Osteochondral lesions of the talus (OLTs) are the third most common type of osteochondral lesion and can cause pain and instability of the ankle joint. Episurf Medical AB is a medical technology company that develops individualized implants for patients who are suffering from focal cartilage lesions. Episurf have recently started a project that aims to implement their implantation technique in the treatment of OLTs. This master thesis was a part of Episurf’s talus project and the main goal of the thesis was to find the optimal implantation angle of the Episurf implant when treating OLTs. The optimal implantation angle was defined as the angle that minimized the maximum equivalent (von Mises) strain acting on the implant shaft during the stance phase of a normal gait cycle. It is desirable to minimize the strain acting on the implant shaft, since a reduction of the strain can improve the longevity of the implant. To find the optimal implantation angle a finite element model of an ankle joint treated with the Episurf implant was developed. In the model an implant with a diameter of 12 millimeters was placed in the middle part of the medial side of the talar dome. An optimization algorithm was designed to find the implantation angle, which minimized the maximum equivalent strain acting on the implant shaft. The optimal implantation angle was found to be a sagittal angle of 12.5 degrees and a coronal angle of 0 degrees. Both the magnitude and the direction of the force applied to the ankle joint in the simulated stance phase seemed to influence the maximum equivalent strain acting on the implant shaft. A number of simplifications have been done in the simulation of this project, which might affect the accuracy of the results. Therefore it is recommended that further, more detailed, simulations based on this project are performed in order to improve the result accuracy. / Fokala broskskador på talusbenet är den tredje vanligaste typen av fokala broskskador och kan ge upphov till smärta och instabilitet av fotleden. Episurf Medical AB är ett medicintekniskt företag som utvecklar individanpassade implantat för patienter med fokala broskskador. Episurf har nyligen påbörjat ett projekt där deras teknik ska användas i behandlingen av fokala broskskador på talusbenet. Den här masteruppsatsen var en del i Episurfs talusprojekt och dess huvudmål var att finna den optimala implantationsvinkeln av Episurfs implantat i behandlingen av fokala broskskador på talusbenet. Den optimala implanteringsvinkeln definierades som den vinkel som minimerade den effektiva von Mises-töjningen som verkade på implantatskaftet under stance-fasen i en normal gångcykel. Det är eftersträvansvärt att minimera belastningen på implantatskaftet eftersom en reducering av belastningen kan förbättra implantatets livslängd. En finita element-modell av en fotled behandlad med Episurfs implantat utvecklades för att för att finna den optimala implantationsvinkeln. I modellen placerades ett implantat med en diameter på 12 millimeter på mittendelen av talus mediala sida. En optimeringsalgoritm utformades för att finna implantationsvinkeln som minimerade den effektiva von Mises-töjningen på implantatskaftet. Den funna optimala implantationsvinkeln bestod av en vinkel på 12.5 grader i sagittalplan och en vinkel på 0 grader i koronalplan. Både storleken och riktningen på kraften som applicerats på fotleden under den simulerade stance-fasen av gångcykeln verkade påverka belastningen på implantatskaftet. Ett antal förenklingar har gjorts i projektets simuleringar, vilket kan påverka noggrannheten i resultatet. Därför rekommenderas att ytterligare, mer detaljerade simuleringar baserade på det här projektet görs för att förbättra resultatets noggrannhet.

Image segmentation and image registration are two fundamental problems in computer vision and medical image processing. In image segmentation, one seeks to partition an image into meaningful segments by assigning a label to each pixel indicating which segment it belongs to. In image registration, one seeks to recover a spatial transformation that geometrically aligns two or more images, which allows downstream image analyses in which the registered images share a coordinate system. Image processing pipelines typically apply these procedures sequentially even though the segmentation of an image could improve its registration and registration of an image could improve its segmentation. With an appropriate parametrization, one can view these two tasks as an inference problem in which the spatial transformation and segmentation are latent variables. In this work, registration and segmentation are integrated through a hierarchical Bayesian generative framework. The framework models the data generating process of a set of magnetic resonance (MR) images of ischemic stroke lesioned brains. Under this framework, we simultaneously estimate a lesion tissue segmentation along with a spatial diffeomorphic transformation that maps a subject image into spatial correspondence with a healthy template image. The framework is evaluated on two-dimensional images both real and synthetic. Experimental results on real MR images show that simultaneous segmentation and registration can significantly improve the accuracy of lesion segmentation as well as the accuracy of registration near the lesion.

