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1.  LC3A‐Positive “Stone‐Like” Structures Predict an Adverse Prognosis of Gastric Cancer 
ABSTRACT
Microtubule‐associated protein light chain 3 (LC3A) is a reliable marker of autophagy that displays three distinct patterns of immunohistochemical staining in solid tumors: diffuse cytoplasmic staining, juxtanuclear staining, and staining of “stone‐like” structures. These three patterns have a different prognostic significance in many solid tumors, but little is known about their influence in gastric cancer (GC). This study was a retrospective analysis of 188 GC patients from stages I to IV. The pattern of LC3A expression was examined in tumor and nontumor tissues by immunohistochemistry. Then, the association between the pattern of LC3A expression in GC and the prognosis was investigated by Kaplan‐Meier analysis and the Cox proportional hazards model. Two distinct patterns of LC3A immunostaining (diffuse cytoplasmic expression and “stone‐like” structures) were observed in GC tissues. LC3A‐positive “stone‐like” structures were found only in the tumors, and the number of such structures was correlated with both the tumor type and tumor stage. In addition, a high number of LC3A‐positive “stone‐like” structures was closely associated with an increased risk of recurrence after radical resection of stages I–III cancer (P < 0.001; HR = 0.205) and was associated with a lower overall survival rate for stage IV cancer (P < 0.001; HR = 0.364). Taken together, our data demonstrate that LC3A‐positive “stone‐like” structures can be used as an independent biomarker for an adverse prognosis of GC, suggesting that “stone‐like” structures are correlated with the malignancy of this disease. Anat Rec, 297:653–662, 2014. © 2014 The Authors The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology Published by Wiley Periodicals, Inc.
doi:10.1002/ar.22895
PMCID: PMC4279981  PMID: 24532538
gastric cancer; autophagy; LC3A; stone‐like structure; prognosis
2.  Characterization of Growth, Glomerular Number, and Tubular Proteins in the Developing Rhesus Monkey Kidney 
An essential step in the translation of cell-based therapies for kidney repair involves preclinical studies in relevant animal models. Regenerative therapies in children with congenital kidney disease may provide benefit, but limited quantitative data on normal development is available to aid in identifying efficient protocols for repair. Nonhuman primates share many developmental similarities with humans and provide an important translational model for understanding nephrogenesis and morphological changes across gestation. These studies assessed monkey kidney size and weight during development and utilized stereological methods to quantitate total number of glomeruli. Immunohistochemical methods were included to identify patterns of expression of tubular proteins including Aquaporin-1 (AQP1), AQP2, Calbindin, E-Cadherin, and Uromodulin. Results have shown that glomerular number increased linearly with kidney weight, from 1.1 × 103 in the late first trimester to 3.5 × 105 near term (P < 0.001). The ratio of glomeruli to body weight tripled from the late first to early second trimester then remained relatively unchanged. Only AQP1 was expressed in the proximal tubule and descending Loop of Henle. The ascending Loop of Henle was positive for AQP2, Calbindin, and Uromodulin; distal convoluted tubules stained for Calbindin only; and collecting tubules expressed AQP2 and E-Cadherin with occasional Calbindin-positive cells. These findings provide quantitative information on normal kidney ontogeny in rhesus monkeys and further support the importance of this model for human kidney development.
doi:10.1002/ar.22756
PMCID: PMC4272578  PMID: 23997038
kidney; nephrogenesis; monkey; stereology; fetus
3.  Rapid Interaction of Helicobacter pylori with Microvilli of the Polar Human Gastric Epithelial Cell Line NCI-N87 
Infection with Helicobacter pylori results often in chronic gastritis, gastric ulcers or even gastric tumor development. Little is known about the initial interaction between gastric epithelial cells and H. pylori. The aim of the present study was to analyze the initial host contact to the bacteria. Monolayers of the human gastric epithelial cell line NCI-N87 grown on porous membranes were used and the apical side of the epithelium was exposed to the H. pylori wild-type strain P1 for 1 hr. Many epithelial cells were colonized by bacteria within the period of 60 min. Using scanning electron microscopy we detected that the bacteria were in close contact with the epithelia via microvilli. Further, transmission electron microscopy of the contact sites revealed no difference in the morphology of the microvilli in comparison to those not attached to the bacteria. The present study demonstrates the importance of microvilli on apical epithelial cells during the initial contact of the host by colonizing H. pylori. Anat Rec, 296:1800–1805, 2013. © 2013 The Authors. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology published by Wiley Periodicals, Inc. on behalf of the American Association of Anatomists.
