Introduction: Key studies have found an association between attachment style and poor diabetes outcomes in the adult diabetic populations. Specifically insecure attachment has been found to predict elevated glycated haemoglobin levels (HbA1c). Further studies have indicated that substance use and mental health difficulties also influence HbA1c. These factors have been looked at individually making it difficult to directly assess the overall effect of attachment on HbA1c and the potential mediating effects of substance use and mental health. The adolescent population has not been considered in studies examining these relationships. This study compares attachment security, level of substance use, interpersonal problems, anxiety and depression in relation to their role in blood glucose control in an adolescent population with Type 1 diabetes. Method: A quantitative, cross sectional, questionnaire design was employed to examine the role of the aforementioned factors in relation to HbA1c level. The target population included all patients aged 14 years to 18 years, inclusive, who attended for review at Diabetes Clinics across Lothian. Participants had a diagnosis of Type 1 Diabetes for at least one year and no additional diagnoses of mental health disorder or other chronic condition. At the clinic patients were approached and asked to complete a set of self report questionnaires. Measures of attachment were adapted versions of the Relationship Questionnaire (RQ) and the Relationship Scales Questionnaire (RSQ). Interpersonal problems were assessed using the short version of the Inventory of Interpersonal Problems (IIP-32). The Hospital Anxiety and Depression Scale (HADS) assessed levels of anxiety and depression. The Adolescent Substance Abuse Subtle Screening Inventory- A2 (SASSI-A2) was used to measure substance use. Blood glucose levels (HbA1c%) were obtained from clinic staff. A total of 88 participants returned completed questionnaires (response rate 79.3%). Results: When all correlations between predictors and HbA1c were examined, a negative correlation was found between attachment and HbA1c level. A positive correlation was found between anxiety and HbA1c level. Multiple regression analyses examined the relationship between attachment security and HbA1c before analysing additional predictors in the same model. No significant relationships emerged however the multiple regression model was not a significant fit for the data. Path Analysis considered all relationships between variables simultaneously while also providing information on how the model fits the data. Attachment security directly related to HbA1c levels when the contributions of gender, interpersonal problems and substance use were considered. Anxiety and depression did not predict HbA1c nor did they contribute to any other relationships with HbA1c. Interpersonal problems had a direct relationship with HbA1c when the contribution of substance use and attachment were considered. Conclusion: Attachment predicts HbA1c. The nature of this relationship is further understood when the contribution of additional psychological variables are considered. Methodological issues, clinical implications and directions for future research are discussed.

Glucocorticoids can reduce infarct size when given immediately after myocardial infarction (MI) but are detrimental when administration is continued into the post-infarct healing phase. A number of experimental studies have shown that reduction of infarct expansion by enhancing blood supply to the infarct border reduces remodelling and improves heart function post-MI. Previous experiments from this laboratory have shown that mice unable to locally regenerate corticosterone due to deficiency in 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) have an enhanced angiogenic response during myocardial infarct healing that is associated with improved cardiac function. We hypothesized that the enhanced angiogenic response in 11HSD1 knock out (-/-) mice would be preceded by augmented inflammation. Moreover this would be associated with improved cardiac function. This thesis aimed firstly to establish that murine cardiac phenotype was not influenced by 11HSD1 deficiency. 11HSD1-/- and C57Bl6 control mice had comparable cardiac structure and function. 11HSD1 expression was localised to fibroblasts and vascular smooth muscle cells in the myocardium. The second aim of this thesis was to characterise the healing response after MI in 11HSD1-/- mice compared to C57Bl6 mice. Neutrophil infiltration peaked 2 days after MI and was significantly enhanced in the 11HSD1-/- mice relative to C57Bl6 mice, despite comparable infarct size in both groups. This was followed by increased macrophage accumulation in the infarct border. Furthermore, in the 11HSD1-/- mice a greater proportion of macrophages were of the alternatively activated phenotype. Left ventricular expression of pro-angiogenic IL-8, but not VEGF, was increased. Cellular proliferation and vessel density at 7 days were greater in 11HSD1-/- compared to C57Bl6 hearts. This was associated with improved cardiac function 7 days post-MI. The third aim of this thesis was to determine whether the enhancement in vessel density and cardiac function was maintained beyond the initial wound healing phase. 11HSD1-/- mice retained the increased vessel density compared to C57Bl6 mice and these vessels were smooth muscle coated suggesting vessel maturation. This was associated with sustained improvement in cardiac function and modification of the scar characteristics. The final aim of this thesis was to establish whether the effect of the knock out could be recapitulated by administration of a small molecule inhibitor of 11HSD1 after MI. Oral administration of the 11HSD1 inhibitor had no effect on inflammation, angiogenesis and heart function as determined at 7 days post-MI relative to vehicle treated animals. In conclusion, the data confirm the enhancement in vessel density and cardiac function in 11HSD1-/- mice and demonstrate that this was preceded by enhanced inflammation. This was not due to an underlying cardiac phenotype or modification of the infarct size. Increased infiltration of alternatively activated macrophages may have been the source of pro-angiogenic factor, IL-8, which was also increased at the time of angiogenesis. Importantly the enhanced vessel density was retained 4 weeks after MI, these vessels were mature suggesting longevity and the improvement in cardiac function was retained. While pharmacological inhibition did not recapitulate the effect of the knock out this may have been due to route of administration. The data provides compelling evidence that further development and use of small molecule inhibitors of 11HSD1 may be of benefit post-MI.