Four studies were conducted to investigate plant-parasitic nematodes (PPN) of corn and soybean in ND. The first study investigated the incidence and abundance of vermiform PPN in ND corn fields in 2015 and 2016. Samples were collected from 300 corn fields across 20 counties. Seventy-two percent of the fields were positive for PPN. The major genera of PPN identified were Helicotylenchus, Tylenchorhynchus, Paratylenchus, Pratylenchus, Heterodera, Xiphinema, Hoplolaimus, and Paratrichodorus. The second study characterized SCN (SCN; Heterodera glycines) virulence phenotypes in ND. A total of 419 soybean fields across 22 counties were sampled during 2015, 2016, and 2017. Among these samples, 73 SCN field populations were successfully virulence phenotyped using the HG type tests. The HG types that were detected and confirmed in ND were HG type 0, 7, 2.5.7, 5.7, 1.2.5.7, and 2.7. The third study developed a new molecular method for detecting and identifying a new Pratylenchus sp. discovered in a soybean field in ND. A species-specific primer set, that can be used in both conventional and real-time polymerase chain reaction (PCR) assays, was designed from the internal transcribed spacer (ITS) region of ribosomal DNA. Laboratory experiments confirmed that the primers only amplified DNA of the target nematode species but not the non-target species used in the specificity tests. Practically, DNA from as little as a single nematode could be used to specifically identify the new Pratylenchus sp. using the molecular diagnostic methods developed in this study. The fourth study was conducted to ascertain resistance levels of 20 soybean cultivars to the new Pratylenchus sp. Combined results of four trials indicated that seven of the cultivars were moderately resistant, ten were moderately susceptible, four were susceptible, and none of the cultivars tested were resistant. Analysis of the habitat preference of the new Pratylenchus sp., revealed that above or close to 50% of the nematode population resided in roots at nine weeks after planting for a majority of the cultivars evaluated. Results from these studies will be helpful in improving nematode detection and developing management strategies to control plant-parasitic nematodes in ND corn and soybean fields.

Several seemingly conflicting sets of data have been reported on the regenerative capacity of central noradrenergic neurons, following transection of the ascending noradrenergic fiber tract in neonatal rats (Iacovitti et al., Dev Brain Res 1: 21-33, 1981; Jonsson and Sachs, Brain Res Bull 9: 641-650, 1982). In order to more fully investigate changes in noradrenergic neurons in the brain after such a transection, rats were lesioned at various times after birth, sometimes in conjunction with administration of the neurotoxin, 6-hydroxydopa (6-OHDOPA). Animals were sacrifced at 7, 10, 14, 28, 42 or 56 days after birth, in order to assess the pattern of noradrenergic neuronal damage, as well as the recovery rate. Dorsal bundle lesions were associated with neocortical and hippocampal hypoinnervation by noradrenergic fibers, and sprouting of a collateral fiber group, with production of noradrenergic hyperinnervation of the cerebellum and pons-medulla. Recovery of the norepinephrine (NE) content to control levels occurred in the neocortex at 8 weeks, when the dorsal bundle was lesioned at birth. When the lesion was produced at a later time (3 days or 5 days after birth), less recovery in the neocortex and hippocampus was found. Histofluorescent fiber number, as observed with a glyoxylic acid method, correlated with NE changes. It appears that 6-OHDOPA (20 μg/g IP) does not modify long-term recovery from a dorsal bundle lesion, when rats are co-treated at 3 days after birth. However, the length of the proximal noradrenergic fiber stump may be an important factor affecting the capacity for recovery from injury. These results suggest that a shorter fiber stump, as produced with a dorsal bundle lesion at the level of the pons, may be associated with a greater degree of recovery from injury. Also, the younger the rat at the time of injury, the greater appears to be the capacity for regeneration. These results demonstrate that regeneration can occur in one part of the brain without modification of a collateral hyperinnervation of a different part of the brain. Therefore, our findings discount a programming of central noradrenergic fibers to express a specific number of nerve terminal arborizations, (i.e., the "pruning hypothesis").