doi:10.1002/ar.22818
PMCID: PMC4225472  PMID: 24136815
gastric epithelial cells; scanning electron microscopy; tight junction; trans epithelial electrical resistance
4.  The Human Tongue Slows Down to Speak: Muscle Fibers of the Human Tongue 
Little is known about the specializations of human tongue muscles. In this study, myofibrillar adenosine triphosphatase (mATPase) histochemical staining was used to study the percentage and distribution of slow twitch muscle fibers (slow MFs) within tongue muscles of 4 neurologically normal human adults and specimens from a 2 year old human, a newborn human, an adult with idiopathic Parkinson’s disease (IPD), and a macaque monkey. The average percentage of slow MFs in adult and the 2 year old muscle specimens was 54%, the IPD was 45%, while the neonatal human (32%) and macaque monkey (28%) had markedly fewer slow MFs. In contrast the tongue muscles of the rat and cat have been reported to have no slow MFs. There was a marked spatial gradient in the distribution of slow MFs with the highest percentages found medially and posterially. Normal adult tongue muscles were found to have a variety of uniquely specialized features including MF type grouping (usually found in neuromuscular disorders), large amounts of loose connective tissue, and short branching MFs. In summary, normal adult human tongue muscles have by far the highest proportion of slow MFs of any mammalian tongue studied to date. Moreover, adult human tongue muscles have multiple unique anatomic features. As the tongue shape changes that are seen during speech articulation are unique to humans we hypothesize that the large proportion of slow MFs and the anatomical specializations observed in the adult human tongue have evolved to perform these movements.
doi:10.1002/ar.22755
PMCID: PMC3787083  PMID: 23929762
tongue; intrinsic tongue muscles; muscle fiber types; muscular hydrostat; myofibrillar ATPase; speech articulation
5.  Mediation of muscular control of rhinarial motility in rats by the nasal cartilaginous skeleton 
The Rhinarium is the rostral-most area of the snout that surrounds the nostrils, and is hairless in most mammals. In rodents, it participates in coordinated behaviors, active tactile sensing, and active olfactory sensing. In rats, the Rhinarium is firmly connected to the nasal cartilages, and its motility is determined by movements of the rostral end of the nasal cartilaginous skeleton. Here we demonstrate the nature of different cartilaginous regions that form the Rhinarium and the nasofacial muscles that deform these regions during movements of the nasal cartilaginous skeleton. These muscles, together with the dorsal nasal cartilage that was described here, function as a rhinarial motor plant.
doi:10.1002/ar.22822
PMCID: PMC4157211  PMID: 24249396
nasofacilal muscles; rhinarium; rodents; vibrissa; whisking
6.  Dorsorostral snout muscles in the rat subserve coordinated movement for whisking and sniffing 
Histochemical examination of the dorsorostral quadrant of the rat snout revealed superficial and deep muscles that are involved in whisking, sniffing, and airflow control. The part of M. nasolabialis profundus that acts as an intrinsic (follicular) muscle to facilitate protraction and translation of the vibrissae is described. An intraturbinate and selected rostral-most nasal muscles that can influence major routs of inspiratory airflow and rhinarial touch through their control of nostril configuration, atrioturbinate and rhinarium position were revealed.
doi:10.1002/ar.22501
PMCID: PMC4153473  PMID: 22641389
active sensing; breathing; nose muscles; rodents
7.  TEMPORAL CHANGES IN EXPRESSION OF FOXA1 AND WNT7A IN ISOLATED ADULT HUMAN ALVEOLAR EPITHELIAL CELLS ENHANCED BY HEPARIN 
Pre- and postnatal developmental studies of the lung have provided compelling evidence demonstrating multiple factors that orchestrate alveolar epithelial cell differentiation. The extent to which reactivation of certain developmental pathways in the adult might influence the course of differentiation of alveolar type 2 cells (AT2) into AT1 cells is not known. In this study, we examined selected members of the forkhead (Fox) family of transcription factors and the Wnt (wingless) family of signaling proteins for expression during human alveolar cell differentiation in vitro and determined their potential responses to sulfated components of extracellular matrix (ECM), like those shed from cell surfaces or found in basement membrane and modeled by heparin. Isolated adult human AT2 cells cultured over a nine day period were used to define the temporal profile of expression of targeted factors during spontaneous differentiation to AT1 cells. FoxA1 protein was up-regulated at early to intermediate time points, where it was strongly elevated by heparin. Gene expression of Wnt7A increased dramatically beginning on day 3 and was enhanced even further on days 7 and 9 by heparin, while protein expression appeared at days 7 and 9. These temporal changes of expression suggest that sulfated ECMs may act to enhance the increase in FoxA1 at the critical juncture when AT2 cells commence the differentiation process to AT1 cells, in addition to enhancing the increase in Wnt7A when the AT1 cell phenotype stabilizes. Collectively, these factors may act to modulate differentiation and stabilize cell numbers in the adult human pulmonary alveolus.
