Objectives: Systematic review: This article presents a systematic review of studies evaluating the evidence for mobile phone-based interventions with adolescents who have Type 1diabetes. Studies were critically appraised and findings synthesised with the aim of answering the question: do mobile phone technologies facilitate improved outcomes in adolescents who have Type 1diabetes? Empirical research study: Diabetes research has indicated an association between attachment security and metabolic control as well as increased prevalence of mental health difficulties in diabetes populations. There is limited research with an adolescent Type 1 diabetes population. The current study aimed to examine attachment, emotional distress and self-esteem in an adolescent Type 1 diabetes population in relation to metabolic control and quality of life. The current study also aimed to evaluate the impact of ‘wellbeing text-messaging support’ with the same population. Method: Systematic review: A systematic search strategy was employed to identify relevant studies. An electronic database search, combined with a hand search of key journals and reference sections of key papers, was undertaken. Methodological quality was determined using an idiosyncratic measure including information relating to study design, sample size, interventions and statistical analyses. A narrative synthesis was performed due to the heterogeneity of the sample. Empirical research study: 60 participants aged between 12-18 years old who had a diagnosis of Type 1 diabetes for over 12 months took part. A longitudinal questionnaire design was used to collect data using five validated psychological measures. HbA1c was used as a measure of metabolic control. Text-messaging comprised a wellbeing module delivered daily over a three-week period. Results: Systematic review: 12 eligible studies were identified. One achieved a rating of ‘very good’, two a rating of ‘good’ and the remaining nine were pilot and/or feasibility studies, of whom four received a rating of ‘fair’ and ‘five received a rating of ‘poor’ methodological quality. Results indicated limited good quality evidence which included improved adherence and self-efficacy and mixed results in relation to metabolic control. Limitations identified included the use of small, convenience samples and short study duration. Empirical research study: High levels of fearful attachment security predicted poorer metabolic control and poorer quality of life, and high levels of emotional distress predicted poorer quality of life. ‘Wellbeing text-messaging support’ resulted in significantly improved quality of life. Conclusion: Systematic review: There is limited evidence that mobile phone technology has consistently improved outcomes in adolescents with Type 1 diabetes. Due to the number of pilot or feasibility studies and predominantly poor/fair quality of the current literature, and the heterogeneity of the sample, only tentative conclusions can be drawn, thus highlighting the need for further research. Empirical research study: Adolescent attachment style and emotional distress may be assessed as part of routine diabetes care in order to identify individuals who are potentially most at risk of failing to engage with diabetes health care. This can subsequently impact negatively on metabolic control and/or quality of life. These findings highlight the importance of clinical psychology input in paediatric diabetes teams. Further research in relation to text-messaging support was recommended.

The development of human society, which is highly dependent on fossil fuels, is now facing a range of global issues, such as rising energy prices, energy security and climate changes. To successfully tackle the resultant issues, the energy transition from fossil fuels to renewable energy sources, such as solar energy, tide energy, hydroelectric power, geothermal heat and biofuels, is under way. Biodiesel, as an important type of biofuels, has been increasingly produced from vegetable oil or used cooking oil, especially in Europe. Nevertheless, considering the high production cost of biodiesel, there is still much to be done to improve the economics of biodiesel industry. Utilisation of crude glycerol, the main by-product of the biodiesel industry, to produce value-added products appears to be a promising solution. Poly(3-hydroxybutyric acid) (PHB), a biodegradable plastic, can be converted from glycerol by Cupriavidus necator DSM 545 under unbalanced growth conditions, such as nitrogen limitation. One way to enhance the batch production of PHB is to genetically engineer the strain of C. necator, which requires insights of the dynamic impact of extracellular environment on cell phenotypes. Hence in this thesis, we aim to perform metabolic modelling based on experimental measurements to gain a better understanding of the behaviour of the metabolic network of Cupriavidus necator DSM 545 and identify potential bottlenecks of the process. Initially, C. necator DSM 545 is a strain that hardly grows on glycerol, so in a preliminary study, we investigate the process by which the strain was adapted to consume glycerol through serial subcultivation. It is found that the adaptation can be achieved within 15 cell generations over three passages in basal mineral medium, and the acquired phenotype is sufficiently stable upon further passage. The study of metabolism started with the reconstruction of the cell's metabolic network, followed by a thermodynamic analysis to check the feasibility and reversibility of all the biochemical reactions included. Then the static flux balance analysis was extended and applied to analyse the shift of metabolic states during the microbial fermentation in different batch conditions. The resulting patterns of flux distribution reveal the TCA cycle to be the major competitor for PHB synthesis at the ACCoA node. Cells have the potential to enter an efficient PHB-production phase that features minimal TCA/PHB flux split ratio, and the length of the phase can be manipulated by aeration. Although low aeration rate favours optimal flux split ratio, such condition that limits respiration also limits nutrient uptake, leading to low PHB productivity overall. To identify the actual limiting factors of PHB synthesis in the system, we further performed metabolic control analysis based on the calculated flux distributions. The analysis demonstrated how the distribution of the metabolic control can vary widely, depending on the aeration conditions used and the flux split ratios. Glycerolipid pathway, glycolysis, PHB metabolism, as well as the electron transport chain are revealed to be potential engineering targets as they contribute to the great majority of the positive control of PHB flux.

In this study, firstly, bioprocess characteristics for Serine Alkaline Protease (SAP) production, using recombinant Bacillus subtilis carrying pHV1431::subC, were examined. The cell concentration, substrate concentration, SAP activity and SAP synthesis rate profiles demonstrated that the system reaches to a steady state in terms of cell growth and SAP synthesis between t=15-25 h, therefore, this time interval is appropriate to employ both metabolic flux analysis and metabolic control analysis, which apply strictly to steady state systems. After that, three separate perturbations were introduced by addition of aspartate to the production medium at a certain time of the bioprocess. The response of the cells were observed and / by comparing the changes in intracellular reactions of aspartate pathway, Asn, Thr and Ile productions were determined to be the bottlenecks in aspartate pathway and the branchpoints splitting from Asp and AspSa were identified to be weakly rigid branchpoints. Lastly, metabolic control analysis principles were applied to determine the elasticity and flux control coefficients of the simplified aspartate pathway. Aspartate formation reaction and Lys, Thr, Ile, Met producing group share the control of asparagine synthesis. The results revealed that lysine producing branch flux dominates the other branch fluxes, therefore to eliminate bottlenecks and increase SAP production, the activity of the branches leading to the formation of Asn, Thr and Ile should be increased while decreasing the activity of lysine synthesizing branch. This could be achieved either by genetic manipulation or by addition of specific inhibitors or activators to the system.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22116号 / 医博第4529号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 妻木 範行, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The purpose of this study was to describe a sample of insulin-dependent diabetic youth in terms of selected anthropometric measurements, level of metabolic control and dietary intake. The 22 subjects (10 males and 12 females) were between the ages of seven to 16 years and, except for one female, regularly attended a multidisciplinary outpatient diabetes clinic. The study involved cross-sectional observation of height, weight, triceps and subscapular skinfold measurements, mid-arm muscle circumference and weight:height ratios, and comparison of these measurements to national norms derived from non-diabetic controls. Levels of metabolic control were observed using glycosylated hemoglobin values, and examined for effect on anthropometric parameters. It was found that the group generally fell within normal distribution patterns for all growth parameters when compared to control data. Level of metabolic control, duration of diabetes and age at onset of disease had no significant effect on the anthropometric parameters studied. Duration of diabetes had no effect on level of metabolic control. The study group consumed most nutrients in amounts consistent with the 1980 Recommended Dietary Allowances, with the exception of vitamin B6 , folacin, iron and zinc. Consumption of total fat, saturated fat and cholesterol were in excess of the current recommendations for diet in diabetes, and proportion of total energy from carbohydrate tended to be lower than recommended. Mean intakes of vitamins A, C, B 6 and s12 , thiamin, riboflavin, niacin, calcium, phosphorous, iron, magnesium and protein appeared to be higher than mean intakes of the same nutrients reported from the Nationwide Food Consumption Survey (1977-78) and the Second National Health and Nutrition Examination Survey (1976-80) for corresponding age groups. It was suggested that since young diabetic individuals usually have close supervision of their dietary intake, their intakes are somewhat superior nutritionally than those of non-diabetic individuals. The study sample reported use of a number of special dietetic foods other than dietetic soda and sucrose-substitutes. Foods used for treatment of hypoglycemic reactions included candy, fruit and juices, regular pop, frosting and special glucose preparations designed specifically for use with insulin-dependent diabetes.

There is evidence for the importance of physical exercise balanced with diet and insulin therapy in the treatment and control of Type I insulin-dependent diabetes mellitus. Recent attention in the literature has focused on the once neglected component of treatment--exercise. A well-controlled exercise state is generally believed to be beneficial for the individual with diabetes. Limited studies are available on the effect of exercise on long-term metabolic control. Before exercise levels can be professionally prescribed for a given population of youth with diabetes, current exercise patterns should be evaluated as to the effect on long-term metabolic control. It is the purpose of this study to examine the effects of exercise balanced with diet and insulin therapy on long-term metabolic control measured by total glycosylated hemoglobin values. The 26 subjects in the study were all Type I insulin-dependent youth with diabetes mellitus. The subjects ranged from 8 to 17 years of age. Sixteen subjects were female and 10 were male. All subjects were Diabetic Clinic outpatients of Primary Children Medical Center located in Salt Lake City, Utah. The research design utilized both descriptive design and statistical analysis. Questionnaries were used by the researcher to collect the data. Described were demographic data, nutrient intake, clinic staff assessment of metabolic control and growth parameters. Statistical analysis using a one-way analysis of variance test was performed to determine relationships between the dependent variable, total glycosylated hemoglobin, and the independent variables--exercise levels, caloric adequacy, insulin dosage administration, and metabolic control assessment. Further statistical tests were completed utilizing the least significant difference test. Among the described data, nutrient intake and growth parameters were compared to standards of a normal non-diabetic population. The nutrient intake of the subjects was well below the standard for iron. Iron was predominantly below the Recommended Dietary Allowance for iron. The growth parameters of the subjects were fairly equally distributed when compared to a normal population. The females showed some growth retardation with four of 16 females (25 percent) falling at or below the 5th percentile for either height or weight. It was found that a majority (88 percent) of the Type I insulin-dependent youth sampled were participating in regular exercise. Further examination of the subjects' exercise patterns demonstrated an influence of exercise on long-term metabolic control. Statistical significance at the 10 percent level was found between the three exercise levels and total glycosylated hemoglobin values. Individuals participating in predominantly moderately heavy activity (7.0-8.0 METS) had the highest degree of metabolic control. The results of the study support the conclusion that physical exercise has an important effect in the long-term metabolic control of youth with Type I insulin-dependent diabetes. A highly statistical significance was found between the clinic staff metabolic control assessment and total glycosylated hemoglobin values. Statistical significance was not found among the other two treatments. Caloric adequacy data failed to show statistical significance with total glycosylated hemoglobin. Insulin dosage administration data also failed to demonstrate a statistical significance with glycosylated hemoglobin.

Within a defined geographical area, all patients, 192 in total, with insulin- dependent diabetes of at least 2 years' duration and free from long-term diabetic complications were identified. Their experiences of the influence of the disease on daily living, tedium, and smoking habits were evaluated using a questionnaire and related to metabolic control. A case-referent study concerning smoking habits among 25 patients with good, and 25 with poor metabolic control was performed. The influence of mentruation on metabolic control was studied among 20 diabetic women and 20 healthy controls. Coping strategies and their outcomes were studied among 20 patients, using the interview technique. Among those with unsatifactory metabolic and/or emotional outcomes, plans for nursing intervention were agreed on, using diagnostic reasoning. Only a minority of the patients reported that the disease caused them considerable problems in their daily lives. The greatest problems occurred in connection with regularity in daily life, diet management, and exercise. Patients with good metabolic control (HbAic&lt;6.7) had a higher number of hypo-glycemic cornata (7 vs 1, p&lt;0.001). Patients with poor metabolic control (HbAic&gt;9.0) reported more often that they were smokers (pcO.Ol) and the women fertile aged in this group more often reported problems with metabolic control during menstruation (p&lt;0.05). Twenty-nine (18%) were defined as suffering from tedium. There was a higher proportion (NS) of high tedium scores among patients in both good and poor metabolic control groups than in those with intermediate metabolic control. Sixty (31%) of the patients were smokers, prevalence of smoking increased significantly with increasing HbAic- levels (17.5% among patients with the best metabolic control, 47.5% among those with the worst metabolic control). In the case referent study exposure to smoking was found to be significantly more common among those with poor control (odds ratio 6.0). No systematic change in metabolic control during the menstrual cycle could be found. Problem-solving coping strategy based on the monitoring of blood glucose in combination with sensitivity to signs of actual blood glucose level and logical reasoning, was found to have the best coping outcome, both regarding metabolic control and well-being. The results are summarized in a model for diagnostic reasoning in nursing. / <p>S. 1-46: sammanfattning, s. 47-117: 6 uppsatser</p> / digitalisering@umu

Background: Specialized adult care of phenylketonuria (PKU) patients is of increasing importance. Adult outpatient clinics for inherited errors of metabolism can help to achieve this task, but experience is limited. Ten years after establishment of a coordinated transition process and specialised adult care for inherited metabolic diseases, adult PKU care was evaluated with respect to metabolic control, therapy satisfaction, life satisfaction, sociodemographic data, economical welfare as well as pregnancy outcome. Methods: All PKU patients transferred from paediatric to adult care between 2005 and 2015 were identified. A retrospective data analysis and a cross-sectional survey in a sub-cohort of 30 patients including a questionnaire for assessing quality of life (FLZm) were performed as a single-centre investigation at the metabolic department of the University Hospital Leipzig, Germany. For statistical analysis, Mann-Whitney-U-test, t-test for independent samples, ANOVA and chi square test were used as appropriate. Results: 96 PKU patients (56 females/40 males; median age 32 years, range 18–62) were included. In the last 3-year period, 81 % of the transferred patients still kept contact to the adult care centre. Metabolic control was stable over the evaluation period and dried blood phenylalanine concentrations mostly remained within the therapeutic range (median 673.0 μmol/l, range 213.0–1381.1). Sociodemographic data, economical welfare and life satisfaction data were comparable to data from the general population. However, differences could be revealed when splitting the cohort according to time of diagnosis and to management during childhood. 83 % of the PKU adults were satisfied with the transition process and current adult care. 25 completed pregnancies were supervised; three newborns, born after unplanned pregnancy, showed characteristic symptoms of maternal PKU syndrome. Conclusions: Continuous care for adult PKU patients in a specialized outpatient clinic is successful, leading to good to satisfactory metabolic control and social outcomes. Uninterrupted good metabolic treatment throughout childhood and adolescence positively influences educational, professional and economic success in later life. Further effort in specialized paediatric and adult metabolic care is needed to prevent loss of follow-up and to support the recommended life-long treatment and/or care.

Thesis (PhD (Biochemistry))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: With the recent advances in the field of molecular biology, there is an increased need to integrate data on the various constituents of the cell in kinetic models that can predict and describe cellular behavior. When working towards a description of the entire cell using such kinetic models, the question arises: How do we compare different models for a given biological network? This is the central question addressed in my thesis and I developed and applied mathematical and computational methods for comparing dozens of existing models of erythrocyte and yeast glycolysis. To compare the steady-state behavior in models of erythrocyte glycolysis, I focussed on the function of the pathway, which is to supply the cell with Gibbs-free energy (γ- phosphate of ATP). I used supply-demand analysis in the framework of metabolic control analysis to make this comparison, which revealed that the ATP concentrations were homeostatically buffered at varying supply rates. I also applied this approach to compare steady-state behavior in models of yeast glycolysis, finding that they were not necessarily optimized for homeostatic maintenance of the ATP concentration and that in models for this organism the rate of ATP production is often determined by the supply reactions of glycolysis. In addition, I tested whether a kinetic model can describe novel behavior if it is adjusted to conditions different from those for which the model was originally constructed. More specifically, using a model of steady-state yeast glycolysis, I showed that small adjustments to the original enzyme concentrations are enough to obtain an oscillating model, which shows a remarkable resemblance to the experimentally observed oscillations. Importantly, some of these enzyme concentrations changes are known to occur during the pre-treatment of the cells which is necessary to obtain oscillatory behavior. To the best of my knowledge, the resulting model is the first detailed kinetic model that describes the experimentally observed strong synchronization of glycolytic oscillations in yeast populations. To analyze the dynamic behavior of yeast glycolytic models and to compare different models in terms of dynamics, I introduced a framework used in physics and engineering to create a vector based, two dimensional graphical representation of the oscillating metabolites and reactions of glycolysis. Not only was it possible to make a concise comparison of the set of models, but with the method I could also quantify the contribution of the interactions in the network to the transduction of the oscillations. Furthermore I could distinguish between different mechanisms of oscillation for each of the models, and demonstrated how the framework can be used to create such representations for experimental data sets. / AFRIKAANSE OPSOMMING: Met die onlangse vooruitgang in die veld van molekulere biologie, is daar ?n toenemende behoefte om data rakende die verskeie komponente van die sel in kinetiese modelle te integreer, om sodanig selgedrag te voorspel en te beskryf. As daar gepoog word om ’n beskrywing van die sel as geheel te verkry d.m.v. sulke kinetiese modelle, onstaan die vraag: Hoe vergelyk ons verskillende modelle van ’n gegewe biologiese netwerk? Dit is die sentrale vraag wat my tesis aanspreek en ek het wiskundige en numeriese metodes ontwikkel en toegepas om talle bestaande modelle van gis- en eritrosietglikolise te vergelyk. Om die bestendige-toestand gedrag in modelle van eritrosietglikolise te vergelyk, het ek gefokus op die funksie van die padweg, naamlik om die sel met Gibbs-vrye energie (γ-fosfaat van ATP) te voorsien. Ek het vraag-aanbod analiese in die raamwerk van metaboliese kontrole analiese gebruik om hierdie vergelyking te maak, wat getoon het dat die ATP konsentrasies homeostaties gebuffer was by verskillende aanbod tempos. Ek het ook hierdie aanpak gebruik om die bestendige-toestand gedrag in modelle van gisglikolise te vergelyk, en het bevind dat hulle nie noodwendig geoptimiseer is om ?n homeostatiese balans in die ATP konsentrasie te handhaaf nie, en dat in modelle vir hierdie organisme, die tempo van ATP produksie dikwels bepaal word deur die aanbod reaksies van glikoliese. Ek het verder ook bepaal of so ?n kinetiese model nuwe soorte gedrag kan beskryf, as dit aangepas word aan omstandighede wat verskil van dié waarvoor die model oorspronklik gekonstrueer was. Meer spesifiek, deur ?n model van bestendige-toestand gisglikolise te gebruik, kon ek wys dat klein veranderinge aan die oorspronkline ensiem konsentrasies genoeg was om ?n ossilerende model te verkry, wat opmerklik ooreenstem met die eksperimenteel waargenome ossilasies. Let ook daarop dat sommige van hierdie ensiem konsentrasie veranderinge plaasvind tydens die voorafbehandeling van die selle, wat essensieel is om die ossilasies waar te neem. Tot die beste van my kennis is die model wat ek met hierdie prosedures verkry het, die eerste gedetaileerde kinetiese model wat die eksperimenteel waargenome sterk sinkronisasie in ossilerende gis populasies voorspel. Om gis glikolitiese modelle te vergelyk in terme van hul dinamiese gedrag, het ek ?n raamwerk wat in fisika en ingeneurswese gebruik word, ingespan om ?n vektor-gebasseerde, twee dimensionele grafiese voorstelling van die ossilerende metaboliete en reaksies te maak. Hierdie raamwerk het dit nie net moontlik gemaak om ?n kompakte vergelyking van ?n stel modelle te maak nie, maar ek kon ook die bydrae van interaksies in die netwerk tot transduksie van die ossilasies kwantifiseer. Ek kon verder onderskeid tref tussen die verskillende ossilasiemeganismes vir elk van die modelle, en het ook gedemonstreer hoe die raamwerk gebruik kan word om sulke voorstellings vir eksperimentele datastelle te skep.

<p>The problem is two fold: how does natural selection operate on systems of interacting genes and how does natural selection operate in natural populations. To address the first problem, I have conducted a theoretical investigation into the evolution of control and the distribution of mutations in a simple system of interacting genes, a linear metabolic pathway. I found that control is distributed unevenly between enzymes, with upstream enzymes possessing the greatest control and accumulating the most beneficial mutations during adaptive evolution. To address the second problem, I investigated the evolution of copper tolerance in the common yellow monkeyflower, Mimulus guttatus. I genetically mapped a major locus controlling copper tolerance, Tol1. A Dobzhansky-Muller incompatibility was hypothesized to also be controlled by Tol1, however, we have demonstrated that it maps to another, tightly linked locus, Nec1. Finally, we investigated the parallel evolution of copper tolerance in multiple new discovered mine populations. We found that copper tolerance has evolved in parallel multiple times via at least two distinct physiological mechanisms. In four mine populations, there was a strong signal of selection at markers linked to Tol1, implying that copper tolerance has evolved via the same genetic mechanisms in these populations.</p> / Dissertation