Master of Science / Department of Clinical Sciences / Hans Coetzee / Dehorning is a painful husbandry procedure that is commonly performed in dairy calves. Parenteral meloxicam combined with local anesthesia mitigates the physiological and behavioral effects of dehorning in calves. The purpose of this study was to determine the influence of timing of oral meloxicam administration on physiological responses in calves after dehorning. Thirty Holstein bull calves 8- 10 weeks of age (28-70 kg) were randomly assigned to one of three treatment groups: placebo-treated control group (CONT) (n=10), calves receiving meloxicam administered orally (1 mg/kg) in powdered milk replacer 12 h prior to cautery dehorning (MEL-PRE) (n=10) and calves receiving meloxicam administered as an oral bolus (1 mg/kg) at the time of dehorning (MEL-POST) (n=10). Following cautery dehorning, blood samples were collected to measure cortisol, substance P (SP), haptoglobin, ex-vivo prostaglandin E2 (PgE2) production after lipopolysaccharide stimulation and meloxicam concentrations. Maximum ocular temperature (MOT) and mechanical nociceptive threshold (MNT) was also assessed. Data were analyzed using non-compartmental pharmacokinetic analysis and repeated measures ANOVA models. Mean peak meloxicam concentrations were 3.61 ± 0 .21 μg/mL and 3.27 ± 0.14 μg/mL with average elimination half-lives of 38.62 ± 5.87 h and 35.81 ± 6.26 h in the MEL-PRE and MEL-POST groups respectively. Serum cortisol concentrations were lower in meloxicam-treated calves compared with control calves at 4 h post-dehorning (P=0.0004). SP concentrations were significantly higher in control calves compared with meloxicam-treated calves at 120 h after dehorning (P=0.038). PgE2 concentrations were lower in meloxicam-treated calves compared with control calves (P=0.001). MNT was higher in control calves at 1 h after dehorning (P=0.02) but meloxicam-treated calves tended to have a higher MNT at 6 h after dehorning (P=0.07). There was no effect of timing of meloxicam administration on plasma cortisol concentrations (P= 0.69), SP concentrations (P=0.86), haptoglobin concentrations (P=0.86), MOT (P=0.90), or MNT (P=0.99). However, PgE2 concentrations in MEL-PRE calves were similar to CONT calves after 12h post-dehorning, while MEL-POST calves had lower PgE2 concentrations for 3 d post dehorning. These findings suggest that meloxicam reduced cortisol, SP and PgE2 after dehorning but only PgE2 production was significantly affected by the timing of meloxicam administration.

Sepsis and septic shock are conditions, with severe outcome or in many cases death. Sepsis is a systemic inflammatory response trigger by bacteraemia but systemic inflammatory response can also be triggered by major trauma, major surgery, pancreatitis, severe burns etc. The systemic inflammatory reaction initiating the evolvement of septic organ dysfunction can be modelled using endotoxin, a Gram-negative bacterial lipopolysaccharide. This thesis used a porcine experimental sepsis model to examine timing of the inflammatory response due to endotoxin infusion (Paper I) and the influence of steroid treatment on the inflammatory response in endotoxemic pigs (Paper II). Timing of steroid treatment and the role of neutrophil granulocyte activation was evaluated with pig specific NGAL assessing neutrophil activation (Paper III). A clinical observational study was performed with the aim to differentiate between sepsis and other inflammatory conditions (e.g. trauma due to major surgery) evaluated by calprotectin as a marker of neutrophil activation (Paper IV). There was a dose-dependency in endotoxin tolerance which was measured with TNF-a. Pre-exposure to endotoxin did not reduce the pulmonary response to endotoxemic challenge. In fact, both PaO2 / FiO2 and static pulmonary compliance were reduced in this group when pre-treated with endotoxin at low dose. Endotoxemic animals treated with hydrocortisone were more stable in circulatory variables than those without such treatment. This was not explained by an ability of steroids to modulate the production of NO (Nitric oxide), which has been suggested to be a mechanism of steroids in this aspect. Pre-treatment with hydrocortisone attenuated the neutrophil granulocyte response and consequently diminished the release of NGAL in plasma. Circulatory derangement was associated with high plasma NGAL levels. Urine NGAL levels did not differ among the four groups. Plasma calprotectin levels on ICU admission is a sensitive marker of systemic inflammation and are markedly increased in patients with sepsis and patients with systemic inflammatory response. Plasma Calprotectin performed better than any of the other inflammatory variables in predicting mortality at 30 days, except from the composite mortality prediction score, SAPS 3.

As with other functions, the aging process can cause changes in swallowing, even in asymptomatic individuals. Purpose: 1. To determine whether timing measures for swallows from healthy older adults differ from comparison measures for healthy young adults. 2. To determine whether timing measures for functional swallows from older adults at risk of dysphagia differ from comparison measures for healthy older adults. 3 To determine whether differences in timing explain the occurrence of transient penetration of material into the airway (Penetration-Aspiration Scale scores of 2) in any of these groups. Method: Duplicate blinded ratings were obtained for swallows of 20%w/v thin liquid barium collected under videofluoroscopy at 30 frames/s from 17 healthy older adults, aged 60-84 (12 women). Swallows were compared to data from a retrospective dataset collected in 20 healthy young adults aged 22- 45 (10 women) and functional swallows (Penetration-Aspiration Scale scores <3) of 11 older adults at risk for dysphagia, aged 62-87 (3 women). Eight timing measures were studied, including parameters related to swallow response, bolus transit, laryngeal vestibule closure and upper esophageal sphincter (UES) function. We used linear mixed model repeated measures ANOVAs to explore the hypothesis that swallow timing measures would be longer in the older adults than in young adults, and even longer in the older adults at risk for dysphagia. Results: Consistent with the hypotheses, significantly longer swallow reaction time, UES opening (UESO) duration, the interval from laryngeal vestibule closure (LVC) to UESO (p<0.01) and the interval following UESO to maximum pharyngeal constriction (MPC) were seen in the healthy older participants compared to the young healthy controls. Furthermore, a significantly longer interval from the onset of hyoid movement to UES opening, and longer laryngeal vestibule closure reaction time (LVCRT), (p<0.01) were seen in the older participants at risk of dysphagia in comparison with healthy older adults. Also, this group presented longer intervals from LVC to UES opening and from maximum pharyngeal constriction to UES closure. For both the healthy young group and the healthy elderly group, in cases where transient penetration of material into the laryngeal vestibule was seen, laryngeal vestibule closure reaction time was longer and laryngeal vestibule closure occurred late, after UES opening. For both the healthy elderly group and elderly at risk of dysphagia, when penetration was observed, a shorter interval from hyoid onset to upper esophageal sphincter opening was seen. Also, laryngeal vestibule closure was late and there was a longer LVC to UESO interval when penetration occurred. Finally, laryngeal vestibule closure duration was shorter in case of penetration in the elderly group at risk of dysphagia Conclusions: Longer swallow timing measures, in general, distinguish swallows in healthy older adults from swallows in young healthy adults, and in older adults at risk of dysphagia from healthy older adults. In cases of transient penetration, laryngeal vestibule closure was delayed. / Introdução: Tal como acontece com outras funções, o processo de envelhecimento pode causar alterações na deglutição, mesmo em indivíduos assintomáticos. Objetivo: 1. Determinar se as medidas temporais da deglutição diferem entre idosos saudáveis e adultos jovens saudáveis. 2. Determinar se as medidas temporais de deglutições funcionais de idosos em risco de disfagia diferem das medidas de idosos saudáveis. 3. Determinar se diferenças nas medidas temporais explicam a ocorrência de penetração transitória (escore PAS igual a 2) em qualquer desses grupos. Método: Foram realizadas análises cegas duplicadas para deglutições de bário líquido diluído a 20%, coletadas em videofluoroscopia a 30 quadros/s de 17 idosos saudáveis, entre 60 e 84 anos (12 mulheres). As deglutições foram comparadas a um banco de dados coletado retrospectivamente de 20 jovens jovens saudáveis entre 22 e 45 anos (10 mulheres) e deglutições funcionais (escores da Escala Penetração-Aspiração <3) de 11 idosos com risco de disfagia, com idade entre 62-87 (3 mulheres). Foram estudadas oito medidas temporais, incluindo parâmetros relacionados à resposta à deglutição, trânsito do bolo, fechamento do vestíbulo laríngeo e função do esfíncter esofágico superior (EES). Utilizamos análise de medidas repetidas em modelos mistos lineares ANOVAs para explorar a hipótese de que as medidas temporais da deglutição seriam maiores nos idosos do que em adultos jovens e ainda maiores nos idosos em risco de disfagia. Resultados: De acordo com as hipóteses, para resposta à deglutição (SRT), duração da abertura do EES (AEES), do intervalo entre o fechamento do vestíbulo laríngeo (FVL) para AEES (p <0,01) e do intervalo entre AEES até a constrição máxima da faringe foram observadas medidas significantemente aumentadas no grupo idosos saudáveis em comparação com jovens saudáveis. Além disso, um intervalo significativamente mais longo desde o inicio do movimento do hióide até a abertura da EES e longo tempo de reação para o fechamento do vestíbulo laríngeo (p <0,01) foram observados nos participantes idosos em risco de disfagia em comparação com idosos saudáveis. Além disso, este grupo apresentou intervalos mais longos entre FVL e AEES e entre a constrição máxima da faríngea e o fechamento do EES. Tanto para o grupo jovem saudável como para o grupo idoso saudável, nos casos em que a penetração transitória do material no vestíbulo laríngeo foi observada, o tempo de reação para fechamento do vestíbulo laríngeo foi maior e o fechamento do vestíbulo laríngeo ocorreu de forma tardia, após a abertura do EES. Tanto para o grupo de idosos saudáveis quanto para os idosos em risco de disfagia, quando ocorreu penetração, observou-se um intervalo menor entre o início do movimento do hióide e a abertura do esfíncter superior do esôfago. Além disso, o FVL estava atrasado e houve um intervalo prolongado entre FVL e AEES quando ocorreu a penetração. Finalmente, a duração do fechamento do vestíbulo laríngeo foi menor em caso de penetração no grupo idoso em risco de disfagia. Conclusões: medidas de tempo de deglutição prolongada, em geral, são um fator claro que distingue as deglutições de idosos saudáveis e deglutições de jovens saudáveis, e de idosos em risco de disfagia e de idosos saudáveis. Quando uma penetração transitória foi encontrada, o mecanismo de fechamento do vestíbulo laríngeo apresentava-se atrasado.

"Timing diagrams are used in industrial practice as a specification language of circuit components. They have been formalized for efficient use in model checking. This formalization is often more succinct and convenient than the use of temporal logic. We explore the relationship between timing diagrams and temporal logic formulas by showing that closure under disjunction does not hold for timing diagrams. We give an algorithm that returns a disjunction (if any) of two given timing diagrams. We also give algorithms that decide satisfiability of a timing diagram and return exact time separations between events in a timing diagram. An Alloy specification for timing diagrams with one waveform has also been built."

The amygdala and hippocampus interact with thalamocortical systems to regulate cognitive-emotional learning, and lesions of amygdala, hippocampus, thalamus, and cortex have different effects depending on the phase of learning when they occur. In examining eyeblink conditioning data, several questions arise: Why is the hippocampus needed for trace conditioning where there is a temporal gap between the conditioned stimulus offset and the onset of the unconditioned stimulus, but not needed for delay conditioning where stimuli temporally overlap and co-terminate? Why do amygdala lesions made before or immediately after training decelerate conditioning while those made later have no impact on conditioned behavior? Why do thalamic lesions degrade trace conditioning more than delay conditioning? Why do hippocampal lesions degrade recent learning but not temporally remote learning? Why do cortical lesions degrade temporally remote learning, and cause amnesia, but not recent or post-lesion learning? How is temporally graded amnesia caused by ablation of medial prefrontal cortex? How are mechanisms of motivated attention and the emergent state of consciousness linked during conditioning? How do neurotrophins, notably Brain Derived Neurotrophic Factor (BDNF), influence memory formation and consolidation? A neural model, called neurotrophic START, or nSTART, proposes answers to these questions. The nSTART model synthesizes and extends key principles, mechanisms, and properties of three previously published brain models of normal behavior. These three models describe aspects of how the brain can learn to categorize objects and events in the world; how the brain can learn the emotional meanings of such events, notably rewarding and punishing events, through cognitive-emotional interactions; and how the brain can learn to adaptively time attention paid to motivationally important events, and when to respond to these events, in a context-appropriate manner. The model clarifies how hippocampal adaptive timing mechanisms and BDNF may bridge the gap between stimuli during trace conditioning and thereby allow thalamocortical and corticocortical learning to take place and be consolidated. The simulated data arise as emergent properties of several brain regions interacting together. The model overcomes problems of alternative memory models, notably models wherein memories that are initially stored in hippocampus move to the neocortex during consolidation.

In this dissertation, I strive to enhance our understanding of the effect of entry timing on firm performance using both empirical and formal modeling techniques. I accomplish this through addressing three major unanswered issues in entry timing research. In the first essay of my dissertation, I theoretically examine the effect of selection bias on entry timing associated performance outcomes via the introduction of a novel concept called First-mover Benefits (FMB) which is both theoretically and empirically distinct from the traditional First-mover Advantages (FMA) concept. The second essay of my dissertation empirically investigates this distinction in a unique entrepreneurial setting: the marijuana retailing industry in the State of Washington. The randomized order of entry into the geographically separate jurisdictions in Washington State via the lottery system gives me the opportunity to look at the overlooked effects of two key macrocontingencies: market growth rate and rivalry intensity without any selection bias concern. The main result of this essay indicates that pioneering advantages are more likely to be found in markets with higher level of rivalry intensity. My final essay focuses on the sustainability dimension of pioneering advantage. Taking advantage of the Washington State marijuana retailing industry dataset that eliminates the selection bias issue, I examine how long entry timing associated performance benefits are sustained in this nascent industry context. I find that pioneering advantages last for only four quarters. Overall, this dissertation helps partially resolve the longstanding controversy surrounding the potential effect of entry timing on performance.

No description available.

Jiang, Mingqi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves [49]-51). / Abstract also in Chinese. / Abstract --- p.i / Acknowledgement --- p.iii / Chapter 1 --- Introduction --- p.1 / Chapter 2 --- Rewiring Background --- p.4 / Chapter 2.1 --- REWIRE --- p.6 / Chapter 2.2 --- GBAW --- p.7 / Chapter 3 --- Retiming --- p.9 / Chapter 3.1 --- Min-Clock Period Retiming --- p.9 / Chapter 3.2 --- Min-Area Retiming --- p.17 / Chapter 3.3 --- Retiming for Low Power --- p.18 / Chapter 3.4 --- Retiming with Interconnect Delay --- p.22 / Chapter 4 --- Rewired Retiming for Flip-flop Reduction --- p.26 / Chapter 4.1 --- Motivation and Problem Formulation --- p.26 / Chapter 4.2 --- Retiming Indication --- p.29 / Chapter 4.3 --- Target Wire Selection --- p.31 / Chapter 4.4 --- Incremental Placement Update --- p.33 / Chapter 4.5 --- Optimization Flow --- p.36 / Chapter 4.6 --- Experimental Results --- p.38 / Chapter 5 --- Power Analysis for Rewired Retiming --- p.41 / Chapter 5.1 --- Power Model --- p.41 / Chapter 5.2 --- Experimental Results --- p.44 / Chapter 6 --- Conclusion --- p.47 / Bibliography --- p.50

The ability to take in one’s environment, integrate relevant information, and then act appropriately is an incredibly complex feat that organisms do continuously. Disruption in the ability to think and act clearly, or cognitive dysfunction, is a debilitating aspect of neuropsychiatric diseases like schizophrenia. The prefrontal cortex and the striatum are key brain regions for functional and dysfunctional cognition, but the way that they interact to allow for cognitive processing is poorly understood. To get at these questions, I manipulated and recorded from medial frontal and striatal neurons—frontostriatal ensembles—while rats engaged in interval timing, an elementary cognitive function that engages both areas. I report four main results. First, ramping activity—a gradual, consistent change in neuronal firing rate across time—is observed throughout frontostriatal ensembles. Secondly, medial frontal areas dynamically reflect changing temporal conditions during learning and precede these same changes in striatal areas. Thirdly, interval timing and striatal ramping activity are disrupted when the medial frontal cortex is inactivated. Finally, this behavioral impairment can be reduced by optogenetic stimulation of frontostriatal terminals. My results support the view that striatal neurons integrate medial frontal activity and suggest a possible mechanism—ramping activity—through which neurons might represent the passage of time. These observations elucidate temporal processing in frontostriatal circuits and provide insight into how the medial frontal cortex exerts top-down control of cognitive processing in the striatum. My hope is that these findings will contribute to a clearer understanding of basic cognitive processing and might inform future approaches to treatments that address cognitive dysfunction.

Baker and Wurgler (2002) define a new theory of capital structure. In this theory capital structure evolves as the cumulative outcome of past attempts to time the equity market. Baker and Wurgler extend market timing theory to long-term capital structure, but their results do not clearly distinguish between the two versions of market timing: perceived mispricing and adverse selection. The main purpose of this dissertation is to empirically identify the relative importance of these two explanations. First, I retest Baker and Wurgler's theory by using insider trading as an alternative to market-to-book ratio to measure equity market timing. I also formally test the adverse selection model of the equity market timing: first by using post-issuance performance, and then by using three measures of adverse selection. The first two measures use estimates of adverse information costs based on the bid and ask prices, and the third measure is based on the close-to-offer returns. Based on received theory, a dynamic adverse selection model implies that higher adverse information costs lead to higher leverage. On the other hand, a naïve adverse selection model implies that negative inside information leads to lower leverage. The results are consistent with the equity market timing theory of capital structure. The results also indicate that a naïve, as opposed to a dynamic, adverse selection model seems to be the best explanation as to why managers time equity issues.