Thesis (Doctor of Engineering in Chemical Engineering)--Cape Peninsula University of Technology, 2018. / Lignocellulosic biomass (agro-waste) has been recommended as the most promising feedstock for the production of bioalcohols, in the biofuel industry. Furthermore, agro-waste is well-known as the most abundant organic matter in the agricultural and forestry product processing industry. However, the challenge with utilizing agro-waste as a feedstock is its highly recalcitrant structure, which limits hydrolysis to convert the holocelluloses into fermentable sugars. Conventional pre-treatment methods such as dilute acid, alkaline, thermal, hot water and enzymatic, have been used in previous studies. The challenge with these conventional methods is the generation of residual toxicants during the pretreatment process, which inhibits a high bioalcohol yield, by reducing the microbial populations’ (fermenter) ability to be metabolically proficient during fermentation. Numerous studies have been developed to improve the engineered strains, which have shown to have an ability to reduce the inhibition and toxicity of the bioalcohols produced or by-products produced during pre-treatment, while enhancing the bioalcohol production. In the present study (chapter 5), evaluation of common conventional methods for the pretreatment of the mixed agro-waste, i.e. (˃45µm to <100µm) constituted by Citrus sinensis, Malus domestica peels, corn cobs from Zea mays and Quercus robur (oak) yard waste without a pre-rinsing step at a ratio of 1:1 at 25% (w/w) for each waste material, was undertaken, focusing on hot water pre treatment followed by dilute acid (H2SO4) pre-treatment. To further pretreat the mixed agro-waste residue, cellulases were used to further hydrolyse the pre-treated agro-waste in a single pot (batch) multi-reaction process. The TRS concentration of 0.12, 1.43 and 3.22 g/L was achieved with hot water, dilute acid and cellulases hydrolysis as sequential pretreatment steps, respectively, in a single pot multi-reaction system. Furthermore, a commercial strain was used to ascertain low (C1 to C3) and high carbon content (C4+) bioalcohol production under aerobic conditions. Multiple bioproducts were obtained within 48 to 72 h, including bioethanol and 1-Butanol, 3-methyl, which were major products for this study. However, undesirable bio-compounds such as phenolics, were detected post fermentation. Since multiple process units characterised by chemical usage and high energy intensivity have been utilized to overcome delignification and cellulolysis, a sustainable, environmental benign pretreatment process was proposed using N. mirabilis “monkey cup” fluids (extracts) to also reduce fermenter inhibitors from the delignification of mixed agrowaste; a process with minimal thermo physical chemical inputs for which a single pot multi-reaction system strategy was used. Nepenthes mirabilis extracts shown to have ligninolytic, cellulolytic and xylanolytic activities, were used as an enzyme cocktail to pretreat mixed agro-waste, subsequent to the furtherance of TRS production from the agro-waste, by further using cellulase for further hydrolysis. N. mirabilis pod extracts were determined to contained carboxylesterases (529.41±30.50 U/L), β-glucosidases (251.94±11.48 U/L) and xylanases (36.09±18.04 U/L), constituting an enzymatic cocktail with a significant potential for the reduction in total residual phenolic compounds (TRPCs). Furthermore, the results indicated that maximum concentration of TRS obtainable was 310±5.19 mg/L within 168 h, while the TRPCs were reduced from 6.25±0.18 to 4.26 ±0.09 mg/L, which was lower than that observed when conventional methods were used. Overall N. mirabilis extracts were demonstrated to have an ability to support biocatalytic processes for the conversion of agro-waste to produce fermentable TRS in a single unit facilitating multiple reactions with minimised interference with cellulase hydrolysis. Therefore, the digestive enzymes in N. mirabilis pods can be used in an integrated system for a second generation biorefinery.

Neste trabalho, o fenômeno de evaporação em gases rarefeitos e analisado, para o caso de uma espécie de gás bem como de misturas binárias. Evaporação fraca e forte são consideradas para escoamentos de gases em canal e semi-espaco. Também e investigado o fenômeno conhecido como reverso de temperatura, típico de gases em estado de rarefação. O método ADO, uma versão analítica do método de ordenadas discretas, é utilizado para construção de soluções em forma fechada para os diversos problemas e quantidades de interesse, como perfis de temperatura e fluxos de calor. Para o caso de um gás, uma solução unificada e desenvolvida para problemas formulados a partir dos modelos cinéticos, derivados da equação de Boltzmann, BGK, S, Gross- Jackson e MRS. No caso de mistura binária de gases, a formulação matemática e baseada no modelo McCormack. Particularmente, quando a evaporação forte e abordada, e aspectos não lineares devem ser incluídos, a versão não linear do modelo BGK e utilizada. Neste caso, a solução ADO do modelo linear e utilizada em um processo chamado de pós-processamento para inclusão dos termos não lineares do problema e reavaliação das quantidades de interesse, evidenciando melhoria dos resultados obtidos pela formulação linear. Uma serie de resultados numéricos são listados e é observada, de forma geral, excelente exatidão e eficiência computacional. / In this work, evaporation phenomena in rarefied gas flow, for one gas case and binary mixtures, are analyzed. Weak and strong evaporation are considered in channel and half-space problems. The reverse of temperature problem, typical in rarefied gas dynamics, is also investigated. The ADO method, an analytical version of the discrete ordinates method, is used to develop closed form solutions, to several problems and quantities of interest, as temperature profiles and heat flows. For the one gas case, an unified solution is developed for the BGK, S, Gross-Jackson and MRS models, derived from the Boltzmann equation. For binary mixtures, the mathematical formulation is based on the McCormack model. Particularly, when strong evaporation is investigated, and nonlinear aspects have to be included, the nonlinear BGK model is used. In this case, the ADO solution, provided by the linear model, is considered in a post-processing procedure which takes into account the nonlinear terms to evaluate the quantities of interest, and improved results are obtained, in comparison with the linear version. A series of numerical results are listed and, in general, an excellent accuracy and good computational efficiency are observed.

Submitted by Morgana Andrade (morgana.andrade@ufes.br) on 2016-04-08T19:43:32Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) tese_8940_Lorena Coelho Benevides verso final.pdf: 1351644 bytes, checksum: 36811571a6fc31c4766e3cc2e0db0ce7 (MD5) / Approved for entry into archive by Patricia Barros (patricia.barros@ufes.br) on 2016-05-13T13:34:04Z (GMT) No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) tese_8940_Lorena Coelho Benevides verso final.pdf: 1351644 bytes, checksum: 36811571a6fc31c4766e3cc2e0db0ce7 (MD5) / Made available in DSpace on 2016-05-13T13:34:04Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) tese_8940_Lorena Coelho Benevides verso final.pdf: 1351644 bytes, checksum: 36811571a6fc31c4766e3cc2e0db0ce7 (MD5) / CAPES / O Brasil produz 1,4 milhões de toneladas de suco de laranja, sendo responsável por 50% da produção mundial. Estima-se que 40-60% do volume processado seja considerado rejeito. Uma alternativa de aproveitamento da biomassa residual é a sua utilização para a obtenção de energia a partir do processo de pirólise. A compreensão desse processo envolve o estudo da cinética de degradação da biomassa residual, dos fenômenos de transporte, bem como do tipo, configuração e condições ótimas de operação do reator. O objetivo principal deste trabalho é o estudo cinético da pirólise de bagaço de laranja. Com relação à análise termogravimétrica, esta foi avaliada em dois estágios: o primeiro referente à perda de água livre até 373 K (secagem) e o segundo referente às reações de pirólise (devolatilização). Para a fase de secagem, modelos semi-empíricos de secagem foram usados em suas formas não isotérmicas. Já para a fase de devolatilização, utilizaram-se os modelos isoconversionais e o das reações paralelas independentes (RPI) reparametrizado. Para o primeiro estágio, o modelo que melhor descreveu a etapa de secagem dinâmica foi o de Overhutz, obtendo-se energia de ativação média de 11,24 kJ/mol. Já para o segundo estágio, os modelos isoconversionais apresentaram energia de ativação entre 104,94 e 417,27 kJ/mol. O modelo de Reações Paralelas Independentes Reparametrizado apresentou energia de ativação entre 130,32 e 153,62 kJ/mol, 144,00 e 194,65 kJ/mol, 59,23 e 85,41 kJ/mol, 74,16 e 148,89 kJ/mol, e 163,95 e 184,23 k/mol para hemicelulose, celulose, lignina, pectina e componente não conhecido, respectivamente. As frações dos subcomponentes do bagaço de laranja também foram estimados e obtiveram-se valores aproximados de 21, 31, 17, 25 e 6% de hemicelulose, celulose, lignina, pectina e componente x, respectivamente. Além disso, avaliou-se a cinética de secagem convectiva do bagaço, visto que o mesmo possui uma alta umidade inicial, empregando-se as equações semi-empíricas de cinética de secagem. A energia de ativação para a cinética convectiva do bagaço de laranja foi de 20,99 kJ/mol e o modelo de Overhultz foi o que melhor se adequou aos dados experimentais. / Brazil produces 1.4 million tons of orange juice, accounting for 50% of world production. It is estimated that 40-60% of the volume processed is considered tailings. An alternative use of residual biomass is their use for obtaining energy from the pyrolysis process. Understanding this process involves the study of the residual biomass degradation kinetics, transport phenomena, and the type, configuration, and optimal conditions of reactor operation. The aim of this work is the kinetic study of orange bagasse pyrolysis. With respect to thermogravimetric analysis, this was assessed in two stages: the first refers to the free water loss to 373 K (drying) and the second referring to the pyrolysis reactions (devolatilization). For the drying step, the semi-empirical models of drying were used in their non-isothermal forms. As for the devolatilization phase, they used the isoconversionais models and independent parallel reactions (RPI) reparametrized. For the first stage, the model that best describes the dynamic drying step was to Overhutz, obtaining average activation energy of 11,24 kJ/mol. As for the second stage, isoconversionais models showed activation energy between 104,94 and 417,27 kJ/mol. The reparametrized Independent Parallel Reactions model presented activation energy between 130,32 and 153,62 kJ/mol, 144,00 and 194,65 kJ/mol, 59,23 and 85,41 kJ/mol, 74,16 and 148,89 kJ/mol, and 163,95 and 184,23 kJ/mol for hemicellulose, cellulose, lignin, pectin, and component not known respectively. Fractions of subcomponents of orange bagasse were also estimated and is obtained approximate values of 21, 31, 17, 25 and 6% hemicellulose, cellulose, lignin, pectin and component x, respectively. In addition, it evaluated the convective drying kinetics bagasse, since it has a high initial moisture content, using the semi-empirical equations drying kinetics. The activation energy for convective kinetics of orange bagasse was 20,99 kJ/mol and the Overhultz model was the one best suited to the experimental data.

Neste trabalho, o fenômeno de evaporação em gases rarefeitos e analisado, para o caso de uma espécie de gás bem como de misturas binárias. Evaporação fraca e forte são consideradas para escoamentos de gases em canal e semi-espaco. Também e investigado o fenômeno conhecido como reverso de temperatura, típico de gases em estado de rarefação. O método ADO, uma versão analítica do método de ordenadas discretas, é utilizado para construção de soluções em forma fechada para os diversos problemas e quantidades de interesse, como perfis de temperatura e fluxos de calor. Para o caso de um gás, uma solução unificada e desenvolvida para problemas formulados a partir dos modelos cinéticos, derivados da equação de Boltzmann, BGK, S, Gross- Jackson e MRS. No caso de mistura binária de gases, a formulação matemática e baseada no modelo McCormack. Particularmente, quando a evaporação forte e abordada, e aspectos não lineares devem ser incluídos, a versão não linear do modelo BGK e utilizada. Neste caso, a solução ADO do modelo linear e utilizada em um processo chamado de pós-processamento para inclusão dos termos não lineares do problema e reavaliação das quantidades de interesse, evidenciando melhoria dos resultados obtidos pela formulação linear. Uma serie de resultados numéricos são listados e é observada, de forma geral, excelente exatidão e eficiência computacional. / In this work, evaporation phenomena in rarefied gas flow, for one gas case and binary mixtures, are analyzed. Weak and strong evaporation are considered in channel and half-space problems. The reverse of temperature problem, typical in rarefied gas dynamics, is also investigated. The ADO method, an analytical version of the discrete ordinates method, is used to develop closed form solutions, to several problems and quantities of interest, as temperature profiles and heat flows. For the one gas case, an unified solution is developed for the BGK, S, Gross-Jackson and MRS models, derived from the Boltzmann equation. For binary mixtures, the mathematical formulation is based on the McCormack model. Particularly, when strong evaporation is investigated, and nonlinear aspects have to be included, the nonlinear BGK model is used. In this case, the ADO solution, provided by the linear model, is considered in a post-processing procedure which takes into account the nonlinear terms to evaluate the quantities of interest, and improved results are obtained, in comparison with the linear version. A series of numerical results are listed and, in general, an excellent accuracy and good computational efficiency are observed.

Neste trabalho, o fenômeno de evaporação em gases rarefeitos e analisado, para o caso de uma espécie de gás bem como de misturas binárias. Evaporação fraca e forte são consideradas para escoamentos de gases em canal e semi-espaco. Também e investigado o fenômeno conhecido como reverso de temperatura, típico de gases em estado de rarefação. O método ADO, uma versão analítica do método de ordenadas discretas, é utilizado para construção de soluções em forma fechada para os diversos problemas e quantidades de interesse, como perfis de temperatura e fluxos de calor. Para o caso de um gás, uma solução unificada e desenvolvida para problemas formulados a partir dos modelos cinéticos, derivados da equação de Boltzmann, BGK, S, Gross- Jackson e MRS. No caso de mistura binária de gases, a formulação matemática e baseada no modelo McCormack. Particularmente, quando a evaporação forte e abordada, e aspectos não lineares devem ser incluídos, a versão não linear do modelo BGK e utilizada. Neste caso, a solução ADO do modelo linear e utilizada em um processo chamado de pós-processamento para inclusão dos termos não lineares do problema e reavaliação das quantidades de interesse, evidenciando melhoria dos resultados obtidos pela formulação linear. Uma serie de resultados numéricos são listados e é observada, de forma geral, excelente exatidão e eficiência computacional. / In this work, evaporation phenomena in rarefied gas flow, for one gas case and binary mixtures, are analyzed. Weak and strong evaporation are considered in channel and half-space problems. The reverse of temperature problem, typical in rarefied gas dynamics, is also investigated. The ADO method, an analytical version of the discrete ordinates method, is used to develop closed form solutions, to several problems and quantities of interest, as temperature profiles and heat flows. For the one gas case, an unified solution is developed for the BGK, S, Gross-Jackson and MRS models, derived from the Boltzmann equation. For binary mixtures, the mathematical formulation is based on the McCormack model. Particularly, when strong evaporation is investigated, and nonlinear aspects have to be included, the nonlinear BGK model is used. In this case, the ADO solution, provided by the linear model, is considered in a post-processing procedure which takes into account the nonlinear terms to evaluate the quantities of interest, and improved results are obtained, in comparison with the linear version. A series of numerical results are listed and, in general, an excellent accuracy and good computational efficiency are observed.

Vid TCF-blekning av pappersmassa är väteperoxid en av huvudkemikalierna. I dagsläget är det svårt att styra blekstegen. Operatörerna måste ta hänsyn till produktionstakt, blekbarheten på massan varierar och fördröjning i trender. PO-bleksteget på Södra Cell Värö har en ungefärlig uppehållstid på 4 timmar och det är först efter så lång tid som man kan se hur en förändring verkligen slår igenom. Överblekning kostar väldigt mycket i kemikalieåtgång och det är därför efterfrågat ett sätt att kunna styra och optimera peroxidblekningssteget. Ett delsteg för detta var att simulera steget experimentellt och från dessa data ta fram en matematisk modell som förutsäger ljusheten. Massa togs ut från fabriken och blektes på labb under kontrollerade förhållanden med satsningar liknande verkliga i fabriken. De parametrar som studerades på labb var temperatur, väteperoxidsats och alkalisats då de påverkar ljusheten mest. En modell för ljushetsökning anpassades sedan till framtagna blekdata. Ekvationer för förbrukning av väteperoxid och hydroxidjoner togs också fram från analyser på blekfiltraten. Med ingående parametrar som startkoncentrationer av kemikalier, temperatur och massakoncentration förutsäger modellen ljusheten väl vid verifiering jämfört med fabrik och verifieringsblekning på labb. Modellen ligger något högre jämfört med fabrik men det var förväntat då förhållanden på labb ger ett renare system. För de parametrar som studerats anpassade sig modellen bra till förändringar och vid verifiering på labb syntes att modellen även svarade med en korrekt ljushet vid förändring i massakoncentration och ingående ljushet i steget. / During TCF-bleaching of pulp, hydrogen peroxide is one of the main chemicals. Today it is difficult to control the bleaching stages. The process operators must consider the production rate, changes in the bleach ability of the pulp and delays of trends in the control system. The PO-bleaching stage at Södra Cell Värö has approximately a retention time of four(4) hours and it is first after that, a result of a change in the process can be seen. Overbleaching is expensive due to high chemical need and therefore it is requested to find a way to control and optimize the peroxide bleaching stage. One way to do this was too simulate the stage experimentally and from those kinetic data accomplish a mathematical model that predicts the brightness increase of the pulp. Pulp from the mill was bleached at the laboratory under controlled conditions and with charges similar to what are used in the plant. The parameters that were studied at lab were temperature, hydrogen peroxide charge and alkali charge as they affect the brightness mostly. A model for brightness increase was adjusted to the achieved bleaching data. Equations for consumption of hydrogen peroxide and hydroxide anions were also developed from analyses of the bleaching filtrates.  From the start parameters, as concentration of the chemicals, temperature and pulp concentration, the model predicts the brightness well according to verification of data from mill and verification bleaching at laboratory. The value from the model is somewhat higher compared to that of the plant but that was expected due to the fact that the conditions at lab give a cleaner system. For those parameters that were studied, the model did adjust well to changes made and according to the verification at lab it was seen that the model also worked for changes in pulp concentration and different brightness at the beginning of the stage.

Laktatkonzentrationszeitkurven nach akuter körperlicher Belastung und im Stufentest haben sich ebenso wie der Dauerleistungstest in der sportwissenschaftlichen Leistungsdiagnostik etabliert. Beide Verfahren erlauben, die Leistungsfähigkeit von Sportlern einzuschätzen und die Trainingsbelastung optimal entsprechend der Sportdisziplin zu steuern. Der Unterarm-Ischämie-Test dient dazu, Muskelerkrankungen auf der Basis von Laktat- und Ammoniakkonzentration zu differenzieren. Die Laktat-Konzentrations-Zeitkurven nach akuter Belastung, im Stufentest oder im Dauerleistungstest sowie im Unterarm-Ischämietest werden vorwiegend deskriptiv durch Parameter wie die maximale Laktatkonzentration oder Leistung bei bestimmter Laktatkonzentration ausgewertet. Das Ziel der vorliegenden Untersuchung ist, pharmakokinetische Modelle für auf der Laktatkonzentration basierende Tests zu prüfen und deren praktische Relevanz zu diskutieren. Dabei können der akute Belastungstest und der Vorderarm-Ischämietest wegen eines ähnlichen Laktatprofils (Peak-Kurven), der Dauerleistungstest (kumulative Kurven) und der Stufentest (stetig monoton steigende Kurven) getrennt betrachtet werden. Die Routinelaktatprofile von 13 männlichen Freizeitsportlern (Alter: 20-35 Jahre), die sich einem 3 Minuten dauernden akuten ergometrischen Leistungstest unterzogen, wurden zur Modellbildung herangezogen. Der Unterarm-Ischämietest wurde bei acht Patienten im Alter zwischen 20 und 45 Jahren, bei denen bei Aufnahme die Verdachtsdiagnose einer Muskelerkrankung des Glukose- oder Eiweißstoffwechsels bestand, durchgeführt. Wird die Laktatkonzentrationszeitkurve, oder im Ischämietest auch der Ammoniakkonzentrationzeitkurve, als Summe eines Produktions- und Eliminationsvorgangs, dagestellt, lassen sich zusätzliche Informationen gewinnen. Blutlaktatkonzentrationen (Cb(t)) nach akuter ergometrischer Belastung wurden mittels nichtlinearer Regression an das Grundmodell Cb(t)=Co+B*(exp(-Lp*t )-exp(-Le*t)) angepasst, wobei Co der Ruhelaktatkonzentration und B einer Konstanten entsprechen. Die Laktatproduktionsrate (Lp) und Laktateliminationsrate (Le) differenzieren zwischen der Laktatproduktion einerseits und der Laktatelimination andererseits. Der Quotient Lp/P (P=erbrachte Leistung) stellt ein standardisiertes Maß für die Laktatproduktion im Muskel dar. Dagegen charakterisiert der Quotient Le/P die Elimination des Laktats aus dem Blutkompartiment. Über die Beziehung HWZp = ln2/Lp und HWZe = ln2/Le können die entsprechenden Halbwertszeiten berechnet werden. Eine reine Laktatproduktionszeitkurve (Cp(t)) lässt sich über die Beziehung Cp(t) = Cb(t) + Le*( ∫Cb(t)-Co*t) rekonstruieren und zeigt anschaulich den Verlauf der Laktatproduktion. Die Produktionszeitkurve erreicht im Verlauf der Elimination asymptotisch einen Maximalwert (Pm) und kann, identische Verteilungsvolumina des Laktats (Vdl) vorausgesetzt, über die Beziehung Ml = Vdl * Pm Informationen über die insgesamt freigesetzte Laktatmenge (Ml) geben. 19 gesunde Probanden unterzogen sich einem standardisierten Stufentest unter folgenden Bedingungen: Vor Beginn der Bergtour (Meereshöhe, SLa), nach Ankunft auf 1700 m (1700a), nach 10tägigem moderaten Training (Bergwandern zwischen 1700 und 3000m, 6 h pro Tag) auf 1700 m (1700b) sowie nach 4 Wochen (kein spezifisches Training) erneut auf Meereshöhe (SLb). Primäres Ziel der Auswertung war, mit der Potenzfunktion der allgemeinen Form Y(x) = A+ B * X^C den funktionalen Zusammenhang zwischen Laktatkonzentration und Belastung bzw. Herzfrequenz und Belastung zu beschreiben. Neben den modellabhängigen Faktoren (Ordinatenabschnitt, Steigungsfaktor, Exponent) ließen sich durch die AUC(70-280) (Area under the curve 70 bis 280 Watt Leistung) das Ausmaß der Laktatproduktion, die entsprechende mittlere Konzentration (Cm) und durch die Laktatkonzentrationen bei 70 und 280 Watt (LT-70, LT-280) der Laktatanstieg charakterisieren. Der Dauerleistungstest hat sich neben dem akuten ergometrischen Belastungstest in der sportmedizinischen Leistungsdiagnostik als Methode etabliert. Bisher konzentrierte sich die Auswertung auf die maximalen Blutlaktatkonzentrationen im steady state. Die Autoren schlagen verschiedene Modelle vor, sowohl empirische als auch mechanistische, um die Laktatkonzentrationszeitkurve im Dauerleistungstest zu beschreiben. Neben der maximalen Konzentration können nach Berechnung der Modellkurven durch nichtlineare Regression Konzentrationen zu definierten Bedingungen (z. B. LT20 = Laktat nach 20 Minuten) oder die Steigung der Kurve beurteilt werden. Darüber hinaus lässt sich die AUC (Area under the curve) als Ausmaß für die Laktatbildung während des Dauerleistungstests mit der Trapezregel bestimmen. Zusammenfassend zeigen die Untersuchungen, dass in allen Verfahren der Laktatdiagnostik, dem akuten Belastungstest, der Standardergometrie, dem Laktatischämietest und dem Dauerleistungstest, signifikante und praktikable pharmakokinetische Modelle berechnet werden können. Sie erlauben es, die Ergebnisse mittels Modellparametern zu quantifizieren und zu vergleichen. / Lactate concentration versus time curves following acute physical exercise, the standard exercise test using increasing levels of work load and the steady state exercise test have been established methods to characterise the fitness of athletes and to control training intensity. The ischemic forearm exercise test (IFET) is used to detect metabolic disorders of muscles based on lactate and ammonia concentration during exercise under ischemia. Lactate concentration curves following acute exercise, standard ergometries and steady state tests as well as IFET are generally analysed descriptively, i. e. maximum lactate concentrations or work load with regard to defined lactate concentrations are used. The primary objective of this study was to assess pharmacokinetic models for lactate in exercise tests and to discuss the relevance in sports science. For practical purpose, the models used in acute and IFET (asymmetric peak curves), the steady state exercise test (cumulative curves) and standard exercise tests (continuously increasing function) are dealt with separately. Routine lactate profiles of 13 male nonprofessional athletes (age: 20-35) years who underwent an acute ergometry lasting 3 minutes were used to assess different pharmacokinetic models. An IFET was performed in 8 patients (Age: 20-45 years) supposed to have disorders of glucose metabolism or lack of myoadenylate deaminase. Lactate concentration versus time curves were fitted by means of non-linear regression to different kinetic models. The modified basic curve Cb(t)=Co+B*(exp(-Lp*t )-exp(-Le*t)), where Cb denotes the baseline concentration, B a constant, Le denotes the lactate elimination constant and Lp the “absorption or production” constant, yielded remarkable nonlinear regression results in for both test settings. Lactate concentration versus time curves in acute exercise tests are mostly assessed descriptively by means of parameters such as maximum concentration or workload with regard to specified lactate levels. Additional diagnostic information can be obtained, if production and elimination processes of the concentration versus time curve are separated. Production rate (Lp) and elimination rate (Le) of lactate are to define the shape of the curve. The ratio Lp/P (P=performance, work load), where Lp denotes the workload of the ergometer, can be considered as a standardized criterion of lactate production in the muscle. On the contrary, the ratio Le/P characterizes the elimination process from the vascular compartment. The corresponding half-lives [Tp, Te] are obtained using the relations Tp = ln2/Lp and Te = ln2/Le. The absolute lactate production versus time curve [Cp(t)] is given by the following equation: Cp(t) = Cb(t) + Le*( ∫Cb(t)-Co*t). The production versus time curve reaches a maximum value (Pm) after termination of the elimination process. If lactate has identical volumes of distribution (Vdl), Pm characterizes the total amount of lactate production (Ml) due to the relation Ml = Vdl*Pm. Nineteen healthy volunteers were exposed to a standardized exercise test at sea level (SLa), at an altitude of 1700 m before (1700a) and after a moderate 10 day mountain training (1700b), with a final control four weeks later at sea level (SLb). Vital signs, blood lactate and arterial oxygen saturation were determined prior, during or after the exercise test. The primary aim of the study was to fit the power function Y(X) = A+ B * X^C as a model for lactate versus workload and heart rate versus workload data. Apart from model characteristics (intercept, slope, exponent) the extent of lactate production could be estimated by the model independent characteristic AUC(70-280) (Area under the curve between 70 and 280 Watt) and the corresponding average concentration (Cm). The degree of lactate increase was characterized by means of the lactate concentration at 70 and 280 Watt (LT-70, LT-280), respectively. Apart from the standard and acute exercise test the steady state exercise test has gained increasing relevance in practice of sports medicine. So far, lactate curves of steady state tests were characterised by means of maximum. The author suggests several models, both empirical and mechanistic models, in order to fit lactate concentration versus time curves of the steady state ergometry. In addition to the maximum lactate concentration fitted nonlinear regression curves allow to assess the concentrations at defined conditions (e.g. LT20=lactate after 20 minutes of steady state workload, EC50 of the Emax model) or the slope of the curve. Moreover, the AUC(0-tx) – a measure for the extent of lactate production – can be calculated using the trapezoidal rule. In conclusion, in all lactate based tests, acute and standard ergometry, ischemic forearm test and steady state exercise test, concentration versus time data were fitted suitable pharmacokinetic models which allow to quantify and compare the results.

The time-course of interaction formation or breaking can be studied using LigandTracer, and the data obtained from an experiment can be analyzed using a model of ligand-target binding kinetics. There are different kinetic models, and the choice of model is currently motivated by knowledge about the interaction, which is problematic when the knowledge about the interaction is unsatisfactory. In this project, a Bayesian model selection procedure was implemented to motivate the model choice using the data obtained from studying a biological system. The model selection procedure was implemented for four kinetic models, the 1:1 model, the 1:2 model, the bivalent model and a new version of the bivalent model.Bayesian inference was performed on the data using each of the models to obtain the posterior distributions of the parameters. Afterwards, the Bayes factor was approximated from numerical calculations of the marginal likelihood. Four numerical methods were implemented to approximate the marginal likelihood, the Naïve Monte Carlo estimator, the method of Harmonic Means of the likelihood, Importance Sampling and Sequential Monte Carlo. When tested on simulated data, the method of Importance Sampling seemed to yield the most reliable prediction of the most likely model. The model selection procedure was then tested on experimental data which was expected to be from a 1:1 interaction and the result of the model selection procedure did not agree with the expectation on the experimental test dataset. Therefore no reliable conclusion could be made when the model selection procedure was used to analyze the interaction between the anti-CD20 antibody Rituximab and Daudi cells. / Interaktioner kan analyseras med hjälp av LigandTracer. Data från ett LigandTracer experiment kan sedan analyseras med avseende på en kinetisk modell. Det finns olika kinetiska modeller, och modellvalet motiveras vanligen utifrån tidigare kunskap om interaktionen, vilket är problematiskt när den tillgängliga informationen om en interaktion är otillräcklig. I det här projektet implementerades en Bayesiansk metod för att motivera valet av modell utifrån data från ett LigandTracer experiment. Modellvalsmetoden implementerades för fyra kinetiska modeller, 1:1 modellen, 1:2 modellen, den bivalenta modellen och en ny version av den bivalenta modellen. Bayesiansk inferens användes för att få fram aposteriorifördelningarna för de olika modellernas parametrar utifrån den givna datan. Sedan beräknades Bayes faktor utifrån numeriska approximationer av marginalsannolikeheten. Fyra numeriska metoder implementerades för att approximera marginalsannolikheten; Naïve Monte Carlo estimator, det harmoniska medelvärdet av likelihood-funktionen, Importance Sampling och Sekventiell Monte Carlo. När modellvalsmetoden testades på simulerad data gav metoden Importance Sampling den mest tillförlitliga förutsägelsen om vilken modell som generade datan. Metoden testades också på experimentell data som förväntades följa en 1:1 interaktion och resultatet avvek från det förväntade resultatet. Följaktligen kunde ingen slutsas dras av resultet från modelvalsmetoden när den sedan används för att analysera interaktionen mellan anti-CD antikroppen Rituximab och Daudi-celler.

<p>Positron Emission Tomography (PET) permits regional myocardial perfusion, fibrosis and oxidative metabolism to be non-invasively quantified with radioactive tracers such as [¹⁵O]-water and [1-¹¹C]-acetate. PET is an established research tool in congestive heart failure (CHF), a major cause of morbidity and mortality. However, as CHF is a syndrome that eventually affects all aspects of cardiac and systemic hemodynamic function, more clinically relevant information from a single PET scan is desirable. The aim of this thesis therefore was to develop and implement some new concepts in cardiac PET.</p><p>A new method for the measurement of cardiac output with any tracer was validated in animal experiments and CHF patients. The early pulmonary retention of [1-¹¹C]-acetate was inversely related to left ventricular (LV) function in animals and was directly proportional to lung water content and severity of LV diastolic dysfunction in patients.</p><p>Eight patients with acute myocardial infarction were followed with serial PET from 3 hours to 3 weeks after trombolytic treatment. PET revealed that myocardial perfusion and the extraction and utilization of fuel substrates all decreased closer to the infarct centre. The rate of oxygen utilization within the infarct at 3 h predicted degree of myocardial fibrosis, pulmonary oedema and tissue viability at 3 weeks. </p><p>Seventeen patients with CHF due to chronic ischemic cardiomyopathy and severely reduced LV function were evaluated with [1-¹¹C]-acetate PET before and after coronary artery bypass surgery. There was a dramatic improvement in physical performance and symptoms, which was not correlated to the standard LV ejection indices. PET revealed that functional improvement was associated with improved LV loading conditions, reversed remodeling and homogenization of oxidative metabolism rather than increased output.</p>

Positron Emission Tomography (PET) permits regional myocardial perfusion, fibrosis and oxidative metabolism to be non-invasively quantified with radioactive tracers such as [15O]-water and [1-11C]-acetate. PET is an established research tool in congestive heart failure (CHF), a major cause of morbidity and mortality. However, as CHF is a syndrome that eventually affects all aspects of cardiac and systemic hemodynamic function, more clinically relevant information from a single PET scan is desirable. The aim of this thesis therefore was to develop and implement some new concepts in cardiac PET. A new method for the measurement of cardiac output with any tracer was validated in animal experiments and CHF patients. The early pulmonary retention of [1-11C]-acetate was inversely related to left ventricular (LV) function in animals and was directly proportional to lung water content and severity of LV diastolic dysfunction in patients. Eight patients with acute myocardial infarction were followed with serial PET from 3 hours to 3 weeks after trombolytic treatment. PET revealed that myocardial perfusion and the extraction and utilization of fuel substrates all decreased closer to the infarct centre. The rate of oxygen utilization within the infarct at 3 h predicted degree of myocardial fibrosis, pulmonary oedema and tissue viability at 3 weeks. Seventeen patients with CHF due to chronic ischemic cardiomyopathy and severely reduced LV function were evaluated with [1-11C]-acetate PET before and after coronary artery bypass surgery. There was a dramatic improvement in physical performance and symptoms, which was not correlated to the standard LV ejection indices. PET revealed that functional improvement was associated with improved LV loading conditions, reversed remodeling and homogenization of oxidative metabolism rather than increased output.