ABSTRACT
BACKGROUND: In 2000, a landmark study showed that women who graduated from U.S. medical schools from 1979 through 1997 were less likely than their male counterparts to be promoted to upper faculty ranks in academic medical centers. It is unclear whether these differences persist. METHODS: We merged data from the Association of American Medical Colleges on all medical school graduates from 1979 through 2013 with faculty data through 2018, and we compared the percentages of women who would be expected to be promoted on the basis of the proportion of women in the graduating class with the actual percentages of women who were promoted. We calculated Kaplan-Meier curves and used adjusted Cox proportional-hazards models to examine the differences between the early cohorts (1979-1997) and the late cohorts (1998-2013). RESULTS: The sample included 559,098 graduates from 134 U.S. medical schools. In most of the cohorts, fewer women than expected were promoted to the rank of associate or full professor or appointed to the post of department chair. Findings were similar across basic science and clinical departments. In analyses that included all the cohorts, after adjustment for graduation year, race or ethnic group, and department type, women assistant professors were less likely than their male counterparts to be promoted to associate professor (hazard ratio, 0.76; 95% confidence interval [CI], 0.74 to 0.78). Similar sex disparities existed in promotions to full professor (hazard ratio, 0.77; 95% CI, 0.74 to 0.81) and appointments to department chair (hazard ratio, 0.46; 95% CI, 0.39 to 0.54). These sex differences in promotions and appointments did not diminish over time and were not smaller in the later cohorts than in the earlier cohorts. The sex differences were even larger in the later cohorts with respect to promotion to full professor. CONCLUSIONS: Over a 35-year period, women physicians in academic medical centers were less likely than men to be promoted to the rank of associate or full professor or to be appointed to department chair, and there was no apparent narrowing in the gap over time. (Funded by the University of Kansas Medical Center Joy McCann Professorship for Women in Medicine and the American Association of University Women.).
Subject(s)
Career Mobility , Faculty, Medical , Physicians, Women , Academic Medical Centers , Female , Humans , Kaplan-Meier Estimate , Male , Proportional Hazards Models , Schools, Medical , Sex Factors , Sexism/statistics & numerical data , Sexual Harassment/statistics & numerical data , United States , Work-Life BalanceABSTRACT
Sound damage induced hearing loss has been shown to elicit changes in auditory and non-auditory brain regions. A protein critical for neuronal migration and brain development, doublecortin (DCX), has been used as a marker of central nervous system (CNS) neuroplasticity. DCX is expressed in unipolar brush cells (UBCs) of the dorsal cochlear nucleus (DCN), cerebellar parafloccular lobe (PFL) and neuronal precursor cells in the sub-granular zone of the hippocampal dentate gyrus (DG). Sound damage induced hearing loss has been shown to differentially impact DCX expression months later. To identify earlier alterations in DCX expression, we utilized immunohistochemistry to detect DCX protein in three brain regions (DCN, PFL, DG) approximately one month following unilateral sound damage. Auditory brainstem response was used to measure hearing loss. Unilateral hearing loss was evident in all sound damaged animals. Hearing loss related decreases in DCX expression were evident bilaterally in the DG while hearing loss related increases in DCX expression were evident bilaterally in the PFL. No changes to DCX expression were evident in the auditory DCN. Gap detection was used to assess whether this sound damage paradigm induced tinnitus-like behavior. However, results obtained from this behavioral test as used here were inconclusive and are presented here only as a guide to others wishing to design similar studies.