To determine whether behavioral sensitization produced by prolonged D-amphetamine administration affects susceptibility of nigrostriatal dopaminergic neurons to the neurotoxic actions of 6-hydroxydopamine (6-OHDA), rats were treated daily from the 23 rd day after birth for 11 consecutive days with D-amphetamine (1.0 mg/kg s.c.) or saline. On the last day of treatment, one group primed with D-amphetamine and one control group of rats were tested to confirm behavioral sensitization development. The remaining animals were additionally treated on the 34 th day (one day after the last D-amphetamine injection) with 6-OHDA HBr (300 μg in 10 μl i.c.v., salt form, half in each lateral ventricle) or its vehicle. Four weeks later the levels of dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-metoxytyramine (3-MT), as well as 5-hydroxytrypatmine (5-HT) and its metabolite 5-hydroxyindoleacteic acid (5-HIAA) were assayed in the striatum, by HPLC/ED. In rats with behavioral sensitization, 6-OHDA reduced endogenous dopamine and its metabolites content to a comparable degree in comparison to controls. This finding indicates that presumed up-regulation of the dopamine transporter in the behaviorially sensitized rats did not increase the neurotoxicity of a high dose of 6-OHDA.

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT 2A/5-HT2C-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT2-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia - a clinical syndrome linked to enhanced sensitivity to N-methyl-D-aspartate (NMDA)-receptor antagonists.

A thesis submitted to the College of Dental Medicine of Nova Southeastern University of the degree of Master of Science in Dentistry. Objective: This study was conducted to determine the resistance to wear and effectiveness of Opal®Seal (Opal Orthodontics by Ultradent, South Jordan, UT, USA) against enamel demineralization in comparison to L.E.D. Pro Seal® (Reliance Orthodontic Products, Itasca, IL, USA). Background: Development of white spot lesions (WSL) is a primary concern during fixed orthodontic treatment. With poor oral hygiene during orthodontic therapy, it is almost inevitable that enamel demineralization will occur and WSLs will be seen clinically. Numerous materials have demonstrated successful prevention of WSLs, including topical varnishes and sealants, gels, pastes and bonding agents. The newly developed sealant Opal Seal is claimed by the manufacturer to prevent demineralization and subsequent WSLs from forming during orthodontic treatment. To evaluate the effectiveness of Opal Seal, we tested and compared it to Pro Seal, which has proven to be successful at WSL prevention and is, like Opal Seal, a fluoride-releasing, light-cured, low viscosity filled resin sealant. Methods: A total of 48 non-carious extracted human premolar teeth were divided into 3 groups representing one of the following topical treatments: no treatment (C), Opal Seal (OS) or L.E.D. Pro Seal (PS). Each group was subdivided into either T1 or T2 time interval groups (C1, C2, OS1, OS2, PS1 and PS2) and teeth were subjected to 10,000 or 20,000 simulated brush strokes, respectively, followed by exposure to an acidic solution for 96 hours. Teeth were examined macroscopically for product wear and assessment of WSL development and then sectioned for quantitative examination with polarized light microscopy. Results: Visual assessment revealed wear of L.E.D. Pro Seal in 62.5% of the PS2 teeth following exposure to toothbrush abrasion and acidic challenge. No L.E.D. Pro Seal or Opal Seal wear was found in any PS1 or OS teeth, respectively. WSLs involving 50-100% of the exposed enamel surface developed in all control teeth and 37.5% of PS teeth had WSLs involving less than 50% of their enamel surface. These WSLs were visible as small, white, isolated points. No visible WSLs were found in any teeth in the OS group. A Fisher's Exact test was used to evaluate any differences in demineralization within groups over time. The results indicate a significant difference in the number of lesions found at T1 compared to T2 in the PS group (p = 0.003). A non-parametric Kruskal-Wallis test using a Wilcoxon test for all multiple comparisons was conducted to evaluate any differences among the treatment groups for change in depth of demineralization (µm) at two different time points. PS and OS groups were found to have significant differences in average lesion depth compared to the control groups at T1 and T2 (pConclusions: Our results showed that both Opal Seal and L.E.D. Pro Seal reduce enamel demineralization when teeth are subjected to simulated toothbrush abrasion and an acidic environment over time. Opal Seal provided superior protection of the enamel surface and demonstrated complete wear resistance and prevention of demineralized lesion development in our experimental groups.

