Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive and severe interstitial lung diseases (ILDs) for which there is no cure. IPF is characterized by an excessive accumulation of fibroblasts which secrete an abundance of extracellular proteins such as collagen. These processes lead to repetitive tissue scarring and fibrosis in the lung parenchyma. As a result, lungs become rigid limiting oxygen intake and gas exchange. Once diagnosed, IPF is fatal within 2-3 years. There is no known cause or proven treatment that significantly improves outcomes. Although the cause is unknown, the current model of IPF suggests that an overactive epithelial repair mechanism caused by genetic and epigenetic factors as well as environmental exposures is responsible for the chronic fibrosis and scarring characteristic of IPF. The transforming growth factor beta (TGF-B) signaling pathway has been implicated as a major contributor in activating this chronic fibrosis. An upstream activator of the TGF-B pathway, avB6, has been identified as a potential therapeutic target. My collaborators in Dr. David Baker's lab at the University of Washington have created a novel avB6 integrin inhibitor (BP2_disulf) whose efficacy in improving IPF outcomes has yet to be tested. In my study, I test the ability of BP2_disulf to combat IPF through the use of the standard IPF murine model and translatable end points like non-invasive uCT scans, pulmonary function tests, bronchoalveolar lavage fluid (BALF) profiles, and histology. With these methods, I demonstrate that intraperitoneal injection of BP2_disulf in bleomycin-injured mice has the ability to decrease rate of fibrotic progression and pulmonary function decline compared to mice treated with bleomycin alone. These results prove that BP2_disulf is a promising therapeutic not only for IPF but other ILDs as well. Further efficacy validation and investigation into an aerosolized delivery method will advance this drug to clinical trials and make it accessible to those in need.

Die Allergische Rhinitis als Allergie vom Typ I (Soforttyp) ist nicht nur in Deutschland und Europa weit verbreitet, sondern eine weltweit auftretende Erkrankung. Als Verursacher werden neben bereits bekannten Aeroallergenen wie Hausstaubmilben, Gräser oder Pollen auch luftgetragene Algen diskutiert, die als möglichen Mechanismus über eine T-Zell-abhängige Stimulation Antigen-bindender B-Zellen zur IgE-Produktion führen. Diese Arbeit befasst sich mit der Untersuchung des allergenen Potentials der luftgetragenen Algenspezies S. bacillaris, T. aeria und X. montanum. Dafür wurden mittels direkter und indirekter Sandwich-ELISA-Verfahren Seren von Patienten mit der Diagnose Allergische Rhinitis oder Idiopathische Rhinitis auf enthaltene IgE-Antikörper getestet, die spezifisch an festphasengebundene Algenproteine binden. Des Weiteren wurden Kompetitionstestungen zur Untersuchung der Kreuzhemmbarkeit der drei Algen sowie SDS-Gelelektrophoresen und Western Blots zur Bestimmung der Molmasse der Algenproteine und zum Nachweis der Spezifität des algenbindenden IgEs durchgeführt. Die Ergebnisse belegen, dass die getesteten Algenproteine in der Lage sind, eine entsprechende Immunantwort mit IgE-Produktion auszulösen. Diese neue Gruppe von Allergenen konnte hinsichtlich der Entstehung einer Allergie vom Soforttyp und der damit verbundenen klinischen Bedeutung bewertet werden.

Untreated human immunodeficiency virus (HIV) can be complicated by opportunistic infections, including disseminated histoplasmosis (DH). Although endemic to portions of the United States and usually benign, DH can rarely act as an opportunistic infection in immunocompromised patients presenting with uncommon complications such as acute kidney injury and idiopathic thrombocytopenic purpura. We report a rare presentation of DH presenting with acute kidney injury and immune thrombocytopenic purpura in an immunocompromised patient with HIV.

Gymnastics is noted for involving highly specialized strength, power, agility and flexibility. Flexibility is perhaps the single greatest discriminator of gymnastics from other sports. The extreme ranges of motion achieved by gymnasts require long periods of training, often occupying more than a decade. Gymnasts also start training at an early age (particularly female gymnasts), and the effect of gymnastics training on these young athletes is poorly understood. One of the concerns of many gymnastics professionals is the training of the spine in hyperextension—the ubiquitous ‘arch’ seen in many gymnastics positions and movements. Training in spine hyperextension usually begins in early childhood through performance of a skill known as a back-bend. Does practising a back-bend and other hyperextension exercises harm young gymnasts? Current information on spine stretching among gymnasts indicates that, within reason, spine stretching does not appear to be an unusual threat to gymnasts’ health. However, the paucity of information demands that further study be undertaken.

Background: This is a case study of an 18-year-old female who suffered a bilateral idiopathic sensorineural hearing loss that was coincident with the removal of four impacted wisdom teeth. Throughout childhood the patient had normal hearing for pure tones bilaterally as measured at the pediatrician's office. One month prior to dental surgery (May) the patient volunteered to participate in an auditory experiment at which time her pure-tone audiogram was normal. Immediately following surgery (June), the patient had substantial swelling of the face and complained of some hearing loss with no other auditory/vestibular complaints. The following month (July) during the course of a routine physical examination a pure-tone audiogram revealed bilateral, air-conduction thresholds of 30-35 dB HL (500-4000 Hz) and 20 dB HL (8000 Hz). Because bone conduction was not tested, it is impossible to know whether the hearing loss was conductive, mixed, or sensorineural. The pediatrician thought that the hearing loss was conductive and would resolve as the edema subsided. A month later (August) the subject again volunteered for an auditory experiment at which time her hearing again was tested. Purpose: The purpose of this report is to detail the dental procedures involved in the extraction of the wisdom teeth, to report the results of a variety and series of post-op hearing tests, and to discuss the possible mechanisms that might be involved in the ''idiopathic'' bilateral sensorineural hearing loss. Research Design: Case report. Results: During the August visit to the laboratory, hearing for pure tones bilaterally was 0 to 5 dB HL at 250-1000 Hz with a 40-45 dB HL notch at 2000 Hz with a return to 10 dB HL at 8000 Hz. Air conduction and bone conduction thresholds were equivalent. Word recognition in quiet was ≥92 percent correct for both ears, whereas the signal-to-noise ratio (SNR) hearing loss measured with the Words-in-Noise test was high normal in the left ear with a mild SNR hearing loss in the right ear. Tympanometry and acoustic reflex thresholds were normal. Distortion product otoacoustic emissions were reduced in the 1000-3000 Hz region for both ears, which is consistent with cochlear hearing loss. The hearing loss has remained unchanged for the past 19 months. Conclusions: The possible etiologies, including insults to the cochleae by vibration trauma and through alterations in the blood supply to the cochleae, are considered.

Polymorphic ventricular tachycardia (PVT) is a life-threatening arrhythmia that is typically related to long QT syndrome, organic heart disease, electrolyte abnormalities, cardiotoxic drugs, or adrenergic stimulation. A review of the literature reveals that PVT with normal QT interval and without underlying cause is quite rare. We report a case of idiopathic spontaneous PVT with structurally normal heart and without electrolyte abnormalities, drug reactions, or evidence of catecholamine induced arrhythmia. We also review the literature on the electrocardiographic characteristics and management of idiopathic PVT.

The present study aimed to test the accuracy of using diffuse idiopathic skeletal hyperostosis (DISH) to make positive identifications using the method of antemortem and postmortem radiographic comparison. An online survey was developed to evaluate whether DISH is a feature of the skeleton that can be used in radiographic image comparison. Three digital radiographic images from 51 individuals were gathered for use in this study: one image taken at a baseline date (Group A), one image taken within 2 years from baseline (Group B), and one image taken greater than 4.5 years from baseline (Group C). A total of 40 survey participants were tasked with comparing between a simulated “antemortem” image and a “postmortem” image from living patients and identifying which image pair represented the same individual at different time intervals. Information about survey participants’ field, degree, experience working with radiographs, and familiarity with DISH were also recorded. Accuracy, sensitivity, and specificity were measured. Series 1 compared Group A images to Group B images and resulted in an accuracy of 87.3%, sensitivity of 46.9%, and specificity of 94.3%. Series 2 compared Group A images to Group C images and resulted in an accuracy of 83.4%, sensitivity of 34.3%, and specificity of 95.8%. The study concluded that the characteristics of DISH did not prove reliable for making positive identifications but established that DISH could be used to narrow down potential matches.

Background: Recent studies have suggested that patients with idiopathic pulmonary fibrosis (IPF) may have a higher risk of venous thromboembolism (VTE) compared to general population even though the results were inconsistent. Objective: To investigate the risk of VTE among patients with IPF. Methods: Comprehensive literature review using MEDLINE and EMBASE database were performed to identify studies that compared the risk of VTE among patients with IPF to general population. Effect estimates from each study were combined together using random effect model, generic inverse variance method of DerSimonian and Laird. Results: Out of 510 retrieved articles, 5 studies met the inclusion criteria and were included in the meta-analysis. A significant risk of VTE in patients with IPF was observed with the pooled risk ratio of 2.11 (95% confidence interval, 1.28-3.48). The heterogeneity was moderate with I2 of 64%. Conclusion: An approximately 2-fold increased risk of VTE among patients with IPF was observed in this meta-analysis.

Juvenile idiopathic arthritis, JIA, is used as an umbrella term covering a heterogeneous group of chronic arthritis forms in children, many of which have important differences compared to adult arthritis, while others possibly represent similar diseases among children and adults. Classification aims to give a better understanding of the pathogenesis, patterns, disease trajectories and treatment responses. For the juvenile psoriatic arthritis, JPsA, the classification criteria are currently being debated. The distribution of affected joints in JIA differs greatly and it is unknown why some joints appear to be more affected than others. The temporomandibular joint (TMJ) can be affected early in the course of the disease and often the symptoms are mild and without obvious swelling. This thesis has its origin in the Nordic Study Group of Paediatric Rheumatology and the population-based prospective study of 510 children with newly diagnosed JIA included between 1997 and 1999. Totally 440 children were included in the eight-year follow-up, and in the TMJ study 265 patients were examined and underwent cone-beam computed tomography, CBCT, 17 years after onset. After eight years a considerable proportion of the children with definite psoriasis were classified as undifferentiated JIA based on the exclusion criteria in the ILAR classification. Our data also presents the heterogenicity of JPsA and the development over time of clinical variables supporting a psoriatic diathesis, as well as the overlap between JPsA and enthesitis-related arthritis in a group of patients.  We found that extensive symptoms and dysfunctions of the TMJ are seen in JIA 17 years after disease onset, even in patients registered with inactive disease or remission. Individuals with substantial condylar damage on CBCT were found in all JIA categories. The deeper understanding of a chronic disease over time is crucial for research initiatives to improve care as well as for clinical decisions and planning of the health care. Our findings suggest a need for a more appropriate classification of JPsA and also that aspects of TMJ involvement should be included in the general health assessment in JIA.

Final publication is avilable at http://www.sciencedirect.com/science/article/pii/S0954611115300172 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19577号 / 医博第4084号 / 新制||医||1013(附属図書館) / 32613 / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 平家 俊男, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM