The ability to perceive speech is related to the listener's ability to differentiate among frequencies (i.e. spectral resolution). Cochlear implant users exhibit variable speech perception and spectral resolution abilities, which can be attributed at least in part to electrode interactions at the periphery (i.e. spatial resolution). However, electrophysiological measures of peripheral spatial resolution have not been found to correlate with speech perception. The purpose of this study was to systematically evaluate auditory processing from the periphery to the cortex using both simple and spectrally complex stimuli in order to better understanding the underlying processes affecting spatial and spectral resolution and speech perception. Eleven adult cochlear implant users participated in this study. Peripheral spatial resolution was assessed using the electrically evoked compound action potential (ECAP) to measure channel interaction functions for thirteen probe electrodes. We evaluated central processing using the auditory change complex (ACC), a cortical response, elicited with both spatial (electrode pairs) and spectral (rippled noise) stimulus changes. Speech perception included a vowel-discrimination task and the BKB-SIN test of keyword recognition in noise. We varied the likelihood of electrode interactions within each participant by creating three experimental programs, or MAPs, using a subset of seven electrodes and varying the spacing between activated electrodes. Linear mixed model analysis was used to account for repeated measures within an individual, allowing for a within-subject interpretation. We also performed regression analysis to evaluate the relationships across participants. Both peripheral and central processing abilities contributed to the variability in performance observed across CI users. The spectral ACC was the strongest predictor of speech perception abilities across participants. When spatial resolution was varied within a person, all electrophysiological measures were significantly correlated with each other and with speech perception. However, the ECAP measures were the best single predictor of speech perception for the within-subject analysis, followed by the spectral ACC. Our results indicate that electrophysiological measures of spatial and spectral resolution can provide valuable information about perception. All three of the electrophysiological measures used in this study, including the ECAP channel interaction functions, demonstrated potential for clinical utility.

The work deals with financial mathematics and its teaching in upper secondary school. This thesis contains introduction to finance, simple and compound in- terest, securities, bonds, loans and savings. The work is also presented in the form of web pages. The web pages are enhanced with interactive features such as applets in GeoGebra and step-by-step solutions for exercises. The web pages include a final test in which one can check his knowledge. The test contains ten randomly generated tasks which cover the curriculum of the thesis. The work is meant as an extending teaching materials for upper secondary school pupils. 1

Current cochlear implant systems use fast pulsatile stimulation to deliver the temporal modulations of speech and to, potentially, improve the neural representation of such modulations by restoring the independence of neural firing. The realization of these benefits may vary with other pulse rate-dependent temporal interactions that occur at the neural membrane, e.g., per(i)stimulatory adaptation and its post-stimulatory or forward masking effects. This study attempted to characterize adaptation and recovery of the electrically evoked compound action potential (ECAP) using probe pulses delivered within and following brief (100 ms) high-rate masker (1800 pps) pulse trains at various current levels in adults and children. With this stimulus paradigm, the ECAP amplitude typically achieved a steady state during the course of pulse train stimulation. The ECAP amplitude at steady state was, on average, a similar proportion (50-70%) of the amplitude at onset for various stimulus levels and in both age groups. However, long-term adaptation effects, evidenced by the decrease in onset ECAP amplitude, were greater in adults particularly at lower levels in the ECAP dynamic range. Instances of alternation in ECAP amplitude were seen at stimulus levels that were higher in the ECAP dynamic range. The forward masking effects of pulse train stimulation were quantified by the ECAP amplitude in response to a subsequent probe pulse normalized by the response to the same pulse presented alone. Pulse train forward masking increased with the level of the masker pulse train and decreased with the level of the probe stimulus. The recovery of the ECAP for probes that were lower in level than the masker pulse train was incomplete at 600 ms after masker offset, consistent with long-term cumulative effects observed in the response to the probe alone. Masker pulse trains that are lower in level than the probe pulse produced proportionally small decrements in the ECAP amplitude with complete recovery within 250 ms of pulse train offset particularly in adults. ECAP recovery of a probe preceded by a masker pulse train of equal level followed a monotonic or non-monotonic pattern consistent with a hypothesis of both adaptation and facilitation occurring with pulse train stimulation. The various patterns of recovery may attest to the occurrence of more than a single process in the same subset of nerve fibers or in different fibers. We hypothesize that the variations in the recovery patterns may be attributable to individual differences in the status of the auditory nerve and possibly, the variations in temporal interactions across the spatial domain at different stimulus levels. Finally, the probe-evoked ECAP amplitude at steady state in children and briefly, e.g., 20 ms, after pulse train offset in both age groups could be predicted by the ECAP amplitude in response to the same probe pulse when preceded at a brief interval (1.2 or 2 ms) by a single masker pulse of the same level as the masker pulse train. Further investigation may reveal if the observed differences in neural responsiveness to pulsatile stimulation, among individuals account for differences in psychophysical measures, including speech perception and whether there may be an "optimal" neural output that could be evoked by an individually "optimized" signal.

The purpose of this study was to investigate how design changes in Cochlear Nucleus cochlear implants (CIs) (CI24M, CI24R, CI24RE and CI422) affected electrode impedance and ECAP measures, and to determine if these design changes affected post-lingually deafened adults and children with congenital hearing loss in a similar way. Results of this study showed that electrode impedance was inversely related to the area of the electrode contacts in the array: lowest for the full-banded CI24M CI and highest for adults who used the CI422 device which has the smallest electrode contacts of all four devices. The noise floor of the NRT system likely plays a significant role in the finding that CI users with older devices (the CI24M, and CI24R CIs) had higher ECAP thresholds than individuals with the CI24RE electrode array. The position of the electrode array in the cochlea was also found to have a significant effect on ECAP measures. CI users with modiolar hugging (the CI24R and CI24RE CIs) electrode arrays were found to have lower ECAP thresholds than CI users whose electrode arrays were seated more laterally in the cochlear duct (e.g. the CI24M and CI422 implants). The position of the electrode contacts relative to the modiolus of the cochlea was found to be related to slope of the ECAP growth functions. The lowest slopes were found in CI24RE users. It also had a significant impact on the width of the channel interaction function. Electrode arrays seated further from the modiolus have significantly more channel interaction than electrode arrays that hug the modiolus of the cochlea. Differences between results recorded from post-lingually deafened adults and children with congenital hearing loss were minimal. The difference only reflected on the ECAP slopes. Slopes in children with congenital hearing loss were significantly steeper than those recorded from adults. This may indicate that children with congenital hearing loss may have better neural survival than adults with acquired hearing loss. In conclusion, the results of the current study show evidence of the effects of variations in design and function of the implanted components of the Nucleus CI. Perhaps the most significant finding from the current data set is that electrode arrays located closer to the modiolus of the cochlea have lower thresholds and exhibit less channel interaction than electrode arrays that are positioned more laterally. An argument could be made that lower stimulation levels and less channel interaction may result in better outcomes and/or longer battery life. For CI candidates who do not have significant residual acoustic hearing, the CI24RE implant might be a better choice than the more recently introduced CI422 electrode array.

My objectives were to determine if nutritional benefits occur when animals are offered foods with compounds -- alkaloids, saponins, and tannins - that are potentially complementary. I hypothesized that food intake and digestibility increase when lambs consume plants such as alfalfa ALF that contain saponins or birdsfoot trefoil (BFT) that contain tannins when the basal diet is endophyte-infected tall fescue (TF) or reed canarygrass (RCG) both of which contain alkaloids. I predicted that the nutritional status of lambs would be enhanced if basal diets of alkaloid-containing grasses were supplemented with ALF or BFT. Lambs fed a basal diet of either endophyte-infected TF or RCG ate more food and consequently digested more dry matter, energy and nitrogen when supplemented with ALF or BFT. Lambs ingested more dry matter and digested more nutrients when fed a basal diet of RCG than one of TF, and supplementing with ALF and BFT was more beneficial for lambs fed TF than for lambs fed RCG. Increased intake of digestible nutrients was due to greater intake when lambs were offered more than one food, not due to an increase in digestibility. In pen trials meant to complement the field trials, lambs were offered an alkaloid-containing (either gramine or 5-methoxy-N,N-dimethyltryptamine) total mixed ration and supplemented with a food that contained saponins or tannins. All rations were isocaloric (3.3Mcal/kg) and isonitrogenous (14% CP). Lambs fed a ration with either alkaloid and offered a food containing saponin digested approximately the same amount of dry matter, energy, nitrogen, and NDF as lambs not offered saponin. When lambs were fed a ration with either alkaloid and supplemented with food that contained tannins, tannin consumption adversely affected dry matter, energy, and NDF digestibility, but lambs offered food with tannins increased dry matter intake, and as a result, they digested the same amount of dry matter, energy, and NDF as lambs not offered the food with tannins. Lambs offered tannin digested and retained more nitrogen than lambs not offered tannin. These findings indicate a nutritional advantage for sheep eating mixtures as opposed to monocultures of foods with different profiles of secondary compounds and nutrients.

[Truncated abstract] The present study investigated whether any of the characteristics of the compound action potential (CAP) waveform or the spectrum of the neural noise (SNN) recorded from the cochlea, could be used to examine abnormal spike generation in the type I primary afferent neurones, possibly due to pathologies leading to abnormal hearing such as tinnitus or tone decay. It was initially hypothesised that the CAP waveform and SNN contained components produced by the local action currents generated at the peripheral ends of the type I primary afferent neurones, and that changes in these local action currents occurred due to changes in the membrane potential of these neurones. It was further hypothesised that the lateral olivo-cochlear system (LOCS) efferent neurones regulate the membrane potential of the primary afferent dendrites to maintain normal action potential generation, where instability in the membrane potential might lead to abnormal primary afferent firing, and possibly one form of tinnitus. We had hoped that the activity of the LOCS efferent neurones could be observed through secondary changes in the CAP waveform and SNN, resulting from changes in the membrane potential of the primary afferent neurones. The origins of the neural activity generating the CAP waveform and SNN peaks, and the effects of the LOCS on the CAP and SNN were experimentally investigated in guinea pigs using lesions in the auditory system, transient ischemia and asphyxia, focal and systemic temperature changes, and pharmacological manipulations of different regions along the auditory pathway. ... Therefore, the CAP and SNN are altered by changes in the propagation of the action potential along the primary afferent neurones, by changes in the morphology of the tissues surrounding the cochlear nerve, and by changes in the time course of the action currents. If the CAP waveform is not altered, the amplitude of the 1kHz speak in the spontaneous SNN can be used as an objective measure of the spontaneous firing rate of the cochlear neurones. However, because the SNN contains a complex mixture of neural activity from all cochlear neurones, and the amplitude of the spontaneous SNN is variable, it would be difficult to use the spontaneous SNN alone as a differential diagnostic test of cochlear nerve pathologies. To record extratympanic electrocochleography (ET ECochG) from humans, a custom-designed, inexpensive, low-noise, optically isolated biological amplifier was built. Furthermore, a custom-designed extratympanic active electrode and ear canal indifferent electrode were designed, which increased the signal-to-noise ratio of the ECochG recording by a factor of 2, decreasing the overall recording time by 75%. The human and guinea pig CAP waveforms recorded in the present study appeared similar, suggesting that the origins of the human and guinea pig CAP waveforms were the same, and that experimental manipulations of the guinea pig CAP waveform can be used to diagnose the cause of abnormal human ECochG waveforms in cases of cochlear nerve pathologies.

中文裡有一種特別的結構，稱為動賓複合詞(Verb-object compound)。根 據李與湯普森(Li & Thompson)觀察：從歷史的觀點來看，這種動賓複合 詞是從動賓詞組衍生得來。在本論文中，嘗試以貝克(Baker,1988)的併入 理論(Incorporation Theory)來證明他們的這個觀察。我們認為有一名為 「名詞併入」(Noun Incorporation)的句法移位律對動賓詞組產生作用。 在經過此規律作用後，動詞和它的直接賓語便在句法層次上結合成一帶動 詞性的複雜結構，此外，我們在此理論中，我們主張應加入一條構詞結合 律。此律在名詞併入後作用，把名詞併入後新產生的句法性複雜結構變換 成一構詞單位，即複合詞。這樣的解釋方式不只具有「解釋充份性」 (explanatory adequacy)，而且從歷史的觀點來看此一名詞併入現象，上 述方式也可以妥善地解決一個爭議已久有關動賓複合詞是否可以離合的問 題，以及有關雙重分類的動賓複合詞所造成的難題。藉著這樣的分析，我 們討論了八類動賓結構。這八類恰好形成一個漸次變化。其大抵反映出動 賓結構從詞組變成複合詞的詞彙化過程。至於此八類之間的句法變異，我 們發現其「分類差異」(status variation)與及物性變異(transitivity variation)是一些規律互相競爭(competition)與互補(complementation) 的結果。此現象在謝(Hsieh,1989)的交互作用理論(Interaction Theory) 中早已被指出。而此理論在解釋句法變異上的完善，更證明了我們先前利 用名詞併入方式分析動賓結構是正確的。 / In Mandarin Chinese, there is a special construction called verb-object compounds. It has been observed by Li & Thompson (1981) that the verb-object compounds are derived historically from verb-object phrases. In this thesis, we attempt to verify this observation by means of the Incorporation Theory by Baker (1988). We argue that a syntactic rule, noun incorporation, applies to verb-object phrases and combines the verb and its direct object together to form a syntactic verbal complex. A morphological merging rule is added into the Theory, and applies immediately after the former rule to transform the newly created syntactic construct into a morphological one, a compound. Such and approach not only achieves the explanatory adequacy, but also resolves the long-standing controversies on the expandability of verb-object compounds and the paradox of verb-object compounds with dual status, if we keep a historical view on the process of the noun incorporation. Based on this analysis, the eight types of verb-object constructions form a continuum which roughly reflects a lexicalization process from verb-object phrases to verb-object compounds. As for the syntactic variation--status variation and transitivity variation--among different types verb-object consrtuctions, it is found to be a result of the competition and complementation among some rules, a fact evidenced in Hsieh's (1989) Interaction theory. the success of the interaction account further justifies our incorporation analysis on verb-object construcitons.

<p>This thesis describes the use of a new technology, the Cytosensor^® microphysiometer, in the in vitro evaluation of cytotoxic drugs, using the lymphoma cell line U-937 GTB and primary cultures of tumour cells from patients as model systems. The method was specifically applied to study the metabolic effects of the novel cyanoguanidine N-(6-(4-chlorophenoxy)hexyl)-N’-cyano-N’’-4-pyridylguanidine, CHS 828, currently in phase I/II clinical trials. </p><p>The Cytosensor^® measures metabolic effects as changes in the rate of extracellular acidification of cells exposed to a drug by perfusion. A number of standard cytotoxic drugs were found to produce typical and reproducible acidification response patterns during observation times up to 20 h. There seemed to be a relationship between a decrease in acidification and cytotoxicity, measured in the fluorometric microculture cytotoxicity assay (FMCA), after 20-24 h of continuous drug exposure.</p><p>In U-937 cells, CHS 828 induced a cytotoxic effect characterised by a steep concentration-response relationship followed by a plateau. After 24 h of incubation the DNA and protein synthesis were turned off. CHS 828 was found to produce a rapid and prolonged increase in extracellular acidification and lactate production similar to that of the structurally related mitochondrial inhibitor m-iodobenzylguanidine (MIBG). The CHS 828 induced acidification was observed in cell lines as well as in cells from various tumour types from patients and probably originates from increased glycolytic flux. The effects may be secondary to block of oxidative phosphorylation in the mitochondria, but the relevance of the early acidification is not clear. CHS 828 seemed to induce a late, at approximately 15 h, inhibition of the glycolysis followed by loss of ATP and subsequent cell death. After exposure to MIBG the loss of ATP and cell death occurred earlier and in parallel. The effects of CHS 828 were not found to resemble those of the structurally related polyamine biosynthesis inhibitor methylglyoxal-bis(guanyl-hydrazone) (MGBG). Thus, CHS 828 may represent a new and, thus, interesting mode of cytotoxic action worthwhile for further development.</p><p>In combinatory studies, a synergistic interaction was demonstrated between CHS 828 and the non-toxic drug amiloride. Additive-to-synergistic effects were also seen between CHS 828 and the bioreductive cytotoxic drug mitomycin C. In U-937 cells as well as in tumour cells from patients, CHS 828 demonstrated synergistic interactions in combination with melphalan and etoposide. </p><p>It is concluded that measurement in the Cytosensor^® microphysiometer of early cellular metabolic changes is a feasible and potentially valuable complement to more conventional methods used in the evaluation of anticancer agents. </p>

The work presented in this thesis has striven toward improving the capability to study proteins using infrared (IR) spectroscopy. This includes development of new and improved experimental and theoretical methods to selectively observe and simulate protein vibrations. A new experimental method of utilising adenylate kinase and apyrase as helper enzymes to alter the nucleotide composition and to perform isotope exchange in IR samples was developed. This method enhances the capability of IR spectroscopy by enabling increased duration of measurement time, making experiments more repeatable and allowing investigation of partial reactions and selected frequencies otherwise difficult to observe. The helper enzyme mediated isotope exchange allowed selective observation of the vibrations of the catalytically important phosphate group in a nucleotide dependent protein such as the sarcoplasmic reticulum Ca2+-ATPase. This important and representative member of P-type ATPases was further investigated in a different study, where a pathway for the protons countertransported in the Ca2+-ATPase reaction cycle was proposed based on theoretical considerations. The transport mechanism was suggested to involve separate pathways for the ions and the protons. Simulation of the IR amide I band of proteins enables and supports structure-spectra correlations. The characteristic stacking of beta-sheets observed in amyloid structures was shown to induce a band shift in IR spectra based on simulations of the amide I band. The challenge of simulating protein spectra in aqueous medium was also addressed in a novel approach where optimisation of simulated spectra of a large set of protein structures to their corresponding experimental spectra was performed. Thereby, parameters describing the most important effects on the amide I band for proteins could be determined. The protein spectra predicted using the optimised parameters were found to be well in agreement with experiment. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Manuscript.</p>

Many phenomena determining the microstructure of a tool steel and consequently the properties of the material, are governed by multicomponent diffusion. The diffusion driven reactions that take place during, for example, tempering of a hot-work tool steel or when the microstructure develops during hot isostatic pressing of cold-work tool steel, are dependent on the types and amounts of alloying elements. In order for computational methods to be usable, these alloying effects need to be understood and incorporated in the models. In this work the influence of some typical tool steel alloying elements on the coarsening behavior of precipitates is investigated. Experimental coarsening studies are performed and the impact of the diffusion mobility descriptions and the thermodynamic descriptions are investigated by means of DICTRA coarsening calculations. The kinetic descriptions for diffusion in the body centered-cubic phase in the case of the chromium-iron-vanadium system and the chromium-iron-molybdenum system are improved by assessments of diffusion mobility parameters, and are shown to have a large impact on the calculated coarsening rate for vanadium-rich and molybdenum-rich precipitates. The effect of cobalt is examined by a coarsening experiment for vanandiumrich carbides and by a diffusion couple experiment for the investigation of the vanadium interdiffusion. The presence of cobalt is experimentally shown to have retarding effect on the coarsening rate of the carbides, but not on the vanadium diffusion. The coarsening rate of nitrogen-rich precipitates is compared to the coarsening rate of carbon-rich precipitates, and a lower coarsening rate for nitrides compared to carbides can be confirmed. Correlation between coarsening calculations and experiments is obtained suggesting that the thermodynamic description of the two systems is the underlaying reason for the different coarsening rates. Further, calculations utilizing the DICTRA software are combined with experimental investigations in order to study the possibility to apply computational methods for compound material development and explore application areas for high nitrogen alloyed tool steels produced by powder metallurgy. / <p>QC 20121011</p>