Indiana University-Purdue University Indianapolis (IUPUI) / In this thesis, we proposed and investigated the efficacy and safety of dental bleaching as a non-invasive aesthetic treatment option for stained arrested caries lesions (s-ACLs). Chapter 1 reports the suitability of this approach in extracted human teeth, as well as in a selected clinical case. Visual improvement in the color lighteness of the s-ACLs was observed and reported in photographs. In order to systematically study the impact of dental bleaching on the s-ACLs, we developed in vitro models simulating the development of metallic and non-metallic s-ACLs (Chapter 2). Human dental specimens were submitted to incipient caries-like lesion formation, followed by a 5-day cycling protocol based on remineralization and staining episodes. The created lesions were then bleached (simulating in-office/40% hydrogen peroxide). Color change was measured spectrophotometrically at baseline, after lesion creation, staining/remineralization cycling and bleaching; while mineral loss and lesion depth were quantified by transversal microradiography after staining/remineralization cycling. Metallic s-ACLs were darker, more remineralized and more difficult to bleach, compared to the non-metallic ones (p<0.05). In Chapter 3, we tested the efficacy and safety of different dental bleaching systems (simulating at-home/15% carbamide peroxide and in-office/40% hydrogen peroxide) using the in vitro models previously developed. Similar methods and outcomes were used, with the addition of demineralization after bleaching to simulate and test changes in caries susceptibility. At-home bleaching showed greater efficacy in color improvement compared to in-office (p<0.05), but also increased susceptibility to further demineralization (p<0.05), regardless of the type of stain. Overall, bleached non-metallic s-ACLs were more susceptible to demineralization compared to metallic ones (p<0.05). Within the limited laboratory testing conditions, we concluded that dental bleaching can improve the aesthetics of s-ACLs, with efficacy being dependent on the nature of the stain. At-home bleaching presented greater efficacy, but also raised some potential safety concerns, which should be further investigated in clinical conditions. In-office bleaching protocol showed to be an effective and safe procedure for the aesthetic treatment of stained arrested caries lesions.

