AIMS: The aims of this study were to examine the cephalometric and airway measurements on children with Sleep Related Breathing Disorders (SRBD) and without SRBD, and to investigate the impact of maxillary expansion on these measurements. MATERIALS AND METHODS: This observational study utilized data from Boston University Orthodontics Department between 2016 and 2020. Lateral cephalograms, acoustic rhinometry and pharyngometry were obtained at two time points. SRBD was determined by a score of 0.33 or higher according to the Pediatric Sleep Questionnaire. Mann–Whitney U test and Spearman correlation analysis were used to analyze the data. Statistical significance was set at <0.05. RESULTS: A total of 163 children (61 male, 102 female) were included in this study. Certain airway measurements (Ph Volume p=0.02, Rh air resistance p=0.05, Rh minimum resistance p=0.001) were significantly higher in SRBD group compared to non-SRBD group. In the SRBD group there was a significant negative correlation between Ph Min Distance and SNA (p=0.001), SND (p=0.05), mandibular arc (p=0.03), U1-SN (p=0.02), U1-Apo (p=0.03). Positive. correlations were observed between Ph Volume with L1-NB (p=0.05) and Rh Min Distance Left with Pog- NB (p=-0.5), mandibular arc p=0.05, L1-NB (p=0.01), L1-Apo (p=0.01). Rh Min Cross-sectional left was positive correlated with overbite (p=0.03) and Rh Min cross-sectional right with posterior face height (p=0.05). Certain airway measurements and cephalometric measurements were statistically different across expansion and non-expansion groups (RhVolumeRt p=0.003. RhMinCrossSectionalLft p=0.03, RhMindistanceRt p=0.03, RhAirResistanceRt p=0.05, ANB p=0.0058, S-N (mm) p=0.05, U1 - NA (mm) p=0.04, U-Incisor Protrusion p=0.01, nterincisal Angle p=0.01, Upper Lip - S Line p= 0.005, Upper Lip to E-Plane p=0.01 CONCLUSION: Airway measurements and cephalometric measurements differ significantly between SRBD and non-SRBD subjects. Significant correlations were observed between cephalometric measurements and airway measurements in the SRBD children. Maxillary expansion can be a treatment option for improving certain airway and cephalometric values among those with sleep-disordered breathing.

Introduction: Orthodontic treatment of anterior open bite can result in a counter-clockwise rotation of the mandible and a more ideal forward position of the tongue. Usually this movement is thought to increase the oropharyngeal airway. The primary aim of the present study was to evaluate changes in vertical dimension and airway in AOB patients following orthodontic treatment. Methods: 52 subjects were included in this retrospective study of anterior open bite malocclusion treated in the graduate orthodontics clinic at the University of the Pacific, Arthur A. Dugoni School of Dentistry between 2006 – 2019. Cephalometric and airway measurements were done by 2 judges. Intraclass correlation coefficient (ICC) was used to evaluate inter-judge reliability for evaluating airway volume and MCA measurements. Chi-square tests were used to compare proportions. Unpaired t-tests were used to compare mean differences and paired t-tests were used to compare pre- and post-treatment changes. Results: More vertical control and intrusion of molars was seen in non-growing (NG) subjects. There was more successful open bite correction in NG subjects. Even though there was a reduction in FMA, LFA, improved incisor position and open bite correction, there was not much influence on airway dimensions. There was no statistically significant change in airway in growing (G) and NG subjects when looking at the whole sample. Conclusion: With correction of an anterior open; intrusion of molars and a more forward mandibular position result. However, these changes did not result in an increase in oropharyngeal airway in our study.

Indiana University-Purdue University Indianapolis (IUPUI) / Airway inflammation is the most common and important component of respiratory diseases, such as influenza and asthma. Severe influenza A virus infection typically triggers detrimental lung inflammation with massive immune cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor known for its function in bone formation and spermatogenesis, in regulating antiviral immune responses and immunopathology. Nmp4-deficient mice are protected from influenza induced immunopathology and body weight loss. While having no effects on viral clearance or CD8/CD4 T cell or humoral immune responses, Nmp4 deficiency in either lung structural cells or hematopoietic cells significantly reduces the recruitment of neutrophils and monocytes to the lungs. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes Ccl2 and Cxcl1 and upregulates their expression in mouse lung epithelial cells and macrophages. These chemokines attract monocytes and neutrophils to the airway, resulting in exaggerated airway inflammation and collateral lung damage. Another transcription factor forkhead box P3 (FOXP3) is critical for the development of regulatory T cells (Tregs) that function to control immune responses. Unlike human FOXP3 gene that encodes two major isoforms, a full length (FOXP3-FL) isoform and a short isoform lacking the exon 2 region (FOXP3-ΔE2), mouse Foxp3 gene only encodes Foxp3-FL isoform. We generate Foxp3-ΔE2 mice to study its function and find that Tregs expressing the Foxp3-ΔE2 isoform have intrinsic defects, thus allowing intensified adaptive immune responses without changes in innate immunity against influenza infection. In a model of chronic asthma, mice expressing only the Foxp3-ΔE2 isoform have significantly increased allergic airway inflammation and elevated production of allergen-specific IgE compared with mice expression the Foxp3-FL isoform. Mechanistically, Tregs expressing the Foxp3-ΔE2 isoform are less stable and prone to trans-differentiation into effector Th9-like cells, which are closely associated with the pathogenesis of asthma. These data suggest that the two Foxp3 isoforms have different functions in regulating airway immune responses. Overall, we have defined the important roles of both transcription factors NMP4 and FOXP3 in regulating airway inflammation. / 2022-08-17

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21413号 / 医博第4403号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 伊達 洋至, 教授 中川 一路 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Solitary extramedullary plasmacytomas are uncommon neoplasms. They occur most frequently in the upper aerodigestive tract and account for 4% of the nonepithelial tumors in this site. The evolution of a plasmacytoma is unsteady and symptoms at presentation have included dystonia, dysphagia, oral pain, cough, and dyspnea on exertion. Plasmaeytoma of the upper aerodigestive tract has not been previously reported as a cause of obstructive sleep apnea.

Allergic asthma is a chronic inflammatory disease of the airways. Importantly, the chronic nature of this disease imparts specific additional consequences that would not otherwise be observed in a strictly acute setting. The development ofvarious structural alterations to the airway wall, collectively tem1ed airway remodeling, represents one such example. Decades of research have provided a great deal of insight into the acute allergic asthmatic response and the processes that govern it. However, less is known about the impact of protracted allergen exposure and chronic immune-inflammatory responses. To this end, the research presented in this thesis explores the consequences of chronic allergen exposure and persistent airway inflammation on asthma pathogenesis, using a mouse model of allergic airway disease induced by respiratory exposure to house dust mite (HDM) allergens. Specifically examined are: i) the impact of continuous allergen exposure and the resulting immune-inflammatory response on the development of de nova sensitization to newly encountered allergens (Chapter 2) and, ii) the roles oftransforming growth factor (TGF)-~ and eosinophils, two putatively critical components of the allergic inflammatory response, in the generation of airway remodeling (Chapters 3 and 4). Our data show that chronic exposure to HDM facilitates the development of the full 'asthmatic phenotype' towards an innocuous antigen. Moreover, they demonstrate that, unlike what has been previously observed in ovalbumin-based models, neither TGF-~ nor eosinophils are critically required for remodeling to develop in the context of HDM exposure. These findings highlight the importance of the lung microenvironment in influencing the type of immune response that develops upon initial antigen encounter and, furthermore, underscore the notion that the role of a particular cell type or molecule in the asthmatic response is contextual and not necessarily broadly applicable. / Thesis / Doctor of Philosophy (PhD)