Background/Objective: Several studies have shown that a low carbohydrate diet (LCHOD) can improve glycaemic control in type 2 diabetes (T2DM). The objective of the current study was to compare two ways of administration of a LCHOD: self-prepared meals versus ready-made meals, and their effects on weight loss, glycaemic control, body composition, cardiovascular risk and resting metabolic rate over 12 months. Research design and methods: Forty-one volunteers with the mean body mass index of 38.8 kg/m2 and poorly controlled T2DM (glycosylated haemoglobin, HbA1c > 7.5%) were randomized to either protein sparing modified fast (< 40g of carbohydrate daily, self-cooked; PSMF) or Go Lower (readymade meals; GL) diet. Both groups received multivitamin supplementation and attended monthly visits. The main outcome was weight loss and its composition. Results: Fourteen (34 %) participants completed 12 months of the intervention. There were no differences in the weight or any other changes between the diet groups at 12 months. Overall, body mass and fat mass decreased (-5.5 ± 7.3 kg, P < 0.001 and -5.1 ± 6.7 kg, P < 0.001 respectively) but fat free mass did not change. There was an overall reduction in HbA1c (-0.4 ± 1.1 %, P < 0.001), increase in HDL-cholesterol (+0.07 ± 0.18 mmol/L, P < 0.001) and decrease in triacylglycerol (-0.6 ± 2.4 mmol/L, P = 0.014). Resting metabolic rate significantly decreased (-137 ± 265 kcal/d, P < 0.001). Conclusion: LCHOD, independently of the approach taken, led to weight loss and improvements in glycaemic control in obese volunteers with poorly controlled T2DM. The results confirm that lifestyle modification using LCHOD is effective for improving T2DM and suggest that the type of approach to the diet can be matched to an individual’s preferences.

Things could have been different, but could it also have been different what things there are? It is natural to think so, since I could have failed to be born, and it is natural to think that I would then not have been anything. But what about entities like propositions, properties and relations? Had I not been anything, would there have been the property of being me? In this thesis, I formally develop and assess views according to which it is both contingent what individuals there are and contingent what propositions, properties and relations there are. I end up rejecting these views, and conclude that even if it is contingent what individuals there are, it is necessary what propositions, properties and relations there are. Call the view that it is contingent what individuals there are first-order contingentism, and the view that it is contingent what propositions, properties and relations there are higher-order contingentism. I bring together the three major contributions to the literature on higher-order contingentism, which have been developed largely independently of each other, by Kit Fine, Robert Stalnaker, and Timothy Williamson. I show that a version of Stalnaker's approach to higher-order contingentism was already explored in much more technical detail by Fine, and that it stands up well to the major challenges against higher-order contingentism posed by Williamson. I further show that once a mistake in Stalnaker's development is corrected, each of his models of contingently existing propositions corresponds to the propositional fragment of one of Fine's more general models of contingently existing propositions, properties and relations, and vice versa. I also show that Stalnaker's theory of contingently existing propositions is in tension with his own theory of counterfactuals, but not with one of the main competing theories, proposed by David Lewis. Finally, I connect higher-order contingentism to expressive power arguments against first-order contingentism. I argue that there are intelligible distinctions we draw with talk about "possible things", such as the claim that there are uncountably many possible stars. Since first-order contingentists hold that there are no possible stars apart from the actual stars, they face the challenge of paraphrasing such talk. I show that even in an infinitary higher-order modal logic, the claim that there are uncountably many possible stars can only be paraphrased if higher-order contingentism is false. I therefore conclude that even if first-order contingentism is true, higher-order contingentism is false.

<p>Fibronectin (FN) is a large extracellular matrix (ECM) protein that is made up of</p><p>type I (FNI), type II (FNII), & type III (FNIII) domains. It assembles into an insoluble</p><p>supra-­‐‑molecular structure: the fibrillar FN matrix. FN fibrillogenesis is a cell‐‑mediated process, which is initiated when FN binds to integrins on the cell surface. The FN matrix plays an important role in cell migration, proliferation, signaling & adhesion. Despite decades of research, the FN matrix is one of the least understood supra-­‐‑molecular protein assemblies. There have been several attempts to elucidate the exact mechanism of matrix assembly resulting in significant progress in the field but it is still unclear as to what are FN-­‐‑FN interactions, the nature of these interactions and the domains of FN that</p><p>are in contact with each other. FN matrix fibrils are elastic in nature. Two models have been proposed to explain the elasticity of the fibrils. The first model: the ‘domain unfolding’ model postulates that the unraveling of FNIII domains under tension explains fibril elasticity.</p><p>The second model relies on the conformational change of FN from compact to extended to explain fibril elasticity. FN contain 15 FNIII domains, each a 7-­‐‑strand beta sandwich. Earlier work from our lab used the technique of labeling a buried Cys to study the ‘domain unfolding’ model. They used mutant FNs containing a buried Cys in a single FNIII domain and found that 6 of the 15 FNIII domains label in matrix fibrils. Domain unfolding due to tension, matrix associated conformational changes or spontaneous folding and unfolding are all possible explanation for labeling of the buried Cys. The present study also uses the technique of labeling a buried Cys to address whether it is spontaneous folding and unfolding that labels FNIII domains in cell culture. We used thiol reactive DTNB to measure the kinetics of labeling of buried Cys in eleven FN III domains over a wide range of urea concentrations (0-­‐‑9M). The kinetics data were globally fit using Mathematica. The results are equivalent to those of H-­‐‑D exchange, and</p><p>provide a comprehensive analysis of stability and unfolding/folding kinetics of each</p><p>domain. For two of the six domains spontaneous folding and unfolding is possibly the reason for labeling in cell culture. For the rest of the four domains it is probably matrix associated conformational changes or tension induced unfolding.</p><p>A long-­‐‑standing debate in the protein-­‐‑folding field is whether unfolding rate</p><p>constants or folding rate constants correlate to the stability of a protein. FNIII domains all have the same ß sandwich structure but very different stabilities and amino acid sequences. Our study analyzed the kinetics of unfolding and folding and stabilities of eleven FNIII domains and our results show that folding rate constants for FNIII domains are relatively similar and the unfolding rates vary widely and correlate to stability. FN forms a fibrillar matrix and the FN-­‐‑FN interactions during matrix fibril formation are not known. FNI 1-­‐‑9 or the N-­‐‑ terminal region is indispensible for matrix formation and its major binding partner has been shown to be FNIII 2. Earlier work from our lab, using FRET analysis showed that the interaction of FNI 1-­‐‑9 with a destabilized FNIII 2 (missing the G strand, FNIII 2ΔG) reduces the FRET efficiency. This efficiency is restored in the presence of FUD (bacterial adhesion from S. pyogenes) that has been known to interact with FNI 1-­‐‑9 via a tandem ß zipper. In the present study we</p><p>use FRET analysis and a series of deletion mutants of FNIII 2ΔG to study the shortest fragment of FNIII 2ΔG that is required to bind FNI 1-­‐‑9. Our results presented here are qualitative and show that FNIII 2ΔC’EFG is the shortest fragment required to bind FNI 1-­‐‑9. Deletion of one more strand abolishes the interaction with FNI 1-­‐‑9.</p> / Dissertation