ABSTRACT
IMPORTANCE: Composite grafting in nasal reconstruction involves transplanting auricular chondrocutaneous grafts, but the optimal design of these grafts is unknown. OBJECTIVES: To investigate the ideal ratio of skin to cartilage as well as study the importance of the perichondrial attachment for graft survival. DESIGN, SETTING, AND PARTICIPANTS: A New England white rabbit model was used in this study, performed at the Laboratory for Animal Research at University of Kansas Medical Center from January 25 to March 18, 2016. Four varying designs of chondrocutaneous auricular grafts were transplanted to dorsal back defects, with a total of 10 grafts per treatment arm completed. The following 4 chondrocutaneous circular grafts were designed: group A, 1.5-cm diameter graft of equal skin to cartilage ratio; group B, 2.0-cm diameter skin and 1.5-cm diameter cartilage; group C, 1.5-cm diameter skin and 2.0-cm diameter cartilage; and group D, 1.5-cm diameter skin and cartilage separated and placed back together in a layered fashion. Grafts were observed until postoperative day 21, harvested, and evaluated with visual observation as well as histopathologic assessment. MAIN OUTCOMES AND MEASURES: Visually graded areas of survival were marked by 2 blinded academic facial plastic surgeons and calculated for approximate survival. Hematoxylin-eosin-stained, paraffin-embedded 5-µm slides were evaluated for overall survival rate, rate of cartilage necrosis, and mean vessel density per high-power field. In both cases, observers were blinded as to the study group. RESULTS: Visual assessments of the 5 female rabbits showed significant agreement between surgeons and consistency, with a Spearman coefficient of 0.84 and an intraclass correlation of 0.98. Group D (skin and cartilage separation) was visually graded to have significantly decreased mean survival (45.4%; 95% CI, 23.3%-67.4%) compared with group A (mean survival, 97.4%; 95% CI, 94.8%-99.9%; P < .001), group B (mean survival, 87.6%; 95% CI, 69.9%-100%; P = .004), and group C (mean survival, 82.1%; 95% CI, 66.0%-98.1%; P = .008). Histopathologic assessment revealed that group D again showed significantly inferior overall survival, increased cartilage necrosis, and decreased mean vessel density compared with group A. Group C additionally showed significantly decreased cartilage survival compared with group A (65% vs 0%; P < .001) and group B (65% vs 35%; P = .02). CONCLUSIONS AND RELEVANCE: These results represent preliminary evidence that the attachment of skin to perichondrium in a composite graft plays an important role for graft survival. Clinicians performing nasal reconstruction with chondrocutaneous composite grafts should consider preserving attachments at this junction to improve graft survival. LEVELS OF EVIDENCE: NA.
Subject(s)
Ear Cartilage/transplantation , Graft Survival , Nose/surgery , Skin Transplantation/methods , Wound Healing , Animals , Female , Models, Animal , RabbitsABSTRACT
Methionine sulfoxide reductases (MsrA and MsrB) protect the biological activity of proteins from oxidative modifications to methionine residues and are important for protecting against the pathological effects of neurodegenerative diseases. In the current study, we characterized the auditory phenotype of the MsrA knockout mouse. Young MsrA knockout mice showed small high-frequency threshold elevations for auditory brainstem response and distortion product otoacoustic emission compared to those of wild-type mice, which progressively worsened in older MsrA knockout mice. MsrA knockout mice showed an increased sensitivity to noise at young and older ages, suggesting that MsrA is part of a mechanism that protects the cochlea from acoustic damage. MsrA mRNA in the cochlea was increased following acoustic stimulation. Finally, expression of mRNA MsrB1 was compromised at 6 months old, but not in younger MsrA knockout mice (compared to controls). The identification of MsrA in the cochlea as a protective mediator from both early onset hearing loss and acoustic trauma expands our understanding of the pathways that may induce protection from acoustic trauma and foster further studies on how to prevent the damaging effect of noise exposure through Msr-based therapy.
Subject(s)
Auditory Threshold/physiology , Evoked Potentials, Auditory, Brain Stem/physiology , Hearing Loss/genetics , Methionine Sulfoxide Reductases/genetics , Acoustic Stimulation , Animals , Mice , Mice, KnockoutABSTRACT
PURPOSE: To assess post-tenure review policies at U.S. medical schools by examining how prevalent post-tenure review is, what models of post-tenure review are employed, and what outcomes result from post-tenure review processes. METHOD: In late 2014, a Web-based survey was sent to the associate dean for faculty affairs (or equivalent) at each U.S. medical school accredited by the Liaison Committee on Medical Education (N = 141). The survey addressed elements of post-tenure review policies, including whether a policy was in place, the frequency of the review, and the review outcomes. Descriptive statistics were calculated. RESULTS: Of the 94 responding schools with a tenure system, 39 (41%) had an established post-tenure review policy. Although these policies showed great variability across schools in duration, having been in place from 1 to 50 years, 12 (31%) were established within the last 5 years. The outcomes of post-tenure review also varied. Superior performance ratings generally resulted in notations in the faculty member's personnel file and notifications to school leadership. Conversely, when a faculty member received an unsatisfactory rating, a remediation or development plan was sometimes required. CONCLUSIONS: At least 40% of medical schools with a tenure system have post-tenure review, and it is becoming more common. These findings about the prevalence and use of post-tenure review across institutions can assist medical school leaders as they strive to shape policies to facilitate faculty engagement and productivity. They also can provide the foundation for future evaluative studies on the effectiveness, outcomes, and impact of post-tenure review.
