The Underlying Effects of Celiac Disease and Subsequent Implications on Deployment in the United States Army.

INTRODUCTION: The purpose of this review is to provide an overview of the etiology, pathology, and treatments for celiac disease (CD), as well as to provide context as to how CD impacts the U.S. military. MATERIALS AND METHODS: To conduct this review, the authors surveyed recent epidemiology and immunology literature in order to provide a detailed summary of the current understanding of CD, its diagnosis, and the real-world impacts within the Department of Defense (DoD). RESULTS: We described the gluten proteins and both the immune response in CD. We further describe the underlying genetic risk factors and diagnosis and pathogenesis of the disease and conclude the review with a discussion of how current DoD regulations impact U.S. military readiness. CONCLUSION: Celiac disease (CD) is an autoimmune disorder that results in damage to the small intestine. Ingestion of gluten in a CD patient is usually followed by villous atrophy in the small intestine, often along with other gastrointestinal symptoms. Around 1% of patients diagnosed with CD can experience complications if gluten-free diet is not followed, including intestinal lymphoma and hyposplenism. Therefore, a patient showing possible symptoms should discuss the diagnostic process with their healthcare providers to ensure adequate understanding of serological and genetic tests along with the histological examination of intestinal biopsy. Patients should seek consults with registered dietitians to structure their diets appropriately. Considering the prevalence and incidence of CD and gluten intolerances are increasing, the military should consider providing gluten-free Meals Ready-to-Eat as an option for all service members. Given the retention of service members with CD, subsequent admission of personnel with mild CD that does not affect the duties will allow the DoD access to a growing population of fully capable service members with critical technical skills who are eager to serve the USA.

Progress and Future Directions of the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium and Mind Matters Challenge at the US Service Academies.

Despite the significant impact that concussion has on military service members, significant gaps remain in our understanding of the optimal diagnostic, management, and return to activity/duty criteria to mitigate the consequences of concussion. In response to these significant knowledge gaps, the US Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) partnered to form the NCAA-DoD Grand Alliance in 2014. The NCAA-DoD CARE Consortium was established with the aim of creating a national multisite research network to study the clinical and neurobiological natural history of concussion in NCAA athletes and military Service Academy cadets and midshipmen. In addition to the data collected for the larger CARE Consortium effort, the service academies have pursued military-specific lines of research relevant to operational and medical readiness associated with concussion. The purpose of this article is to describe the structure of the NCAA-DoD Grand Alliance efforts at the service academies, as well as discuss military-specific research objectives and provide an overview of progress to date. A secondary objective is to discuss the challenges associated with conducting large-scale studies in the Service Academy environment and highlight future directions for concussion research endeavors across the CARE Service Academy sites.

Persistent motor dysfunction despite homeostatic rescue of cerebellar morphogenesis in the Car8 waddles mutant mouse.

BACKGROUND: Purkinje cells play a central role in establishing the cerebellar circuit. Accordingly, disrupting Purkinje cell development impairs cerebellar morphogenesis and motor function. In the Car8wdl mouse model of hereditary ataxia, severe motor deficits arise despite the cerebellum overcoming initial defects in size and morphology. METHODS: To resolve how this compensation occurs, we asked how the loss of carbonic anhydrase 8 (CAR8), a regulator of IP3R1 Ca2+ signaling in Purkinje cells, alters cerebellar development in Car8wdl mice. Using a combination of histological, physiological, and behavioral analyses, we determined the extent to which the loss of CAR8 affects cerebellar anatomy, neuronal firing, and motor coordination during development. RESULTS: Our results reveal that granule cell proliferation is reduced in early postnatal mutants, although by the third postnatal week there is enhanced and prolonged proliferation, plus an upregulation of Sox2 expression in the inner EGL. Modified circuit patterning of Purkinje cells and Bergmann glia accompany these granule cell adjustments. We also find that although anatomy eventually normalizes, the abnormal activity of neurons and muscles persists. CONCLUSIONS: Our data show that losing CAR8 only transiently restricts cerebellar growth, but permanently damages its function. These data support two current hypotheses about cerebellar development and disease: (1) Sox2 expression may be upregulated at sites of injury and contribute to the rescue of cerebellar structure and (2) transient delays to developmental processes may precede permanent motor dysfunction. Furthermore, we characterize waddles mutant mouse morphology and behavior during development and propose a Sox2-positive, cell-mediated role for rescue in a mouse model of human motor diseases.

T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergy.

In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2. This was a general phenomenon, as T cells presenting influenza (flu) antigen also fail to activate otherwise potent flu-specific CTLs either in vitro or in vivo. Moreover, transfer of flu peptide-pulsed T cells into flu-infected mice inhibits endogenous flu-specific CTLs. Our finding that T cells serve as a site of immune privilege, inhibiting effector CTL function, uncovers an autorepressive loop with general biologic and clinical relevance.

Intrinsic Axonal Growth and the Drive for Regeneration.

Following damage to the adult nervous system in conditions like stroke, spinal cord injury, or traumatic brain injury, many neurons die and most of the remaining spared neurons fail to regenerate. Injured neurons fail to regrow both because of the inhibitory milieu in which they reside as well as a loss of the intrinsic growth capacity of the neurons. If we are to develop effective therapeutic interventions that promote functional recovery for the devastating injuries described above, we must not only better understand the molecular mechanisms of developmental axonal growth in hopes of re-activating these pathways in the adult, but at the same time be aware that re-activation of adult axonal growth may proceed via distinct mechanisms. With this knowledge in hand, promoting adult regeneration of central nervous system neurons can become a more tractable and realistic therapeutic endeavor.

Extrinsic and intrinsic signals converge on the Runx1/CBFß transcription factor for nonpeptidergic nociceptor maturation.

The generation of diverse neuronal subtypes involves specification of neural progenitors and, subsequently, postmitotic neuronal differentiation, a relatively poorly understood process. Here, we describe a mechanism whereby the neurotrophic factor NGF and the transcription factor Runx1 coordinate postmitotic differentiation of nonpeptidergic nociceptors, a major nociceptor subtype. We show that the integrity of a Runx1/CBFß holocomplex is crucial for NGF-dependent nonpeptidergic nociceptor maturation. NGF signals through the ERK/MAPK pathway to promote expression of Cbfb but not Runx1 prior to maturation of nonpeptidergic nociceptors. In contrast, transcriptional initiation of Runx1 in nonpeptidergic nociceptor precursors is dependent on the homeodomain transcription factor Islet1, which is largely dispensable for Cbfb expression. Thus, an NGF/TrkA-MAPK-CBFß pathway converges with Islet1-Runx1 signaling to promote Runx1/CBFß holocomplex formation and nonpeptidergic nociceptor maturation. Convergence of extrinsic and intrinsic signals to control heterodimeric transcription factor complex formation provides a robust mechanism for postmitotic neuronal subtype specification.

Whole-mount imaging of mouse embryo sensory axon projections.

The visualization of full-length neuronal projections in embryos is essential to gain an understanding of how mammalian neuronal networks develop. Here we describe a method to label in situ a subset of dorsal root ganglion (DRG) axon projections to assess their phenotypic characteristics using several genetically manipulated mouse lines. The TrkA-positive neurons are nociceptor neurons, dedicated to the transmission of pain signals. We utilize a TrkA(taulacZ) mouse line to label the trajectories of all TrkA-positive peripheral axons in the intact mouse embryo. We further breed the TrkA(taulacZ) line onto a Bax null background, which essentially abolishes neuronal apoptosis, in order to assess growth-related questions independently of possible effects of genetic manipulations on neuronal survival. Subsequently, genetically modified mice of interest are bred with the TrkA(taulacZ)/Bax null line and are then ready for study using the techniques described herein. This presentation includes detailed information on mouse breeding plans, genotyping at the time of dissection, tissue preparation, staining and clearing to allow for visualization of full-length axonal trajectories in whole-mount preparation.

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS.

Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

Tracking cell lineage and fate into cerebellar circuits.

Understanding how cells from different neuronal and glial lineages contribute to functional circuits has been complicated by the difficulty in tracking cells as they integrate into brain circuits. Sudarov et al. (J Neurosci 31(30):11055-11069, 2011) used a powerful genetics-based lineage marking approach to birth date ventricular zone-derived cells in the mouse cerebellum. The authors use their novel tools to elucidate the spatial and temporal dynamics of how distinct ventricular zone lineages are generated and assemble into the cerebellar microcircuitry. In this journal club, we discuss and evaluate the author's major findings.

The onconeural antigen cdr2 is a novel APC/C target that acts in mitosis to regulate c-myc target genes in mammalian tumor cells.

Cdr2 is a tumor antigen expressed in a high percentage of breast and ovarian tumors and is the target of a naturally occurring tumor immune response in patients with paraneoplastic cerebellar degeneration, but little is known of its regulation or function in cancer cells. Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis. Loss of cdr2 leads to functional consequences for dividing cells, as they show aberrant mitotic spindle formation and impaired proliferation. Conversely, cdr2 overexpression is able to drive cell proliferation in tumors. Together, these data indicate that the onconeural antigen cdr2 acts during mitosis in cycling cells, at least in part through interactions with c-myc, to regulate a cascade of actions that may present new targeting opportunities in gynecologic cancer.