Disease identification is one of the most important aspects of a physician's duties. Radiologists play a very important role in disease recognition based on the increasing use of diagnostic images. Nowadays, medical scanning devices such as MRI and CT produce thousands of images per patient which makes the radiologist's job even more onerous; indeed radiologists look at approximately 50,000 images per day leading to fatigue and a higher probability for missing smaller lesions. Therefore it is critical to assist radiologists in their duties.In this PhD work, research is focused on developing segmentation-based mathematical algorithms and computer programs for automatically characterizing lung CT images. There are two kinds of segmentation methods; the first group contains the methods that find edges of all objects in the image and the second group contains the methods that focus on one object in the image. By assessing many segmentation methods and based on the concept of this project, the level set method, from the second group, has the capability to accurately find the boundary of an object in medical images. Although this method does not need any threshold for segmenting an object in an image, it does require the setting of seven parameters. Genetic algorithms were employed to optimize seven parameters of the level set method for use as a boundary detection method. A streamlined automatic mechanism, essential for successful and fast segmenting processes, provided the level set method with a good initial contour.This segmentation step was fundamental for further measurements such as bronchial lumen diameter and wall thickness measurement. The developed program automatically measures airway lumen diameter with exceptional repeatability. Also, by simulating manual methods used by radiologists for measuring luminal wall thickness, the automated fitting method consistently finds the wall thickness at the thinnest part, minimizing partial volume problems. The current standard for measuring luminal wall thickness is the full-width at half-maximum method. The technique formulated here is more accurate and reproducible and can be performed automatically. To find the lumen airway tapering, in order to recognize some prominent lung diseases, a method for tracing of an airway through various CT slices was developed. These measurements are of critical importance in the understanding of a number of lung diseases including asthma and COPD; this tracing step was fundamental for bronchial bifurcation angle measurement. This tracing method was extended to detect and follow bifurcation branches. Then, an estimation method for finding a fitted line through airway center points was developed. For the last portion of this PhD work an approach for measuring lung airway bifurcation angle from CT datasets, which is important in lung diseases such as asthma, was created. The current goal, characterizing lung CT images, was achieved as a working form of this software development. This mathematical approach has been shown to be accurate with phantom studies. The ultimate goal of this work was to develop software for recognizing key lung diseases and to compare serially (weeks or months apart) acquired images to assess any progress, regression, or stability in a disease. / Thesis / Doctor of Philosophy (PhD)

Communication between epithelial and immune cells is critical for the maintenance and repair of mucosal tissues, with dysregulated epithelia contributing to pulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma, cancer and pulmonary fibrosis. While the role of immune cells in regulating epithelial maintenance and repair has been extensively studied in the distal lung, relatively little is known about the immune microenvironment in the proximal conducting airways, including the function of these immune cells in epithelial regeneration and repair. To study the biology of the human conducting airways, we utilized the mouse trachea as a model tissue and sought to characterize the global immune landscape at homeostasis by multi-parameter flow cytometry and single cell RNA sequencing (scRNA-seq). We then utilized a well-characterized model of tracheal epithelial injury to study changes in the immune landscape in response to injury. These studies revealed that neutrophils are early responders to airway epithelial injury and may function to phagocytose epithelial cell debris. Monocytes and macrophages are then recruited to the injured airway and adopt an activated anti-inflammatory phenotype to participate in tissue repair. Finally, we examined the impact of severe combined immunodeficiency on epithelial cells at homeostasis and following injury. Airway basal stem cells in immunodeficient animals have altered expression of genes related to cytoskeletal support, epithelial adhesion and critical signaling pathways that may impact airway epithelial morphology, barrier integrity, and proliferation and differentiation following injury. Together, these data suggest a functional tracheal immune microenvironment is critical for both the normal development and functional regeneration of the airway epithelium. Macrophages are heterogenous and adaptable immune cells that have has important functions in pulmonary homeostatic maintenance and tissue repair. Distinct subtypes of macrophages have important implications for injury response and repair in the lungs, though relatively little is known about the phenotypes and roles of macrophages in the proximal conducting airways. To address this gap, we characterized murine tracheal macrophages relative to more distal pulmonary macrophages using scRNA-seq and flow cytometry. Tracheal macrophages have a cell surface signature distinct from any previously characterized pulmonary macrophage subtype and were shown to be largely monocyte-derived macrophages generated via fetal liver kinase-2 (Flk2)-dependent adult hematopoiesis. Following polidocanol airway injury, these specialized monocyte-derived tracheal macrophages are recruited to the trachea to become pro-regenerative activated macrophages to aid in regeneration and repair. This macrophage injury response is largely dependent on the chemokine receptor CCR2, with CCR2-deficient mice showing decreased tracheal macrophage recruitment and activation, abnormal epithelial morphology, altered proliferation of airway stem cells, and delayed epithelial repair. Overall, this work highlights the importance of tissue-specific injury-responsive macrophages in airway epithelial regeneration and repair. / 2025-02-12T00:00:00Z

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25003号 / 医博第5037号 / 新制||医||1070(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 後藤 慎平, 教授 平井 豊博, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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