Rheumatoid arthritis (RA) which affects 0.5-1% of the world population and is characterised by joint erosions and presence of the autoantibodies anti-citrullinated protein antibodies (ACPA) and rheumatoid factor. Collagen II (CII) is a joint-specific antigen and we have shown that antibodies against CII (anti-CII) are present in around 8% of RA patients. RA patients with anti-CII are characterized by acute RA onset with elevated CRP and early joint erosions at the time of RA onset. Polymorphonuclear granulocytes (PMN) and peripheral blood mononuclear cells (PBMC) are abundant in RA synovial fluids, where they can interact with anti-CII, thus forming immune complexes (IC) with CII. In my thesis I have shown that PMN upregulated the cell surface markers CD66b and CD11b and downregulated CD16 and CD32 after stimulation with anti-CII IC. These changes in CD66b and CD16 associated to joint erosions to a larger extent than did PBMC responses to anti-CII IC. PMN cocultured with PBMC and stimulated with anti-CII IC showed augmented chemokine production that was dependent on TLR4 and functionally active PMN enzymes. This mechanism can lead to accumulation of inflammatory cells in joints of RA patients who are anti-CII positive around the time of RA diagnosis, and may thus help explain the acute onset RA phenotype associated with anti-CII. In a large Swedish RA cohort, anti-CII associated with elevations in clinical and laboratory measures of disease activity at diagnosis and until 6 months, whereas ACPA associated with late inflammation. Anti-CII seropositive RA was associated with improvements in clinical measurements and was negatively associated with smoking in contrast to ACPA that was associated with worseneing of clinical symptoms and associated positively with smoking. Anti-CII levels associated to  HLADRB1*03 and  HLADRB1*01 whereas ACPA showed negative association to HLA-DRB1*03. In a Malaysian RA cohort anti-CII also associated to elevated CRP at the time of diagnosis. Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse  to the clinical, genetic and smoking associations described for ACPA. Early determinations of anti-CII in parallel to ACPA predict the inflammatory outcome in RA.

Background: Diabetes is a chronic metabolic disease and an increasing public health problem. Treatment of type 1 diabetes requires daily insulin injections. Young people living with diabetes may feel that they do not fit in among others of the same age. Aim: Illustrate young people's experiences of living with diabetes type 1. Method: This study was a qualitative literature-based study with an inductive approach. The result was based on 10 qualitative scientific articles. Result: The analysis resulted in three main themes and seven subthemes. The main themes were: To live in a process of adaptation, A buffet of challenges and How the social surroundings impact the life. Conclusion: The results showed that young people who lived with type 1 diabetes felt that they had to adapt their lives to the disease. For young people it was also important to become independent in their illness. It was obvious that living with type 1 diabetes was an experience of both physical and mental challenge, and the people in the studies expressed a desire to be normal and to be able to compare themselves with others. The social surroundings had a clear impact in many ways, though the support from the environment was perceived as valuable. / Diabetes typ 1 är en ständigt ökande folksjukdom som ofta drabbar unga människor. Diabetes typ 1 är en kronisk ämnesomsättningssjukdom som ställer krav på den unga individen och skapar utmaningar i vardagen. Unga som lever med diabetes påverkas av sin omgivning och är i behov av stöd på olika sätt. Diabetes innebär att individen ständigt har förhöjda blodsockernivåer, till följd av brist på insulin. Unga människor lever i en turbulent period av livet, och att leva med en kronisk sjukdom kan förhindra en utveckling av den egna identiteten. Egenvården upplevs som en viktig del på vägen mot självständighet hos de unga, och sjuksköterskan har en central del i att hjälpa den unga individen att främja hälsa. Syftet är att belysa unga människors upplevelse av att leva med diabetes typ 1. Tio kvalitativa vetenskapliga artiklar har använts som material i resultatet. Resultatet visar att sjukdomen kräver en anpassning av livet. Det är en dragkamp om ansvaret för sjukdomen mellan de unga och deras föräldrar, då självständighet anses viktigt av unga människor för att uppnå frihet, vilket relateras till begreppen livsvärld och hälsa. De unga upplevde både känslomässiga och praktiska utmaningar i livet med diabetes, vilket diskuteras i relation till livskvalitet. En önskan om att få vara normal och kunna jämföra sig med andra i samma ålder finns, eftersom det är en betydande del i de ungas sökande efter en egen identitet. De unga anser att omgivningen påverkar dem på olika sätt, stödet från vänner och familj upplevs som betydelsefullt.

Dans la décennie précédente les supernovae se sont imposées comme une des sondes les plus puissantes pour reconstruire l'histoire globale de l'Univers. Cependant la standardisation des supernovae de type Ia est toujours une relation empirique. De futures expériences, tel que JDEM, sont prévues pour apporter une meilleure caractérisation de l'équation d'état de l'énergie noire responsable de l'accélération de l'Univers. Ces expériences nécessiterons un contrôle des erreurs systématiques pour assurer aux conclusions futures de n'être pas dominées par des effets non liés à la cosmologie. L'évolution des supernovae avec le redshift ou la présence de sous-classes parmi elles peuvent être à l'origine de ce type de systématiques. Ainsi une meilleure compréhension des propriétés des supernovae et de leur environnement pourrait apporter, une meilleure compréhension de leur standardisation, finalement une meilleure description des supernovae en tant qu'objets astrophysiques. Cette étude apporte également des informations traitant de la simulation de missions spatiales telles que JDEM / Over the past decade supernovae have emerged as one of the most powerful tools for reconstructing the global history of the Universe. However type Ia supernovae are still empirical tools. Future experiments, as JDEM, are planned to better characterize the equation of state of the dark energy leading to the observed acceleration thousands of objects. These experiments will need to carefully control systematic errors to ensure future conclusions are not dominated by effects unrelated to cosmology. The evolution of N Ia with redshift or the presence of subclasses among them can be at the origin of that kind os systematics. So a better understanding of the properties of supernovae in their host galaxies could provide information about the correlation between supernovae and their environment, a better understanding of their standardization, finally a better description of supernovae as astrophisical object. this study can also provide informations for more realistic simultations of a space mission like JDEM

Class of 2010 Abstract / OBJECTIVES: To evaluate glycemic control, therapy associated weight loss/gain, and hypoglycemic events for the newer type 2 diabetic agents pramlintide, exenatide, and sitagliptin. METHODS: The meta-analysis examined the efficacy of three currently FDA approved peptide analogues in nonpregnant adults with type 2 diabetes mellitus. All randomized, placebo controlled trials of exenatide, pramlintide, and sitagliptin that were indexed in MEDLINE or and the Cochrane Database of Systematic Reviews that fit the inclusion criteria were included. The drug treatment efficacy was analyzed in terms of HbA1c (glycosylated hemoglobin) change from baseline compared to placebo in trials lasting at least 12 weeks. Weight change from baseline per treatment group was also a primary measure. The safety of the treatments was assessed in terms of number of hypoglycemic events noted in the clinical trials. Each of these dependent variables was assessed separately for the three products. RESULTS: The meta-analysis of the six exenatide articles included in the analysis found statistically significant reductions in both HbA1c and weight when compared to placebo. However, patients were three times as likely to experience hypoglycemia with exenatide than placebo (RR= 3.01 95%CI[0.427 to 3.865]). Meta-analysis of pramlintide studies showed statistically significant lowering of HbA1c and weight. Overall pramlintide resulted in a rate of hypoglycemia nearly equal to that of placebo (RR= 0.94 95%CI[0.699 to 1.265]). Meta-analysis of sitagliptin found statistically significant reductions in HbA1c compared to placebo. However, sitagliptin use was not associated with a reduction in weight in the random effects meta-analysis model. In terms of hypoglycemic events, sitagliptin use was associated with 2.89 times greater risk of causing hypoglycemic episodes compared to placebo (RR=2.89 95%CI[0.704 to 5.877]). CONCLUSIONS: All three newer products were associated with improved glycemic control compared to placebo. Improvement in weight was associated with exenatide and pramlintide treatment. Pramlintide was not associated with an increase in hypoglycemic episodes.

Class of 2009 Abstract / OBJECTIVES: An estimated 26.3 million Americans have Diabetes Mellitus (DM). Currently six classes of agents are approved for the treatments of Type 2 DM. Problems with current options have led to searches for new medications and adjunctive therapy. Prickly pear (Opuntia species) has been traditionally used by Mexicans and Pima Indians for the treatment of DM. This is a retrospective analysis of data obtained from a randomized placebo-controlled prospective experiment in 28 Type 2 DM rodents (ZDF). There were 2 negative control groups which consisted of non-DM rodents and ZDFs; each receiving water. The positive control group consisted of ZDFs who received rosiglitazone 4.75 mg/kg/day. The treatment group consisted of ZDFs who received 5-10 mL/kg/dose of Opuntia ficus indica (Jugo De Nopal) liquid, given twice daily. Weight, blood glucose and platelet aggregation were recorded and analyzed. At baseline, there were no significant differences in weight or blood glucose among ZDF groups. The lean control rodents had significantly lower blood glucose compared to the ZDF rodents (p<0.001). Treatment with Jugo de Nopal resulted in a statistically significant reduction in blood glucose (p<0.001), with a mean decrease in blood glucose of 7%. All treatment groups demonstrated a significant weight gain, however, the prickly pear group had significantly less weight gain than the rosiglitazone group (p=0.028). CONCLUSIONS: There was not a significant difference among the treatment groups with regard to platelet responsiveness. Further studies are necessary to determine the efficacy of prickly pear as a blood glucose lowering agent.