Phonotaktik beschreibt die mögliche Anordnung von Phonemen innerhalb eines Wortes, Morphems oder einer Silbe in einer bestimmten Sprache. Im Deutschen ist /br/ ein zulässiger, „legaler“ Silbenkopf und steht am Anfang von Worten wie Brot, breit und Brief. /bz/ hingegen ist ein nicht zulässiger, „illegaler“ Silbenkopf, mit dem kein Wort beginnt. Im Slovakischen hingegen ist /bz/ ein legaler Silbenkopf. Diese Studie untersucht erstmals die Verarbeitung von phonotaktischem Material bei Patienten, die eine Läsion der perisylvischen Sprachareale in der linken Hirnhemisphäre erlitten haben, im Vergleich zu gesunden Probanden. Methodische Grundlagen der Studie sind die Elektroenzephalographie (EEG) und die strukturelle Magnetresonanztomographie (MRT), sowie drei klinische Aphasietests zur phonologischen, semantischen und lexikalischen Unterscheidung (LEMOs). Diese wurden sowohl einzeln ausgewertet, als auch mit der Methode der Voxel-basierten Läsion-Symptom-Kartierung (VLSM) miteinander korreliert. Die EEG soll vor allem den Zeitverlauf darstellen, während die VLSM-Analysen Regionen abgrenzen sollen, die an der Verarbeitung von phonotaktischem Material beteiligt sind. In den vereinzelten Studien, die die neuronale Grundlage phonotaktischer Verarbeitung untersuchten, wurde bisher der Gyrus temporalis superior (STG) dafür identifiziert. Bis dato ist unklar, ob phonotaktische Verarbeitung eher ein sublexikalischer Prozess ist der „Bottom-up“ stattfindet, oder ob er eher „Top-down“ vom Lexikon beeinflusst wird. In der vorliegenden Arbeit wurden 252 einsilbige Pseudowörter den 70 Probanden auditorisch präsentiert und währenddessen ein EEG abgeleitet. Die Stimuli wurden als unabhängige Variable so manipuliert, das je 84 mit legalem und illegalem Silbenkopf begannen, und 84 rückwärts abgespielte Stimuli aus beiden Kategorien waren. Lexikalische Einflüsse wurden durch das Verwenden von Pseudowörtern ausgeschlossen. Hinsichtlich ihrer Sprachnatürlichkeit wurden die Stimuli mit Pseudowörtern kontrolliert, die mit slovakischen Silbenköpfen begannen und die entgegengesetzte Legalität hatten. Die Studie zeigte folgende Ergebnisse: EEG: Es ergab sich ein signifikanter Unterschied zwischen vorwärts und rückwärts abgespielten Stimuli für beide Gruppen (Patienten und Kontrollen) und über alle Elektroden verteilt im Zeitfenster (300-450ms). Zwischen legalen und illegalen Stimuli zeigte sich kein Unterschied im EEG. EEG/MRT (VLSM): Der Kontrast zwischen vorwärts und rückwärts abgespielten Stimuli korrelierte mit Bereichen im hinteren und unteren Parietallappen, einschließlich des Gyrus supramarginalis und Gyrus angularis (IPC/PPC). Der Kontrast zwischen legalen und illegalen Stimuli im EEG korrelierte mit Bereichen im mittleren und vorderen Bereich des mittleren und oberen Temporallappens (MTG/STG). LEMO: In allen drei klinischen Aphasietests (phonologisch, lexikalisch und semantisch) machten die Patienten signifikant mehr Fehler als die Kontrollprobanden. LEMO/MRT (VLSM): Frontale Läsionen im Bereich des IFG korrelierten mit einem schlechteren Ergebnis im semantischen Test (SEM). Läsionen im hinteren temporo-parietalen Bereich (Gyrus angularis) korrelierten mit einem schlechteren Abschneiden im phonologischen Test (PHON). Die Korrelation von Läsion und Ergebnis im lexikalischen Test (LEMO , LEX) wurde nicht signifikant. Die Ergebnisse legen nahe, dass Patienten mit Läsion im Sprachnetzwerk