doi:10.1002/ar.20805
PMCID: PMC4133099  PMID: 20503388
β-catenin; differentiation; heparin; sulfated extracellular matrices
8.  Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice 
Our previous postmortem study of girls with Rett Syndrome (RTT), a development disorder caused by MECP2 mutations, found increases in the density of NMDA receptors in the prefrontal cortex of 2–8 year-old girls, while girls older than 10 years had reductions in NMDA receptors compared to age matched controls (Blue et al., 1999b). Using [3H]-CGP to label NMDA type glutamate receptors in 2 and 7 week old wildtype (WT), Mecp2-null and Mecp2-heterozygous (HET) mice (Bird model), we found that frontal areas of the brain also exhibited a bimodal pattern in NMDA expression, with increased densities of NMDA receptors in Mecp2-null mice at 2 weeks of age, but decreased densities at 7 weeks of age. Visual cortex showed a similar pattern, while other cortical regions only exhibited changes in NMDA receptor densities at 2 weeks (retrosplenial granular) or 7 weeks (somatosensory). In thalamus of null mice, NMDA receptors were increased at 2 and 7 weeks. No significant differences in density were found between HET and WT mice at both ages. Western blots for NMDAR1 expression in frontal brain showed higher levels of expression in Mecp2-null mice at two weeks of age, but not at 1 or 7 weeks of age. Our mouse data support the notion that deficient MeCP2 function is the primary cause of the NMDA receptor changes we observed in RTT. Furthermore, the findings of regional and temporal differences in NMDA expression illustrate the importance of age and brain region in evaluating different genotypes of mice.
doi:10.1002/ar.21380
PMCID: PMC4122218  PMID: 21901842
Rett syndrome; NMDA; Mouse models; Development
9.  Proteoglycans: Key Regulators of Pulmonary Inflammation and the Innate Immune Response to Lung Infection 
Exposure to viruses and bacteria results in lung infections and places a significant burden on public health. The innate immune system is an early warning system that recognizes viruses and bacteria, which results in the rapid production of inflammatory mediators such as cytokines and chemokines and the pulmonary recruitment of leukocytes. When leukocytes emigrate from the systemic circulation through the extracellular matrix in response to lung infection they encounter proteoglycans, which consist of a core protein and their associated glycosaminoglycans. In this review, we discuss how proteoglycans serve to modify the pulmonary inflammatory response and leukocyte migration through a number of different mechanisms including: 1) The ability of soluble proteoglycans or fragments of glycosaminoglycans to activate Toll-like receptor signaling pathways; 2) The binding and sequestration of cytokines, chemokines, and growth factors by proteoglycans; 3) the ability of proteoglycans and hyaluronan to facilitate leukocyte adhesion and sequestration; and 4) The interactions between proteoglycans and matrix metalloproteinases that alter the function of these proteases. In conclusion, proteoglycans fine-tune tissue inflammation through a number of different mechanisms. Clarification of the mechanisms whereby proteoglycans modulate the pulmonary inflammatory response will most likely lead to new therapeutic approaches to inflammatory lung disease and lung infection.
doi:10.1002/ar.21094
PMCID: PMC4121077  PMID: 20503391
extracellular matrix; proteoglycan; glycosaminoglycans; lungs; infection; cytokine; chemokine; matrix metalloproteinases
10.  Dystrophic Serotonin Axons in Postmortem Brains from Young Autism Patients 
Autism causes neuropathological changes in varied anatomical loci. A coherent neural mechanism to explain the spectrum of autistic symptomatology has not been proposed because most anatomical researchers focus on point-to-point functional neural systems (e.g. auditory, social networks) rather than considering global chemical neural systems. Serotonergic neurons have a global innervation pattern. Their cell bodies are found in the midbrain but they project their axons throughout the neural axis beginning in the fetal brain. This global system is implicated in autism by animal models and by biochemical, imaging, pharmacological, and genetics studies. However, no anatomical studies of the 5-HT innervation of autistic donors have been reported. Our review presents immunocytochemical evidence of an increase in 5-HT axons in post-mortem brain tissue from autism donors aged 2.8 to 29 years relative to controls. This increase is observed in the principle ascending fiber bundles of the medial and lateral forebrain bundles, and in the innervation density of the amygdala and the piriform, superior temporal, and parahippocampal cortices. In autistic donors eight years of age and up, several types of dystrophic 5-HT axons were seen in the termination fields. One class of these dystrophic axons, the thick heavily stained axons, was not seen in the brains of patients with neurodegenerative diseases. These findings provide morphological evidence for the involvement of serotonin neurons in the early etiology of autism, and suggest a diet therapy may be effective to blunt serotonin’s trophic actions during early brain development in children.
doi:10.1002/ar.21243
PMCID: PMC4112519  PMID: 21901837
11.  Two myristoylated alanine-rich C-kinase substrate (MARCKS) paralogs are required for normal development in zebrafish 
Myristoylated alanine-rich C-kinase substrate (MARCKS) is an actin binding protein substrate of protein kinase C (PKC) and critical for mouse and Xenopus development. Herein two MARCKS paralogs, marcksa and marcksb, are identified in zebrafish and the role of these genes in zebrafish development is evaluated. Morpholino-based targeting of either MARCKS protein resulted in increased mortality and a range of gross phenotypic abnormalities. Phenotypic abnormalities were classified as mild, moderate or severe, which is characterized by a slight curve of a full-length tail, a severe curve or twist of a full-length tail and a truncated tail, respectively. All three phenotypes displayed abnormal neural architecture. Histopathology of Marcks targeted embryos revealed abnormalities in retinal layering, gill formation and skeletal muscle morphology. These results demonstrate that Marcksa and Marcksb are required for normal zebrafish development and suggest that zebrafish are a suitable model to further study MARCKS function.
doi:10.1002/ar.21453
PMCID: PMC4103011  PMID: 21809467
12.  Distribution and Size of Mucous Glands in the Ferret Tracheobronchial Tree 
A transgenic ferret model of cystic fibrosis has recently been generated. It is probable that malfunction of airway mucous glands contributes significantly to the airway pathology of this disease. The usefulness of the ferret model may therefore depend in part on how closely the airway glands of ferrets resemble those of humans. Here, we show that in the ferret trachea glands are commonest in its most ventral aspect and disappear about half way up the lateral walls; they are virtually absent from the dorsal membranous portion. Further, the aggregate volume of glands per unit mucosal surface declines progressively by about 60% between the larynx and the carina. The average frequency of glands openings for the ferret trachea as a whole is only about one-fifth that in humans (where gland openings are found at approximately the same frequency throughout the trachea). Glands in the ferret trachea are on average about one-third the size of those in the human. Therefore, the aggregate volume of tracheal glands (per unit mucosal surface area) in the ferret is only about 6% that in humans. As in other mammalian species, airway glands in the ferret disappear at an airway internal diameter of ~1 mm, corresponding approximately in this species to airway generation 6.
doi:10.1002/ar.22783
PMCID: PMC4096109  PMID: 24106034
ferret; cystic fibrosis; airway mucous gland
13.  The Use of Neurotrophin Therapy in the Inner Ear to Augment Cochlear Implantation Outcomes 
This review will cover the roles of neurotrophins in inner ear development, neuronal maintenance, neuronal process regeneration, and clinical applications including possible augmentation of cochlear implant function. Severe to profound deafness is most often secondary to a loss of or injury to cochlear mechanosensory cells, and there is often an associated loss of the peripheral auditory neural structures, specifically the spiral ganglion neurons and peripheral auditory fibers. Cochlear implantation is currently our best hearing rehabilitation strategy for severe to profound deafness. These implants work by directly electrically stimulating the remnant auditory neural structures within the deafened cochlea. When administered to the deafened cochlea in animal models, neurotrophins, specifically BDNF and NT3, have been shown to dramatically improve spiral ganglion neuron survival and stimulate peripheral auditory fiber regrowth. In animal models, neurotrophins administered in combination with cochlear implantation has resulted in significant improvements in the electrophysiological and psychophysical measures of outcome. While further research must be done before these therapies can be applied clinically, neurotrophin therapies for the inner ear show great promise in enhancing cochlear implant outcomes and the treatment of hearing loss.
doi:10.1002/ar.22586
PMCID: PMC4081524  PMID: 23044834
neurotrophin; BDNF; NT3; cochlear implant
14.  Analysis of the Effect of Estrogen/Androgen Perturbation on Penile Development in Transgenic and Diethylstilbestrol-Treated Mice 
Anatomical record (Hoboken, N.J. : 2007)  2013;296(7):10.1002/ar.22708.
Because both androgens and estrogens have been implicated in penile morphogenesis, we evaluated penile morphology in transgenic mice with known imbalance of androgen and estrogen signaling using scanning electron microscopy (SEM), histology, and immunohistochemistry of androgen and estrogen receptors α/β. Penises of adult wild-type, estrogen receptor-α knockout (αERKO), estrogen receptor-β knockout (βERKO), aromatase knockout (Arom-KO), and aromatase overexpression (Arom+) mice were evaluated, as well as adult mice treated with diethylstilbestrol (DES) from birth to day 10. Adult penises were examined because the adult pattern is the endpoint of development. The urethral orifice is formed by fusion of the MUMP (male urogenital mating protuberance) with the MUMP ridge, which consists of several processes fused to each other and to the MUMP. Similarly, the internal prepuce is completed ventrally by fusion of a ventral cleft. In adult murine penises the stromal processes that form the MUMP ridge are separated from their neighbors by clefts. αERKO, βERKO, and Arom-KO mice have penises with a MUMP ridge clefting pattern similar to that of wild-type mice. In contrast, Arom+ mice and neonatally DES-treated mice exhibit profound malformations of the MUMP, MUMP ridge clefting pattern, and internal prepuce. Abnormalities observed in Arom+ and neonatally DES-treated mice correlate with the expression of estrogen receptor-beta (ERβ) in the affected structures. This study demonstrates that formation of the urethal orifice and internal prepuce is due to fusion of separate epithelial-surfaced mesenchymal elements, a process dependent upon both androgen and estrogen signaling, in which ERβ signaling is strongly implicated.
doi:10.1002/ar.22708
PMCID: PMC3709018  PMID: 23653160
mouse penis; prepuce; androgen receptor; estrogen receptor
15.  A 3-Dimensional Atlas of Human Tongue Muscles 
The human tongue is one of the most important yet least understood structures of the body. One reason for the relative lack of research on the human tongue is its complex anatomy. This is a real barrier to investigators as there are few anatomical resources in the literature that show this complex anatomy clearly. As a result, the diagnosis and treatment of tongue disorders lags behind that for other structures of the head and neck. This report intended to fill this gap by displaying the tongue’s anatomy in multiple ways. The primary material used in this study was serial axial images of the male and female human tongue from the Visible Human (VH) Project of the National Library of Medicine. In addition, thick serial coronal sections of three human tongues were rendered translucent. The VH axial images were computer reconstructed into serial coronal sections and each tongue muscle was outlined. These outlines were used to construct a 3-dimensional computer model of the tongue that allows each muscle to be seen in its in vivo anatomical position. The thick coronal sections supplement the 3-D model by showing details of the complex interweaving of tongue muscles throughout the tongue. The graphics are perhaps the clearest guide to date to aid clinical or basic science investigators in identifying each tongue muscle in any part of the human tongue.
doi:10.1002/ar.22711
PMCID: PMC3687025  PMID: 23650264
tongue; intrinsic and extrinsic tongue muscles; neuromuscular compartments; tongue movement; speech; swallowing; respiration; 3-D reconstruction
16.  Progress Toward Development of a Multichannel Vestibular Prosthesis for Treatment of Bilateral Vestibular Deficiency 
This article reviews vestibular pathology and the requirements and progress made in the design and construction of a vestibular prosthesis. Bilateral loss of vestibular sensation is disabling. When vestibular hair cells are injured by ototoxic medications or other insults to the labyrinth, the resulting loss of sensory input disrupts vestibulo-ocular reflexes (VORs) and vestibulo-spinal reflexes that normally stabilize the eyes and body. Affected individuals suffer poor vision during head movement, postural instability, chronic disequilibrium, and cognitive distraction. Although most individuals with residual sensation compensate for their loss over time, others fail to do so and have no adequate treatment options. A vestibular prosthesis analogous to cochlear implants but designed to modulate vestibular nerve activity during head movement should improve quality of life for these chronically dizzy individuals. We describe the impact of bilateral loss of vestibular sensation, animal studies supporting feasibility of prosthetic vestibular stimulation, the current status of multichannel vestibular sensory replacement prosthesis development, and challenges to successfully realizing this approach in clinical practice. In bilaterally vestibular-deficient rodents and rhesus monkeys, the Johns Hopkins multichannel vestibular prosthesis (MVP) partially restores the three-dimensional (3D) VOR for head rotations about any axis. Attempts at prosthetic vestibular stimulation of humans have not yet included the 3D eye movement assays necessary to accurately evaluate VOR alignment, but these initial forays have revealed responses that are otherwise comparable to observations in animals. Current efforts now focus on refining electrode design and surgical technique to enhance stimulus selectivity and preserve cochlear function, optimizing stimulus protocols to improve dynamic range and reduce excitation–inhibition asymmetry, and adapting laboratory MVP prototypes into devices appropriate for use in clinical trials.
doi:10.1002/ar.22581
PMCID: PMC4058831  PMID: 23044664
vestibular; prosthesis; implant; areflexia; labyrinth; hypofunction; dizziness; oscillopsia
17.  The Anatomical and Physiological Framework for Vestibular Prostheses 
This article reviews the structure function of the vestibular system and its pathology with respect to requirements for the design and construction of a functional vestibular prosthesis. The ultimate goal of a vestibular prosthesis is to restore balance and equilibrium through direct activation of vestibular nerve fibers. An overview of the peripheral and central vestibular systems that highlights their most important functional aspects re: the design of a prosthesis is provided. Namely, the peripheral labyrinth faithfully transduces head motion and gravity in both the time and frequency domains. These signals are described in hopes that they may be prosthetically replicated. The peripheral and central connections of the vestibular nerve are also discussed in detail, as are the vestibular nuclei in the brainstem that receive VIIIth nerve innervation. Lastly, the functional effector pathways of the vestibular system, including the vestibulo-ocular, vestibulo-spinal, vestibulo-colic, vestibulo-autonomic, and vestibular efferent innervation of the labyrinth are reviewed.
doi:10.1002/ar.22582
PMCID: PMC4039022  PMID: 23044714
balance; ototoxicity; labyrinthectomy; dizziness; Meniere’s disease
18.  Corticosteroid Therapy for Hearing and Balance Disorders 
This review addresses the current status of steroid therapies for hearing and vestibular disorders and how certain misconceptions may be undermining the efficacy in restoring normal ear function, both experimentally and clinically. Specific misconceptions addressed are that steroid therapy is not effective, steroid-responsive hearing loss proves an underlying inflammatory problem in the ear, and steroids only have application to the hearing disorders listed below. Glucocorticoid therapy for hearing and balance disorders has been employed for over 60 years. It is recommended in cases of sudden hearing loss, Meniére’s disease, immune-mediated hearing loss, and any vestibular dysfunction suspected of having an inflammatory etiology. The predominant steroids employed today are dexamethasone, prednisone, prednisolone, and methyl-prednisolone. In spite of years of use, little is known of the steroid responsive mechanisms in the ear that are influenced by glucocorticoid therapy. Furthermore, meta-analyses and clinical study reviews occasionally question whether steroids offer any benefit at all. Foremost in the minds of clinicians is the immune suppression and antiinflammatory functions of steroids because of their efficacy for autoimmune hearing loss. However, glucocorticoids have a strong binding affinity for the mineralocorticoid (aldosterone) and glucocorticoid receptors, both of which are prominent in the ear. Because the auditory and vestibular end organs require tightly regulated endolymph and perilymph fluids, this ion homeostasis role of the mineralocorticoid receptor cannot be overlooked in both normal and pathologic functions of the ear. The function of the glucocorticoid receptor is to provide anti-inflammatory and anti-apoptotic signals by mediating survival factors.