Subject(s)
Efficiency, Organizational/standards , Faculty, Medical/standards , Internet , Organizational Policy , Schools, Medical/organization & administration , Humans , Surveys and Questionnaires , United StatesABSTRACT
CONTEXT: Although the liver is the primary target organ in acetaminophen (APAP) toxicity, other organs are affected. Previous data suggested that chronic APAP abuse can be ototoxic and the mechanism involves APAP-induced oxidative stress and reactive metabolite (N-acetyl-p-benzoquinone imine, NAPQI)-induced endoplasmic reticulum stress. However, the effect of a single acute overdose on hearing has not been tested. OBJECTIVES: To determine if a single acute APAP overdose causes hearing damage, and to explore possible mechanisms of APAP ototoxicity. MATERIALS AND METHODS: Male C57BL/6 J mice were treated with a single human-relevant overdose of APAP (300 mg APAP per kg bodyweight). Blood, liver and cochleae were harvested at 0, 2, 6 and 24 h post-APAP. In some mice, auditory brainstem responses (ABRs) to a range of frequencies were measured at 24 h. The furosemide plus kanamycin (FS/K) model of drug ototoxicity was used as a positive control for hearing loss. NAPQI formation after APAP was assessed by measuring glutathione depletion and covalent protein binding, and oxidative stress was assessed by measuring glutathione disulfide. RESULTS: There was no evidence of reactive metabolite formation or hearing loss after a single overdose of APAP at a clinically relevant dose. However, there was a transient increase in oxidative stress. DISCUSSION: Although a single acute overdose was not ototoxic, there was evidence of oxidative stress which may support a role for oxidative stress in hearing loss due to chronic APAP abuse. CONCLUSION: A single human-relevant acute overdose of APAP causes transient oxidative stress in cochleae but not hearing loss.
Subject(s)
Acetaminophen/toxicity , Chemical and Drug Induced Liver Injury , Cochlea/drug effects , Drug Overdose , Hearing/drug effects , Oxidative Stress/drug effects , Acetaminophen/administration & dosage , Acetaminophen/metabolism , Alanine Transaminase/blood , Animals , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/physiopathology , Cochlea/metabolism , Drug Overdose/metabolism , Drug Overdose/physiopathology , Glutathione Disulfide/blood , Male , Mice, Inbred C57BL , Protein BindingABSTRACT
Exposure to intense sound can damage or kill cochlear hair cells (HC). This loss of input typically manifests as noise induced hearing loss, but it can also be involved in the initiation of other auditory disorders such as tinnitus or hyperacusis. In this study we quantify changes in HC number following exposure to one of four sound damage paradigms. We exposed adult, anesthetized Long-Evans rats to a unilateral 16 kHz pure tone that varied in intensity (114 dB or 118 dB) and duration (1, 2, or 4 h) and sacrificed animals 2-4 weeks later. We compared two different methods of tissue preparation, plastic embedding/sectioning and whole mount dissection, for quantifying hair cell loss as a function of frequency. We found that the two methods of tissue preparation produced largely comparable cochleograms, with whole mount dissections allowing a more rapid evaluation of hair cell number. Both inner and outer hair cell loss was observed throughout the length of the cochlea irrespective of sound damage paradigm. Inner HC loss was either equal to or greater than outer HC loss. Increasing the duration of sound exposures resulted in more severe HC loss, which included all HC lesions observed in an analogous shorter duration exposure.
Subject(s)
Cochlea/physiopathology , Hair Cells, Auditory/pathology , Hearing Loss, Noise-Induced/physiopathology , Sound , Animals , Auditory Threshold , Hair Cells, Auditory, Inner/pathology , Hair Cells, Auditory, Outer/pathology , Male , Noise , Plastics , Rats , Rats, Long-Evans , Reproducibility of Results , Tissue Preservation/methodsABSTRACT
IMPORTANCE: Treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) uses a multidisciplinary approach often limited by the toxicity and drug resistance of platinum agents. OBJECTIVES: To test whether a nanocarrier-conjugated cisplatin boosting locoregional drug delivery improves tumor efficacy while decreasing systemic toxicity over systemic cisplatin in a murine model of locally advanced HNSCC. DESIGN: A randomized, controlled, in vivo study compared standard cisplatin with nanocarrier (hyaluronan [HA])-conjugated cisplatin (HA-cisplatin) each at 50% of the maximum tolerated doses in a murine model of locally advanced HNSCC (10 mice/arm, each injected with 1 × 106 MDA-1986 HNSCC cells, with phosphate-buffered saline and HA-only control arms). Mice were treated for 3 weeks and observed for 3 additional weeks. SETTING: Academic medical center. PARTICIPANTS: Forty female Nu/Nu mice. Randomization and treatment arms were initiated once tumor volumes reached 30 mm3. INTERVENTION: Injection with MDA-1986 HNSCC cells followed by 3 weeks of treatment with cisplatin, HA-cisplatin, phosphate-buffered saline, or HA only. MAIN OUTCOMES AND MEASURES: Animal weights and tumor volumes were measured 3 times each week (modified RECIST [Response Evaluation Criteria in Solid Tumors]). At necropsy, animal kidneys were examined for nephrotoxic effects and cochleae were examined for ototoxic effects. RESULTS: The mice treated with HA-cisplatin showed superior tumor efficacy (1 with complete clinical response, 3 with partial response, 1 with stable disease, and 5 with progressive disease) compared with standard cisplatin (no animals with complete clinical response, 1 with partial response, 1 with stable disease, and 8 with progressive disease), which was statistically significant (P = .003). All control animals developed progressive disease. Weight loss and body score were surrogate measures of treatment toxicity. The HA-cisplatin group had the least weight loss (mean [SD], 10.8% [4.7%]) compared with the cisplatin group (13.6% [5.6%]; P = .25). Body score dropped to 2 or less in all cisplatin-treated mice but not in any HA-cisplatin-treated mice, which also lacked any histologic signs of nephrotoxic or ototoxic effects. CONCLUSIONS AND RELEVANCE: Nanoconjugated HA-cisplatin significantly improves tumor efficacy with lower toxicity compared with standard cisplatin in locally advanced HNSCC in vivo, justifying additional translational studies.
Subject(s)
Carcinoma, Squamous Cell/drug therapy , Cisplatin/administration & dosage , Head and Neck Neoplasms/drug therapy , Neoplasms, Experimental , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Cisplatin/toxicity , Dose-Response Relationship, Drug , Drug Delivery Systems , Female , Maximum Tolerated Dose , Mice , Mice, Nude , Squamous Cell Carcinoma of Head and Neck , Treatment Outcome , Tumor BurdenABSTRACT
This article presents a unique approach for the delivery of gene therapy vectors into the cochlea of the laboratory rat. Mice and guinea pigs are established in vivo models for cochlear gene therapy each of which has distinct advantages and disadvantages. The rat has some of the molecular advantages of a mouse model combined with size advantages for surgical approaches. Vector delivery via cochleostomy or injection through the round window causes concomitant sensorineural hearing loss and is therefore not suitable for studies where the change in hearing is being followed. Compared to the mouse, the rat does not demonstrate easily recognizable landmarks that allow for use of the semicircular canal as an approach to the inner ear. We analyzed sagittal and coronal temporal bone sections of Long Evans rats and identified the bony entrance of the facial nerve as a crucial landmark for canalostomy. Auditory brainstem response and distortion product otoacustic emission measurements revealed minimal differences in the hearing threshold after adenovirus vector application when large volumes of vector were infused to the inner ear. Canalostomy and infusion of adenoviral vectors also resulted in temporary balance disturbance in the rat. Immunohistochemical assessment after delivery of a green fluorescent protein expressing vector showed significant GFP expression in the cochlea.
Subject(s)
Cochlea/metabolism , Evoked Potentials, Auditory, Brain Stem , Genetic Therapy , Genetic Vectors , Hearing Loss/prevention & control , Round Window, Ear/metabolism , Temporal Bone/metabolism , Animals , Cochlea/surgery , Facial Nerve/anatomy & histology , Facial Nerve/metabolism , Facial Nerve/surgery , Green Fluorescent Proteins/metabolism , Hearing Loss/genetics , Immunoenzyme Techniques , Male , Mice , Rats , Rats, Long-Evans , Round Window, Ear/anatomy & histology , Round Window, Ear/surgery , Temporal Bone/anatomy & histology , Temporal Bone/surgeryABSTRACT
BACKGROUND: Neurons rely exclusively on mitochondrial oxidative phosphorylation to meet cellular energy demands, and disruption of mitochondrial function often precipitates neuronal cell death. Auditory neurons in the chick brain stem (n. magnocellularis [NM]) receive glutamatergic innervation exclusively from ipsilateral eighth nerve afferents. Cochlea removal permanently disrupts afferent support and ultimately triggers apoptotic cell death in 30-50% of ipsilateral, deafferented neurons. Here, we evaluated whether disruption of mitochondrial function occurs during deafferentation-induced neuronal cell death. PURPOSE: To determine whether mitochondrial dysfunction occurs preferentially within dying NM neurons. RESEARCH DESIGN: An experimental study. All birds underwent unilateral cochlea removal. Normally innervated neurons contralateral to surgery served as within-animal controls. STUDY SAMPLE: Hatchling broiler chickens between 8 and 12 days of age served as subjects. A total of 62 birds were included in the study. INTERVENTION: Cochlea removal was performed to deafferent ipsilateral NM neurons and trigger neuronal cell death. DATA COLLECTION AND ANALYSIS: Following unilateral cochlea removal, birds were sacrificed 12, 24, 48, or 168 hours later, and brain tissue was harvested. Brainstems were sectioned through NM and evaluated histochemically for oxidative enzyme reaction product accumulation or reacted for Mitotracker Red, an indicator of mitochondrial membrane potential (m) and cytoplasmic TdT-mediated dUTP Nick-End Labeling (TUNEL), an indicator of cell death. Histochemical staining intensities for three mitochondrial enzymes, succinate dehydrogenase (SDH), cytochrome c oxidase (CO), and ATP synthase (ATPase) were measured in individual neurons and compared in ipsilateral and contralateral NM. Comparisons were made using unpaired t-tests (CO) or Kruskal Wallis one way ANOVA followed by Dunn's post hoc pairwise comparisons (ATPase, SDH). Mitotracker Red tissue was examined qualitatively for the presence of and extent of colocalization between Mitotracker Red and TUNEL label in NM. RESULTS: RESULTS showed global upregulation of all three oxidative enzymes within deafferented NM neurons compared to contralateral, unperturbed NM neurons. In addition, differential SDH and ATPase staining intensities were detected across neurons within the ipsilateral nucleus, suggesting functional differences in mitochondrial metabolism across deafferented NM. Quantitative analyses revealed that deafferented neurons with preferentially elevated SDH and ATPase activities represent the subpopulation destined to die following cochlea removal. In addition, Mitotracker Red accumulated intensely within the subset of deafferented NM neurons that also exhibited cytoplasmic TdT-mediated dUTP Nick-End Labeling (TUNEL) and subsequently died. CONCLUSIONS: Taken together, our results demonstrate that a subset of deafferented NM neurons, presumably those that die, preferentially upregulates SDH, perhaps via the tricarboxylic acid (TCA) cycle. These same neurons undergo ATPase uncoupling and an eventual loss of Deltapsi(m).
Subject(s)
Apoptosis/physiology , Auditory Pathways/pathology , Brain Stem/pathology , Cochlea/surgery , Mitochondria/physiology , Sensory Receptor Cells/pathology , Adenosine Triphosphatases/metabolism , Animals , Animals, Newborn , Auditory Pathways/ultrastructure , Brain Stem/enzymology , Brain Stem/ultrastructure , Chickens , Electron Transport Complex IV/metabolism , In Situ Nick-End Labeling , Membrane Potential, Mitochondrial/physiology , Sensory Receptor Cells/enzymology , Sensory Receptor Cells/ultrastructure , Succinate Dehydrogenase/metabolismABSTRACT
Effects of unilateral noise exposure on spontaneous activity (SA) in the anteroventral and dorsal cochlear nuclei (AVCN and DCN) and the central nucleus of the inferior colliculus (ICc) were studied in cortically intact and decorticate rats. SA was measured 1 week following exposure using uptake of 14C-labeled 2-deoxyglucose (2DG) in quiet. Optical density (OD) measurements were obtained in low- and high-frequency (LF and HF) areas of each nucleus. We refer to the ipsilateral AVCN and DCN (side of the noise-exposed ear) and the contralateral ICc as direct nuclei and to their opposite side counterparts as indirect nuclei. Noise exposure altered the tonotopic profile of SA in the direct pathway by causing a decrease in the ratio of HF OD to LF OD (HF/LF ratio). In intact animals, the decreased HF/LF ratio was due to decreased HF OD. In decorticate animals, it was due to decreased HF OD and increased LF OD, the latter occurring mainly in the DCN and ICc. Decorticate-intact differences may reflect corticofugal feedback inhibition. Lesion of the dorsal acoustic stria caused a substantial decrement of SA in the contralateral ICc. Furthermore, strong positive correlations between HF/LF ratios in the DCN, AVCN, and contralateral ICc suggest that the cochlear nucleus is a major contributor to SA in the ICc. Noise exposure had opposite and weaker effects on 2DG uptake in the indirect pathway that were attributed to crossed inhibition. Noise-induced changes in the tonotopic profile of SA may represent a neural correlate of tinnitus.
Subject(s)
Brain Mapping , Cochlear Nucleus/metabolism , Decerebrate State , Inferior Colliculi/metabolism , Noise , Acoustic Stimulation , Animals , Auditory Pathways/metabolism , Decerebrate State/metabolism , Decerebrate State/physiopathology , Deoxyglucose/metabolism , Disease Models, Animal , Functional Laterality , Male , Rats , Tinnitus/physiopathologyABSTRACT
In the chicken auditory system, cochlear nucleus (nucleus magnocellularis, NM) neurons receive their only excitatory input from the ipsilateral cochlea. Cochlea removal (CR) results in an immediate decrease in NM neuron electrical activity, followed by death of approximately 30% of NM neurons. Previous work showed a decrease in NM activity and subsequent loss of NM neurons in all chicks. Egg layer adults showed NM neuron loss after CR, while neuron number remained stable in broiler adults. This suggested that effects of CR on NM were age- and breed-dependent. We now know that most aging egg layer chickens maintain largely normal cochleae throughout adulthood. Some exhibit cochlear damage with age. The converse is true of broiler chickens. Most aging broiler chickens display cochlear degeneration, with some maintaining normal cochlear anatomy throughout adulthood. The presence of extensive cochlear damage may alter the effect of CR on NM, leading to the described differences. Here, we examine the effect of unilateral CR on NM glucose metabolism and neuron number in 2, 30, 39, and 52 week-old broiler chickens found to have normal cochleae. Chickens with damaged cochleae were excluded. Using 2-deoxyglucose uptake to evaluate bilateral NM glucose metabolism, we found significantly decreased uptake ipsilateral to CR at each age examined. Bilateral cell counts revealed significant neuron loss ipsilateral to CR at each age examined. This suggests that NM glucose metabolism decreases and subsequent neuron death occurs in aging broiler chickens when a normal cochlea is removed. The status of the cochlea must play a role in the effect of deafferentation on NM glucose metabolism and neuron survival. The effect of CR appears to be dependent upon neither age nor breed, but upon cochlear integrity instead.
Subject(s)
Aging/physiology , Cochlea/physiology , Cochlear Nucleus/metabolism , Glucose/metabolism , Neurons, Afferent/metabolism , Aging/metabolism , Analysis of Variance , Animals , Cell Count , Cell Death/physiology , Chickens , Cochlea/pathology , Cochlea/ultrastructure , Cochlear Nucleus/pathology , Deoxyglucose/metabolism , Female , Hair Cells, Auditory/pathology , Hair Cells, Auditory/physiology , Hair Cells, Auditory/ultrastructure , Microscopy, Electron, Scanning , Neurons, Afferent/cytologyABSTRACT
Abrupt removal of excitatory input is devastating to post-synaptic neurons in normally functioning sensory systems. In both mammalian and avian auditory systems, abrupt temporary or permanent experimental deafferentation stimulates a cascade of changes in central auditory structures that can result in neuron death. Effects of naturally occurring progressive deafferentation on central auditory structure and function have not been fully described. Extensive naturally occurring cochlear damage is found in some aged chickens, despite their regenerative capacity, providing the opportunity to examine the effects of this type of deafferentation on the avian cochlear nucleus (nucleus magnocellularis, NM). Previous evaluation of NM oxidative metabolism using cytochrome oxidase histochemistry revealed that naturally occurring cochlear damage results in down-regulated metabolism in corresponding regions of NM. It is unknown how progressive hair cell damage and loss affects NM glucose uptake. Here, NM glucose metabolism is assessed using 2-deoxyglucose uptake as a marker for metabolic activity in the presence of normal, mildly damaged, severely damaged, and totally damaged cochlear hair cells. Results indicate that while severe and total cochlear damage significantly decrease NM oxidative metabolism, only total damage results in significantly decreased NM glucose metabolism. Results are discussed in the context of functional reorganization and trophic support.
Subject(s)
Aging/metabolism , Chickens/metabolism , Cochlea/physiopathology , Cochlear Nucleus/metabolism , Glucose/metabolism , Neurons/metabolism , Animals , Brain Stem/metabolism , Cochlea/pathology , Cochlear Nucleus/pathology , Deoxyglucose/pharmacokinetics , Female , Glucose/antagonists & inhibitors , Microscopy, Electron, Scanning , Oxidation-ReductionABSTRACT
Commercially available chickens fall into two categories: egg layers and broilers. Durham et al. (Hear. Res. 166 (2002) 82-95) showed that despite similar noisy living environments, cochleae of most adult broilers show extensive damage, while cochleae of adult egg layers are largely normal. This finding suggests that egg layers and broilers differ in their susceptibility to noise damage. Here, we evaluate breed differences in susceptibility to acoustic trauma. Young egg layers and broilers (10-17 weeks) were exposed to a 1500Hz pure tone (120dB SPL; 24h) and killed 24 or 72h later. Cochleae were prepared for scanning electron microscopy and photomicrographs of the cochlear surface were used to determine location and severity of damage. Cochleae were grouped based upon damage severity (moderate or severe). While location and area of damage were similar between both breeds at each recovery time, cochlear damage at 72h was more extensive than at 24h. We found no quantitative breed differences within either damage category or recovery time. However, more egg layers (25/27) than broilers (16/32) displayed severely damaged cochleae. Our findings conflict with those reported by Durham et al. (2002). Our results identify a breed-dependent difference in susceptibility to acute sound exposure, with young egg layers displaying increased sensitivity.
Subject(s)
Chickens/genetics , Cochlear Diseases/etiology , Cochlear Diseases/genetics , Genetic Predisposition to Disease , Noise , Animals , Cell Count , Cochlea/pathology , Cochlear Diseases/pathology , Female , Hair Cells, Auditory/pathology , Microscopy, Electron, Scanning , Severity of Illness Index , Species Specificity , Time FactorsABSTRACT
Distortion product otoacoustic emissions (DPOAE) were recorded from the ear canal of aged broiler chickens which have been shown to present with age-related cochlear degeneration [Hear. Res. 166 (2002) 82]. We describe the relationship between the shape of the DPOAE input-output (I/O) function and the type of hair cell damage present at and between the cochlear frequency places of the DPOAE primary tones (f1 and f2). The mid stimulus level compressive growth of the mean DPOAE I/O functions is reduced in a graded fashion relative to the severity of hair cell damage. However, individual DPOAE I/O functions within most hair cell damage groups show large variability from this characteristic. Various least squares regression models were used to predict hair cell density from indices derived from the DPOAE I/O function (area, threshold and slope). The results showed that no simple linear relationship exists between hair cell density and the DPOAE I/O function indices. Multivariate binary logistic regression used DPOAE I/O function indices to predict membership in hair cell damage groups. The logistic model revealed that DPOAE threshold can be used to predict the occurrence of severe/total hair cell damage with good specificity though poor sensitivity.
Subject(s)
Aging/physiology , Hair Cells, Auditory/physiopathology , Otoacoustic Emissions, Spontaneous/physiology , Presbycusis/physiopathology , Aging/pathology , Analysis of Variance , Animals , Chickens , Female , Hair Cells, Auditory/pathology , Hair Cells, Auditory/ultrastructure , Logistic Models , Microscopy, Electron, Scanning , Observer Variation , Presbycusis/pathology , Severity of Illness IndexABSTRACT
Most commercially raised broiler chickens display progressive cochlear degeneration with age [Hear. Res. 166 (2002) 82]. Recent work examining the effects of age and cochlear degeneration on avian cochlear nucleus (nucleus magnocellularis, NM) metabolism showed that changes in metabolic activity occur with age and cochlear damage [Hear. Res. 175 (2003) 101]. The auditory environment also differed between facilities housing young and adult birds. The relative contributions of age, cochlear degeneration, and auditory environment to these changes in NM metabolism are unknown. Using cytochrome oxidase (CO) histochemistry, NM neuron metabolism is examined in several age groups of birds under varying conditions. When normal cochlear integrity and auditory environment are held constant, CO staining is significantly decreased in adult vs. young birds. When age and auditory environment are held constant, CO staining is significantly decreased in birds with damaged vs. normal cochleae. When age and normal cochlear integrity are held constant, CO staining is significantly decreased in birds living in a quiet vs. noisy environment. All factors examined cause changes in CO staining, which is indicative of NM metabolic activity. Results are discussed in the context of mitochondrial aging, afferent regulation, and auditory deprivation and enrichment.
Subject(s)
Aging/metabolism , Cochlea/physiology , Cochlear Nucleus/metabolism , Environment , Noise , Animals , Chickens , Cochlear Diseases/enzymology , Cochlear Nucleus/cytology , Cochlear Nucleus/enzymology , Electron Transport Complex IV/metabolism , Female , Histocytochemistry , Neurons/enzymology , Staining and LabelingABSTRACT
Avians have the unique ability to regenerate cochlear hair cells that are lost due to ototoxins or excessive noise. Many methodological techniques are available to damage the hair cells for subsequent scientific study. A recent method utilizes topical application of an ototoxic drug to the round window membrane. The current study examines the pharmacokinetics of gentamicin in the inner ear of chickens following topical application to the round window membrane or a single systemic high dose given intraperitoneally. Chickens were given gentamicin topically or systemically and survived for 1, 4, 12, 24, or 120 h (controls at 4 and 120 h). Serum and perilymph samples were obtained prior to sacrifice and measured for gentamicin levels. Results revealed higher levels of gentamicin in the perilymph of topically treated chickens than systemically treated chickens, with significant amounts of gentamicin still present in both at the latest survival time of 5 days. As expected, systemically treated chickens had much higher levels of gentamicin in the serum than topically treated chickens. Advantages and disadvantages to each method of drug administration are discussed.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Cochlea/drug effects , Gentamicins/pharmacokinetics , Perilymph/metabolism , Administration, Topical , Animals , Chickens , Cochlea/pathology , Cochlea/ultrastructure , Hair Cells, Auditory/drug effects , Hair Cells, Auditory/pathology , Injections, Intraperitoneal , Microscopy, Electron, Scanning , Round Window, Ear/metabolism , Sodium ChlorideABSTRACT
BACKGROUND: Early identification of students who may have difficulty with the United States Medical Licensing Examination-Step 1 examination is important for medical schools and students. Numerous models that predict Step 1 performance have been identified, but few of these models have been cross-validated. PURPOSE: To cross-validate different prediction models of Step 1 performance. METHODS: The development sample was 686 students from a Midwestern medical school. The cross-validation sample was 147 different students. Logistic regression was used to develop the multiple model and Year 1 grade point average (GPA) and Year 2 Fall GPA were used as the simple models. Receiver Operating Characteristic graphs were used to select optimal cutoffs for each model. Kappa coefficients were used to determine level of agreement, and sensitivity and specificity were used to assess classification accuracy. RESULTS: The Year 1 GPA model had relatively poor agreement with actual Step 1 performance, but the other models evidenced fair agreement. The multiple and Year 1 GPA models demonstrated statistically significant loss of classification accuracy on cross-validation, whereas the Year 2 Fall GPA model did not. CONCLUSIONS: Cross-validation is necessary to determine the generalizability and overall utility of prediction models.
Subject(s)
Education, Medical , Foreign Medical Graduates , Licensure , Logistic Models , Models, Educational , Midwestern United StatesABSTRACT
Most aging commercially raised broiler chickens display a progressive loss of cochlear hair cells in a pattern similar to the cochlear degeneration found in aging humans: basal (high frequency) hair cells are affected first, followed by apical (low frequency) hair cells [Durham et al., Hear. Res. 166 (2002) 82-95]. Here, cochlear anatomy was assessed from scanning electron micrographs. Then, the metabolic activity of cochlear nucleus (nucleus magnocellularis, NM) neurons in 15-19, 30, 39, 40, and 65-66 week old broiler chickens was examined using cytochrome oxidase histochemistry and compared to the degree of cochlear abnormality. Cochleae of 15-19 week old birds are largely normal; therefore the level of NM metabolic activity is considered the baseline. Cochleae of the 30 week old group display mild damage and hair cell regeneration in the base. Metabolic activity in rostral (high frequency) NM is increased relative to the baseline, while activity remains unchanged in caudal (low frequency) NM. The 39 and 65-66 week old groups display severe and total damage extending into the apex of the cochlea. Metabolic activity is decreased in rostral and caudal NM at these ages. These results suggest that auditory central nervous system metabolism (cytochrome oxidase activity) is affected by changes in the aging chicken cochlea.
Subject(s)
Aging/physiology , Chickens/anatomy & histology , Chickens/metabolism , Cochlea/ultrastructure , Cochlear Nucleus/metabolism , Acoustic Stimulation , Animals , Brain Stem/metabolism , Cochlea/metabolism , Cochlear Nucleus/physiology , Electron Transport Complex IV/metabolism , Hair Cells, Auditory/physiology , Histocytochemistry , Microscopy, Electron, Scanning , Nerve RegenerationABSTRACT
Unlike mammals, adult avians are able to regenerate cochlear sensory hair cells following injury. Brainstem auditory neurons in chicken nucleus magnocellularis (NM), which receive their sole excitatory afferent input from the cochlea, were examined for evidence of mitosis during ototoxin-induced loss and regeneration of cochlear hair cells. Using tritiated thymidine as a mitotic marker in tissue processed for autoradiography and counterstained with thionin, labeled NM neurons and glia were counted from chickens killed 16 days after gentamicin or saline injections. Newly generated NM neurons were observed during cochlear hair cell regeneration. More labeled neurons were observed in the experimental chickens, but a few were also seen in the control chickens. We predicted labeled NM neurons would be found solely in the rostral high frequency region, given the gentamicin-induced high frequency cochlear hair cell loss and regeneration. However, the labeled NM neurons were located throughout the tonotopic axis of the nucleus. The total number of labeled neurons was lower than predicted. Many labeled NM glia were observed in experimental and control chickens. Labeled cells were also observed throughout the chicken brainstem and cerebellum in both experimental and control chickens, indicating great potential for CNS plasticity. Results in NM indicate the avian auditory system is capable of regenerating brainstem auditory neurons in addition to the previously well-established capability of regenerating cochlear hair cells in response to ototoxic injury. Recovery of both central and peripheral auditory components will be necessary to restore hearing damaged by noise or ototoxic drugs.