phonotaktisches Material ähnlich wie gesunde Probanden verarbeiten. Insgesamt unterstützt die Studie eher die These eines Top-down lexikalischen Einflusses als einer Bottom-up sublexikalischen Verarbeitung. Rückwärtssprache wird von beiden Gruppen anders als Vorwärtssprache verarbeitet und führt zu einer signifikanten Negativierung im EEG um 400ms. Die Studie bestätigt den Gyrus temporalis superior (STG) als relevante Region zur Unterscheidung von phonotaktischen Merkmalen. Erstmals wurde in diesem Zusammenhang die Methode der Voxel-basierten Läsion-Symptom-Kartierung (VLSM) angewendet. Die Kongruenz der Ergebnisse mit der vorhandenen Literatur gibt erste Hinweise für die Validität dieses Verfahrens, sodass vorgeschlagen wird, es in weiteren Studien zur Sprachverarbeitung fortzuführen und zu etablieren.:Inhalt Zusammenfassung 1 1. Einleitung 3 1.1 Neuronale Netzwerke der Sprachverarbeitung 3 1.1.1 Das duale Pfadsystem 4 1.1.2 Weitere Studien zur Bildgebung von Sprachverarbeitungsmodellen 5 1.2 Psycholinguistische Modelle der Sprachverarbeitung 8 1.3 Phonotaktik 10 1.4 N400 als ereigniskorreliertes Potential in der Wortverarbeitung 12 1.5 Weitere ERPs im Zusammenhang mit phonotaktischer/sublexikalischer Verarbeitung 13 1.6 Phonotaktische/Sublexikalische Verarbeitung in der Bildgebung 13 1.7 Rückwärtssprache 14 1.8 ERPs auf wiederholte Stimuli 14 2. Fragestellung 15 3. Material und Methoden 16 3.1 Probanden 16 3.2 Material 18 3.3 Durchführung 19 3.4 Methodik des EEG 21 3.5 ERPs (Ereigniskorrelierte Potentiale) 22 3.6 Durchführung des EEG 23 3.7 Datenanalyse 24 3.7.1 Auswertung des EEG 24 3.8. Behaviorale Messungen 27 3.8.1 Klinisches Assessment der phonologischen, lexiko-semantischen und semantischen Kompetenz (LEMOs) 27 3.8.2 Reaktionszeit und Hit-Rate 27 3.9 Analyse von Läsion und behavioralen Daten und Läsion und EEG 27 3.9.1 MRT-Daten 27 3.9.2 Voxel-basierte Läsion-Symptom –Kartierung (Voxel-Based Lesion-Symptom Mapping) 28 4. Ergebnisse 29 4.1. EEG globale Analyse (ERP-Daten) 30 4.1.1 Einfaktorielle ANOVA 30 4.1.2 Mehrfaktorielle ANOVAs 34 4.1.3 Trial versus Wiederholung 46 4.3 Verhaltensdaten 62 4.3.1 Klinisches Assessment der phonologischen, lexiko-semantischen und semantischen Kompetenz (LEMOs) 62 4.3.2 Reaktionszeit und Trefferrate 62 4.4 Läsionsanalyse 64 4.4.1 Korrelation von Läsions- und Verhaltensdaten 64 Hinweis zu den Zeitfenstern: 66 4.4.2 Korrelation von Läsion und EEG 66 4.4.3 Übersicht der durch die Läsionsanalysen abgegrenzten Regionen 68 5. Diskussion 69 5.1 Diskussion der Verhaltensdaten 69 5.1.1 Experimentelle Verhaltensdaten: Trefferrate und Reaktionszeit 69 5.1.2 Klinische Verhaltensdaten: Aphasietests 70 5.2 Diskussion der EEG-Daten und Vergleich mit bisherigen Studien zur Phonotaktik 71 5.2.1 Bisherige Erkenntnise zu ERPs und Phonotaktik 71 5.2.2 Top-Down stärker als Bottom-Up (i) 72 5.3.3 Möglicher Einfluss der Aufmerksamkeitsaufgabe (ii) 75 5.2.4 Wahl des Zeitfensters (iii) 77 5.2.5 Rückwärtssprache 77 5.2.6 Zusammenfassung im Hinblick auf die Fragestellungen 78 5.3 Läsionsort und Verarbeitung 78 6. Literaturverzeichnis 81 7. Abbildungsverzeichnis 85 8. Tabellenverzeichnis 86 9. Eigenständigkeitserklärung 87 10. Danksagung 88 11. Anlagen 89

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20083号 / 医博第4176号 / 新制||医||1018(附属図書館) / 33199 / 京都大学大学院医学研究科医学専攻 / (主査)教授 増永 慎一郎, 教授 妹尾 浩, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM