In the last decade aluminium started to be considered as an alternative to steel to produce car body panels, especially considering the strict demands to decrease fuel consumption which require vehicle weight reduction. In order to keep their leading role, steel companies have to produce stronger materials to reduce the thickness of steel sheets used in cars and are now considering non-conventional steel making processes. The purpose of this PhD research was to investigate the possibility of strengthening thin sheets of interstitial free steel (IF steel) by using carbon rich films deposited on the steel surface using Physical Vapour Deposition (PVD). These films then act as a carbon reservoir which upon heat treatment release carbon in the IF steel and strengthen it. Coated tensile coupons 200 μm thick were annealed at different temperatures under high vacuum. Tensile tests show that a 100 MPa increase in yield stress can be obtained after annealing at 430 ˚C for 1h in high vacuum. The effects of annealing environment, film thickness and prestrain on carbon diffusion were also investigated. It was shown that carbon diffusion from the film to the IF steel substrate is limited by the film transformation into cementite at temperatures equal or higher than 530 ˚C. All tensile curves showed a plastic instability known as Lüders plateau, which is undesirable as it results in surface markings on the deformed part. FEM analyses were performed to find ways to suppress the Lüders plateau, proving that increasing strain-hardening or having a graded instead of uniform carbon content through thickness can suppress or limit Lüdering. The possibility of creating a through thickness gradient of microstructure was investigated as it could suppress Lüdering and result in higher strength. For these tests, FeC coated coupons were induction heated to 820 ˚C followed by water quenching. After only 2 minutes of heat treatment the yield stress was increased by 250 MPa and the ultimate tensile strength reached 400 MPa. With an annealing of 4 minutes, the Lüders plateau was fully suppressed and the microstructure consisted in ferrite grains and TiC nanocarbides. This work demonstrates that FeC films can be effectively used to diffuse carbon into steel and that a significant increase in mechanical properties can be obtained after a heat treatment of only a few minutes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22883号 / 医博第4677号 / 新制||医||1048(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 平井 豊博, 教授 川上 浩司, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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.

Les mutations du gène codant pour la protéine C (SP-C) du surfactant pulmonaire (SFTPC) sont à l’origine de pathologies interstitielles chroniques du nourrisson, de l’enfant mais également de l’adulte. Une importante hétérogénéité phénotypique est cependant observée, y compris au sein d’une même famille. Par un épissage alternatif, le gène SFTPC permet la synthèse de deux isoformes du précurseur protéique de SP-C (proSP-C) pour aboutir à la protéine mature après plusieurs modifications post-traductionnelles. Les conséquences des mutations de SFTPC sur l'homéostasie du surfactant ne sont pas clairement élucidées, mais il semble que le mauvais repliement de la protéine soit une caractéristique commune. A l’issue de nos travaux antérieurs, nous avons mis en évidence un effet de certaines mutations et de polymorphismes sur l’épissage de SFTPC faisant ainsi varier significativement l’expression de chacune des deux isoformes protéiques, sans qu’à l’heure actuelle nous ne connaissions le rôle de chacune dans la synthèse de la protéine SP-C mature. Notre projet, s’inscrivant dans la continuité de mon master 2, a pour but de mieux comprendre les mécanismes physiopathologiques pré et post-transcriptionnels associés aux variations de SFTPC et leurs conséquences sur le développement des pneumopathies interstitielles. Le premier axe de notre projet repose sur l’étude in vitro (lignées cellulaires) et in vivo (modèle murin, ARN des patients) des variations de chacun des isoformes. Dans un second axe, nous souhaitons poursuivre l'étude de facteurs pouvant influencer le phénotype des patients porteurs de mutations du gène SFTPC, qu'ils soient d'origine externes (infections virales et bactériennes ou environnementaux comme le tabac) ou génétique. Collectivement, ces études nous permettrons de fournir une signature moléculaire pour cette maladie et d’identifier de nouvelles cibles thérapeutiques afin d’en améliorer le pronostic mais également la prise en charge et la qualité de vie des patients. / Surfactant pathologies linked to mutations in the SFTPC gene, via autosomal dominant transmission, are most commonly associated with diffuse interstitial diseases in infants, children and adults, and may also be responsible for acute respiratory distress syndrome in newborns. They are most often accompanied by a high morbidity and mortality rate, thus rendering early diagnosis essential for ideal intervention and support. Mutations in the SFTPC gene lead to alveolar and intracellular accumulation of an abnormal form of the precursor protein SP-C (ProSP-C), which is responsible for the resulting tissue damage. However, the pathophysiological mechanisms are not yet completely deciphered. The gene encodes two isoforms of ProSP-C from three alternative transcripts. The expression level of each is currently unknown and the vast majority of studies evaluating the effect of mutations are performed on only one isoform. Incidentally, our preliminary results on the analysis of RNA extracted from bronchoalveolar washing, both from control subjects and patients harboring a mutation, show that the all three SFTPC transcripts are expressed and that the presence of a mutation is associated with a variation in the expression levels of the transcripts. The aim of my project is to study the expression level of SFTPC transcripts and ProSP-C isoforms from the heterologous expression of the SFTPC gene (exons and introns) in cell lines. I will beanalyzing the post-translational maturation profile of these pro-proteins and evaluating the effect of the mutations on their expression and maturation in both our cellular models and in vivo with two Knock-in mice models.A better understanding of the pathophysiology of genetic abnormalities associated with mutations in the SFTPC gene will not only greatly contribute to earlier management of patients, but also it will help in modifying the progression of lung injury and its prognosis.

Intravenous fluid infusion during surgeries is based on clinical practice guidelines. Many factors impact the fluid distribution in the body, mainly the effect of anesthetic gases and surgical stress. Volume kinetics is a method to simulate the distribution and elimination of infusion fluids by considering the dilution of plasma over time. In this work, two volume kinetic models for fluid therapy are described – the single and two-fluid space model. The goal was to estimate five volume kinetic parameters for implementation in a population kinetic model. The method was based on data from an experiment at the University of Texas Medical Branch where the purpose was to examine the effect of the anesthetic gas isoflurane on fluid distribution after a controlled bleeding. In this project, measured hemoglobin concentrations from the experiment were used to determine the plasma dilution over time. Volume kinetic models were constructed by approximating terms in corresponding differential equations. As opposed to the single-fluid space model, the two-fluid space model gave a closer estimation to the experimental data. The two-fluid space model parameters were considered to be suitable for further population kinetic analysis.

Introduction Acute interstitial nephritis (AIN), also called tubulointerstitial nephritis, is a renal pathology that can cause a significant decline in kidney function. Drug-induced AIN accounts for 70% of all cases and is often due to non-steroidal anti-inflammatory drugs (NSAIDs), antimicrobials, and proton pump inhibitors. However, there have been isolated reports of other drugs being responsible for AIN. We hereby report a case of furosemide-induced AIN. Case Presentation A 68-year-old caucasian male with a medical history significant for chronic kidney disease (CKD) stage 3 due to hypertensive nephrosclerosis with a baseline serum creatinine (Cr) of 1.3-1.5, hypertension, hyperlipidemia, atrial fibrillation, heart failure with preserved ejection fraction (HFpEF), and hypogonadism was admitted for evaluation of worsening renal failure. At initial evaluation, the patient had nonspecific symptoms like malaise, nausea, and vomiting but denied any other complaints. Physical examination was unremarkable, without any rashes or abdominal bruit. The patient’s creatinine progressively trended up from his baseline to 3.5 over three months. Pre-renal pathology was suspected initially, and the patient's furosemide was held on admission with concurrent fluid resuscitation. However, this did not improve his kidney function as repeat lab work showed a worsening Cr level of 4.4, along with a blood urea nitrogen (BUN) of 72. Further evaluation showed a complete blood count significant for mild eosinophilia with urinalysis revealing hematuria, pyuria with eosinophiluria but no protein, WBC casts, or RBC casts. Renal ultrasound and abdominal CT scan were unremarkable. The patient had no known drug allergies until that point and was on a stable medication regimen for his chronic conditions for several years, except for a daily dose of furosemide started three months ago for fluid retention and elevated BNP. Ultrasound-guided renal biopsy revealed findings consistent with acute interstitial nephritis on top of chronic tubulointerstitial fibrosis plus underlying moderate arterial sclerosis from hypertension. Other extensive workup was negative for any autoimmune process, IgG4 related disease, sarcoidosis, or infection, thus favoring the diagnosis of drug-induced acute interstitial nephritis. Given the temporal relationship between the initiation of furosemide in this patient and his worsening kidney function makes it the likely offending agent. He was observed off furosemide without any immunosuppressant treatment. The patient’s creatinine level gradually trended down and ultimately returned to his baseline at a one-month follow-up. Discussion Furosemide is a loop diuretic, often used in patients to prevent volume overload. Therefore, furosemide is often implicated as a cause of pre-renal acute kidney injury (AKI) secondary to volume depletion. However, interstitial inflammation as a mechanism of furosemide-induced kidney injury is uncommon and can often be overlooked as a potential cause, especially in patients with long medication lists. In such patients, a causal link can be established by correlating the onset of decline in kidney function with the time of initiation of a new drug and resolution of AKI after discontinuation of the drug.

No description available.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a disabling chronic disease of still unknown origin and complex pathophysiology. The disease affects mainly female patients, with a female to male ratio of about 9 to 1. Prevalence ranges from 52 to 500/100,000 in females and 8 to 41/100,000 in males. The diagnosis of IC/BPS is mainly hampered by the lack of appropriate biomarkers and, therefore, extensive clinical examinations are required to exclude “confusable” diseases [1]. In consequence, most patients experience several years of ineffective treatments of various urinary tract symptoms often associated with, but by themselves not characteristic of, IC/BPS. Unequivocal diagnosis of IC/BPS is the prerequisite to find more effective therapeutic approaches. Therefore, more specific biomarkers are needed to facilitate IC/BPS diagnosis and to stratify patients for treatment at earlier stages of the disease. In this Special Issue, we gathered reviews and original work elucidating the current developments in IC/BPS biomarker research.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23782号 / 医博第4828号 / 新制||医||1057(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 羽賀 博典, 教授 波多野 悦朗, 教授 溝脇 尚志 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.