements.

Human leukocyte antigens (HLA) in patients with Graves' disease were investigated according to the ophthalmic classification system of the American Thyroid Association. All prior HLA studies of Graves' disease have disregarded the patients' specific ophthalmic manifestations. Examination of 18 A and 34 B loci antigens disclosed an increased frequency (corrected P = 0.002, relative risk = 13.1) of HLA-BW35 in patients improving with oral corticosteroids who have severe extraocular muscle and orbital inflammation (class 4-5) when compared to a geographically and racially matched control population. No statistically significant associations were found when patients without ophthalmic manifestations or with other categories of Graves' ophthalmopathy were compared to controls. The association of severe Graves' ophthalmopathy with HLA-BW35 may provide immunologic evidence to explain both the unpredictable association of the orbital and thyroid disturbances of Graves' disease as well as the unpredictable response of the orbital inflammation to oral corticosteroids.