doi:10.1002/ar.22576
PMCID: PMC3999710  PMID: 23044978
auditory; hearing loss; vestibular; corticosteroids; glucocorticoid receptor; mineralocorticoid receptor; Meniére’s disease; sudden hearing loss
19.  Muscle Patterning in Mouse and Human Abdominal Wall Development and Omphalocele Specimens of Humans 
Human omphalocele is a congenital defect of the abdominal wall in which the secondary abdominal wall structures (muscle and connective tissue) in an area centered around the umbilicus are replaced by a translucent membranous layer of tissue. Histological examination of omphalocele development and moreover the staging of normal human abdominal wall development has never been described. We hypothesized that omphalocele is the result of an arrest in the secondary abdominal wall development and predicted that we would observe delays in myoblast maturation and an arrest in secondary abdominal wall development. To look for evidence in support of our hypothesis, we performed a histological analysis of normal human abdominal wall development and compared this to mouse. We also conducted the first histological analysis of two human specimens with omphalocele. In these two omphalocele specimens, secondary abdominal wall development appears to have undergone an arrest around Carnegie Stage 19. In both specimens disruptions in the unidirectional orientation of myofibers were observed in the external and internal obliques, and rectus abdominis but not in the transversus abdominis. These latter findings support a model of normal abdominal wall development in which positional information instructs the orientation of myoblasts as they organize into individual muscle groups.
doi:10.1002/ar.22556
PMCID: PMC3976953  PMID: 22976993
human omphalocele; body wall; muscle development; mouse; human
20.  MACROPHAGES ARE UNSUCCESSFUL IN CLEARING AGGREGATED ALPHA-SYNUCLEIN FROM THE GASTROINTESTINAL TRACT OF HEALTHY AGED FISCHER 344 RATS 
Anatomical record (Hoboken, N.J. : 2007)  2013;296(4):10.1002/ar.22675.
With age, alpha-synuclein (α-SYNC) misfolds and forms insoluble deposits of protein in the myenteric plexus, leading presumably to dystrophy and degeneration in the circuitry controlling gastrointestinal (GI) function. The present experiment examined aggregates of α-SYNC in the aging small intestine and investigated how macrophages in the wall of the GI tract respond to these aberrant deposits. Groups of adult and aged Fisher 344 rats were studied. Whole mounts of duodenal, jejunal and ileal smooth muscle wall, including the myenteric plexus, were prepared. Double labeling immunohistochemistry was used to stain α-SYNC protein and the phenotypic macrophage antigens CD163 and MHCII. Alpha-synuclein accumulated in dense aggregates in axons of both postganglionic and preganglionic neurons throughout the small intestine. Staining patterns suggested that deposits of protein occur initially in axonal terminals and then spread retrogradely towards the somata. Macrophages that were adjacent to dystrophic terminal processes were swollen and contained vacuoles filled with insoluble α-SYNC, and these macrophages commonly had the phenotype of alternatively activated phagocytes. The present results suggest that macrophages play an active phagocytotic role in removing α-SYNC aggregates that accumulate with age in the neural circuitry of the gut. Our observations further indicate that this housekeeping response does not clear the protein sufficiently to eliminate all synucleinopathies or their precursor aggregates from the healthy aging GI tract. Thus, accumulating deposits of insoluble α-SYNC in the wall of the GI tract may contribute, especially when compounded by disease or inflammation, to the age-associated neuropathies in the gut that compromise GI function.
doi:10.1002/ar.22675
PMCID: PMC3851024  PMID: 23441091
Aging; Enteric; Myenteric; Resident Macrophage
21.  Alveolar Epithelial Dynamics in Post-pneumonectomy Lung Growth 
The intimate anatomic and functional relationship between epithelial cells and endothelial cells within the alveolus suggests the likelihood of a coordinated response during post-pneumonectomy lung growth. To define the population dynamics and potential contribution of alveolar epithelial cells to alveolar angiogenesis, we studied alveolar Type II and Type I cells during the 21 days after pneumonectomy. Alveolar Type II cells were defined and isolated by flow cytometry using a CD45−, MHC class II+, phosphine+ phenotype. These phenotypically defined alveolar Type II cells demonstrated an increase in cell number after pneumonectomy; the increase in cell number preceded the increase in Type I (T1α+) cells. Using a parabiotic wild type/GFP pneumonectomy model, less than 3% of the Type II cells and 1% of the Type I cells were positive for GFP—a finding consistent with the absence of a blood-borne contribution to alveolar epithelial cells. The CD45−, MHC class II+, phosphine+ Type II cells demonstrated the active transcription of angiogenesis-related genes both before and after pneumonectomy. When the Type II cells on day 7 after pneumonectomy were compared to non-surgical controls, 10 genes demonstrated significantly increased expression (p<.05). In contrast to the normal adult Type II cells, there was notable expression of inflammation-associated genes (Ccl2, Cxcl2, Ifng) as well as genes associated with epithelial growth (Ereg, Lep). Together, the data suggest an active contribution of local alveolar Type II cells to alveolar growth.
doi:10.1002/ar.22659
PMCID: PMC3576046  PMID: 23408540
22.  Comparative Anatomy of Mouse and Human Nail Units 
Recent studies of mice with hair defects have resulted in major contributions to the understanding of hair disorders. To use mouse models as a tool to study nail diseases, a basic understanding of the similarities and differences between the human and mouse nail unit is required. In this study we compare the human and mouse nail unit at the macroscopic and microscopic level and use immunohistochemistry to determine the keratin expression patterns in the mouse nail unit. Both species have a proximal nail fold, cuticle, nail matrix, nail bed, nail plate, and hyponychium. Distinguishing features are the shape of the nail and the presence of an extended hyponychium in the mouse. Expression patterns of most keratins are similar. These findings indicate that the mouse nail unit shares major characteristics with the human nail unit and overall represents a very similar structure, useful for the investigation of nail diseases and nail biology.
doi:10.1002/ar.22660
PMCID: PMC3579226  PMID: 23408541
animal model; microscopic; claw; nail
24.  Tensor Tympani Motoneurons Receive Mostly Excitatory Synaptic Inputs 
The tensor tympani is a middle ear muscle that contracts in two different situations: in response to sound or during voluntary movements. To gain insight into the inputs and neural regulation of the tensor tympani, we examined the ultrastructure of synaptic terminals on labeled tensor tympani motoneurons (TTMNs) using transmission electron microscopy. Our sample of six TTMNs received 79 synaptic terminals that formed 126 synpases. Two types of synapses are associated with round vesicles and form asymmetric junctions (excitatory morphology). One of these types has vesicles that are large and round (Lg Rnd) and the other has vesicles that are smaller and round (Sm Rnd) and also contains at least one dense core vesicle. A third synapse type has inhibitory morphology because it forms symmetric synapses with pleomorphic vesicles (Pleo). These synaptic terminals can be associated with TTMN spines. Two other types of synapse are found on TTMNs but they are uncommon. Synaptic terminals of all types form multiple synapses but those from a single terminal are always the same type. Terminals with Lg Rnd vesicles formed the most synpases per terminal (avg. 2.73). Together, the synaptic terminals with Lg Rnd and Sm Rnd vesicles account for 62% of the terminals on TTMNs, and they likely represent the pathways driving the contractions in response to sound or during voluntary movements. Having a high proportion of excitatory inputs, the TTMN innervation is like that of stapedius motoneurons but proportionately different from other types of motoneurons.
doi:10.1002/ar.22620
PMCID: PMC3896885  PMID: 23165747
middle ear muscle; acoustic reflex; vesicle morphometry; dense core vesicle; electron microscopy
25.  MT2-MMP Expression During Early Avian Morphogenesis 
Membrane-type 2 matrix metalloproteinase (MT2-MMP; also called MMP15) is a membrane-bound protease that degrades extracellular matrix and activates proMMPs such as proMMP-2. MMP-2 expression in avian embryos is well documented, but it is not clear how proMMP-2 is activated during avian embryogenesis. Here, we report that MT2-MMP mRNA is expressed in several tissues including the neural folds and epidermal ectoderm, intermediate mesoderm, pharyngeal arches, limb buds, and dermis. Several, but not all, of these tissues are known to express MMP-2. These observations suggest MT2-MMP may play a role during embryonic development not only through its own proteolytic activity, but also by activating proMMP-2.
doi:10.1002/ar.22618
PMCID: PMC3535580  PMID: 23161772
MT-MMP; MMP15; chicken embryo

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