Geofiltracija po statiniais bei aplink ar per juos, yra vienas svarbiausių veiksnių, darančių įtaką jų ilgaamžiškumui, patvarumui ir naudojimo sąlygoms. Darbo tikslas- nusausinus priesmėlio, smėlio gruntus jų svoris padidėja, šis svorio padidėjimas yra netoli pamatų duobės esančio grunto apkrovimas papildoma apkrova. Nuo papildomos apkrovos, greta projektuojamo statinio išsivysto papildomos deformacijos, kurios tampa anksčiau statytų statinių papildomų deformacijų priežastimi. Atliekant magistro darbą, spręstas pagrindinis klausimas- kokiais atstumais būtina atlikti geologinius ir hidrogeologinius tyrimus, kad gautume patikimus geofiltracijos proceso parametrus ir išvengtume neigiamų pagrindo deformacijų. Geofiltracijos matematinis modeliavimas atliktas kompiuterine programa PLAFI. / Geofiltration under, around paling and through it is one of the main factors that influence its durability, longevity and condition of use. Geofiltration is proceeding everywhere and always in natural conditions. Thats why it is essential to know its main parameters when projecting, building, using palings so we would be able to avoid to master it to holes of foundation. The purpose of this topic . When we drain sand, sandy loam grounds their weight starts to increase. From additional strain near building that is under construction developes additional strain that becomes the main cause of previously builted paling cracking. To fulfill the purpose of master‘s work topic we have to solve the main problem which is in what distance it is necessary to accomplish geological and hydra- geological research so we would make reliable geofiltration parameters so we would avoid negative base deformations. This designing was accomplished with computer- based programme PLAFI.

Kūrybinis baigiamasis bakalauro darbas. Darbą sudaro du tapybos darbai (diptikas) „Transformacija“. Pateikiama vizualių kūrybos analogų, interpretuojančių laišką, pateikiami kūrybinio darbo eskizai, aptariamos jų kūrimo aplinkybės, idėjos paieška ir kitimas. Kūrybinis darbas buvo atliktas su užuomina į konceptualizmo tendencijas. Bakalauro darbo „Transformacija“ tema paliesta, norint atkreipti žiūrovo dėmesį į tai, kad XXI a. spausdintinis laiškas tampa supaprastintas, naudojamas pieštinis raštas, šriftas atlieka daugiau informacinę funkciją. Peržiūrėjus nemažai kūrybinių darbų, kurių tematika „Laiškas“, padariau išvadą, kad kiekvienas objektas, turintis savyje informacijos, gali būti laikomas laišku. Bakalauro baigiamasis darbas buvo atliktas aliejiniais dažais. Kūrybinis darbas, savo atlikimo technika, spalviniu koloritu, kompoziciniu spendimu leidžia perteikti temą. Kūrybinis dviejų dalių darbas „Transformacija“ nėra skirtas konkrečiai aplinkai. Darbai gali būti eksponuojami: parodinėse erdvėse, visuomeninės paskirties interjere, bei privačiuose būstuose. / There is creative Bachelor Paper of painting. Work consists of two work of painting (diptych) “Transformation”. Presentation of visual art analogy, interpreting letter, the creative work, sketches and discuss the development context, the ideas of search and transition. The creative work has been carried out with a hint of conceptualism trends. Bachelor's work "Transformation" theme touched upon in order to draw the viewer's attention to the fact that the twenty-first century printed message is simplistic, using a drawing letter, font out more information function. A review of creative work, whose themes "Letter", I concluded that every object has in itself the information may be considered by letter. Bachelor’s Final was carried out in oil paint. Creative work, his technique, color coloring, composition by decision of permits to convey the theme. The creative work of the two parts of "transformation" is not addressed specifically to the environment. Works may be displayed: exhibition spaces, public room, and private homes.

Exposure to microorganisms is considered an environmental factor which can contribute to diabetes mellitus via cytotoxicity or autoimmune responses against pancreatic cells. Firstly, the effects on rat insulinoma pancreatic β-cell line of secondary metabolites pyrrolnitrin (Burkholderia spp), phenazine compounds (Pseudomonas aeruginosa and Burkholderia spp) were investigated. Both compounds separately showed significant cytotoxicity after 24 h and at concentrations of 10 & 100 ng/ml potentiated insulin gene transcription, Ca2+ content and glucose-stimulated insulin secretion (GSIS). Furthermore, the outward membrane current was inhibited by phenazine (100 ng/ml) or pyrrolnitrin (10 or 100 ng/ml). Secondly, the capacity of 45 microbial species to bind insulin was screened in order to assess how common insulin binding was amongst microorganisms Burkholderia multivorans, B. cenocepacia and Aeromonas salmonicida bound insulin. A genomic library of B. multivorans was constructed in λ Zap Express and screened successfully for insulin binding recombinants. Recombinant phagemids p1 & p2 were excised, p1, encoded an insulin binding protein (IBP1 30 kDa) with homology to the iron complex siderophore receptor. For p2, two IBPs were detected at 20 & 30 kDa (IBP2 & IBP3), representing an intracellular and outer membrane peptide transporter. Comparison of IBP1 and human insulin receptor (HIR) produced 6 linear epitopes, and for IBP2 & IBP3 produced 3 epitopes. Thirdly, glutamic acid decarboxylase GAD65 is a major pancreatic autoantigen contributing to autoimmune diabetes. To assess the likelihood that microorganisms possess epitopes that mimic regions on GAD, 45 microbial species were tested for homology. This was facilitated by purifying recombinant GAD protein which was used to produce GAD antiserum. Four E. coli cross-reacting proteins were identified using mass spectrometry, outer-membrane protein A, formate dehydrogenase, superoxide dismutase and DNA starvation protein. Epitopes occurred at the C-terminal region of GAD65 (residues 419–565), a region previously reported to be targeted by autoantibodies. This study suggests that pyrrolnitrin and phenazine are cytotoxic to pancreatic β-cells and B. multivorans IBPs linear epitopes may be diabetogenic, particularly in patients with cystic fibrosis related diabetes (CFRD) who suffer a long term infections with Pseudomonas and Burkholderia species. Furthermore, microbial GAD epitopes could potentially induce an autoimmune response leading to diabetes.

The prefrontal cortex (PFC) is critically involved in many higher cognitive functions such as goaldirected behaviour, affective behaviour and especially working memory. In vivo extracellular recordings of PFC neural activity during working memory tasks show high variety in observed spiking patterns. These complex dynamics are critically shaped by intrinsic, synaptic and structural parameters of respective prefrontal networks. Moreover, dopamine (DA) is crucial for correct functioning of the PFC during working memory tasks. DA modulates a number of synaptic and intrinsic biophysical properties of single neurons, in particular deep layer pyramidal cells, which represent the major output neurons of the PFC. Despite a high variability of cortical pyramidal cell firing patterns, and somatodendritic morphology, no study has yet systematically examined correlations between intrinsic properties, morphological features and dopaminergic modulation of intrinsic properties. This study investigated properties of deep layer pyramidal cells through whole cell patch clamp in acute brain slices of the adult rat PFC. Cells were characterised physiologically through a variety of stimulation protocols surveying different time scales and wide intensity ranges, while all fast synaptic transmission was blocked. Furthermore the same catalogue of stimuli was recorded whilst applying specific DA receptor agonists to elucidate effects of DA receptor activation on intrinsic properties. All recorded cells were injected with biocytin and dendritic morphology was reconstructed from confocal image stacks of fluorescently labelled neurons. From the resulting data a set of characteristic variables were defined and a combination of principal components analysis and hierarchical cluster analysis was used to identify similarity between recorded cells in different parameter spaces spanned by intrinsic properties, intrinsic properties under dopaminergic modulation and morphology, respectively. The analysis presents evidence for distinct subpopulations within prefrontal deep layer pyramidal cells, as seen by clustering of recorded cells in these high dimensional parameter spaces. These subpopulations also show distinct input-output relationships, bearing implications for computational functions of these subpopulations. Furthermore, this study presents for the first time evidence of subpopulation specific DA effects in deep layer pyramidal cells. The quantitative analysis of somatodendritic morphology confirms physiological subpopulations and identifies characteristic morphological features of deep layer pyramidal cells. Moreover, cluster observed in different parameter spaces overlap, leading to a definition of subpopulations that concurs with previously described prefrontal pyramidal cell types. In conclusion, the results presented provide some deeper insight into fundamental principles of information processing in prefrontal pyramidal cells under the influence of dopamine.

Background and Methods: The involvement of iron in the risk for, and complications of, type 2 diabetes has generated substantial interest over the past 15 years, initially sparked by an association with raised serum ferritin, and the observation that people with iron overload diseases frequently develop diabetes. Considerable advances have since been made in understanding the effect glucose has on molecules, cells, and tissues; and the role that oxidative stress plays in the development of the pathologies of long-term diabetes. Poorly liganded iron is potentially both a contributor to, and consequence of, these complications. In vitro experiments with glucose-incubated transferrin by earlier workers have demonstrated loss of function with increasing glycation, leading to the suggestion that the failure of this key iron-binding protein may contribute to diabetic pathology, via the presence of redox active non-transferrin-bound iron (NTBI). In vitro glycated transferrin is examined here by ultrafiltration, to assess loss of function and possible oxidative fragmentation. Mass spectrometry is used to identify a range of amino acid glycation sites on in vitro glycated transferrin for the first time. Finally, several groups have previously measured NTBI in people with diabetes, finding little agreement in results. NTBI is measured here in a cohort of people with type 2 diabetes, using a new adaptation of earlier NTBI assays. NTBI is also assessed in pre-dialysis chronic kidney disease (CKD) stages I to III for the first time. Results and Conclusions: Experiments with glycated transferrin in vitro demonstrate oxidative fragmentation, explaining the loss of function reported by earlier groups. In vitro glycated transferrin examined by mass spectrometry reveals a substantial number and range of amino acids subject to glycation. Comparison with in vivo glycated transferrin suggests that many of the in vitro glycation sites are not glycated in vivo, and that there are many oxidized methionine residues which are potential artefacts, or likely to be repaired by methionine sulphoxide reductases in vivo. A study of people with type 2 diabetes finds no direct association between NTBI and protein glycation. Unexpected correlations between NTBI and LDL, and LDL and haemoglobin with increasing protein glycation, are reported for the first time. NTBI is suggested to be iron sourced from haemoglobin or haem, from erythrocyte haemolysis prior to sample collection. In people with pre-dialysis CKD stages I to III no significant difference in NTBI level compared to controls is seen, or correlations with markers of renal function. No link between NTBI and kidney function at this stage of disease is indicated.

Hypertensive patients exhibit impaired exercise capacity, a strong independent risk factor for cardiovascular disease, and the mechanisms responsible for this are not fully determined. Potential candidates may include endothelial vasomotor dysfunction and arterial stiffness, both of which are associated with hypertension. Impairment of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a major role in the development of these abnormalities, suggesting that enhancement of NO-cGMP signalling through phosphodiesterase type 5 (PDE5) inhibition may offer therapeutic potential in arterial hypertension. This thesis investigated the effects of the PDE5 inhibitor sildenafil citrate on exercise-induced vasodilatation, maximal exercise capacity and arterial stiffness in hypertensive patients, using different studies involving local limb and whole body exercise. Preliminary dose-ranging studies were initially performed to investigate the intraarterial (brachial) effects of sildenafil on forearm blood flow (FBF), and to select an appropriate, cGMP-independent, vasodilator to use as a control. On the basis on these studies, it was established that sildenafil, infused at 50μg/min, and verapamil, infused at 5μg/min, had similar vasodilator effect on FBF. Ten untreated hypertensive patients and ten matched normotensive subjects were then studied in a three-way, randomised, single-blind and placebo-controlled FBF study. The aim was to investigate the effects of sildenafil on handgrip exercise-induced vasodilatation, and to compare this response with verapamil and saline (placebo). Preinfusion exercise-induced vasodilatation was significantly reduced in hypertensive compared with normotensive subjects (P<0.001). However, after the infusions, while verapamil did not affect the vasodilator response to exercise in either group, sildenafil substantially enhanced this response in hypertensive patients, but not in normotensive subjects (P<0.05). These results suggested that sildenafil, through an increase in cGMP levels in the vasculature, substantially and selectively improves the vasodilator response to handgrip exercise in hypertensive patients.

The deleterious effects of Type 2 diabetes on the brain have been shown to result in a greater prevalence of age-associated cognitive impairment and an enhanced risk of age-related cognitive decline in older diabetic populations. Type 2 diabetes is a complex metabolic disorder. Apart from the negative impact of abnormalities intrinsic to diabetes, diabetes-associated cerebral microvascular disease may contribute to this accelerated cognitive ageing. Direct in vivo evaluation of the cerebral microcirculation is difficult in humans and the vessels themselves are too small to permit detailed visualisation with current neuroimaging methods. The microvasculature of the retina may offer a window into such vascular status of the brain as there is considerable homology between the retina and cerebral microcirculations. Moreover, the retinal vasculature is known to be affected by a wide range of systemic pathologies and is unique in that it is the only vasculature that can be directly visualised and photographed. Retinal microvascular abnormalities (RMAs) have been understudied risk factors in cognitive ageing epidemiological research. Few reports have comprehensively examined cognitive function in relation to diabetic retinopathy. Also the relationship between cognitive function and quantitative aspects of retinal vascular network geometry has not been investigated in people with Type 2 diabetes. The results of a systematic review reported in this thesis showed inconsistent findings on the importance of the association between retinal microvascular abnormalities and cognitive dysfunction in predominantly non-diabetic populations. This may have reflected substantial differences between studies regarding the choice of population under study, the methods applied for measuring and defining RMAs, the types of neuropsychological tests administered for assessing cognitive function, and the approach taken in data analysis. The principal aim of the original research described in this thesis was to examine the associations of cognitive test performance with severity of diabetic retinopathy and quantitative parameters of retinal vascular network in a population-based sample of older people with Type 2 diabetes. Objective, reproducible and computerized retinal image analysis was used to quantify retinal vessel calibres and arteriolar bifurcation geometry in order to detect subtle changes in retinal vascular network. A valid estimation of peak prior cognitive ability allowed the further exploration of the impact of retinal microvascular abnormalities on imputed cognitive decline from best-ever levels of cognitive function to that measured in old age. The analysis was based on a cohort of 547 men and 519 women aged 60-75 years with Type 2 diabetes, randomly sampled from the Lothian Diabetes Register, Scotland, in 2006/2007 (the Edinburgh Type 2 Diabetes Study). A battery of seven cognitive tests was administered and standard 7-field binocular digital retinal photography undertaken. The Mill Hill Vocabulary Scale was used to estimate pre-morbid cognitive ability. Diabetic retinopathy was evaluated independently by two optometrists using a standardised grading protocol (a modification of the Early Treatment of Diabetic Retinopathy Scale). Quantitative retinal vascular parameters were measured by myself from a digital image of field 1 using semi-automated, computer-based methods. Retinal vessel calibres were summarised as the central retinal arteriolar and venular equivalents (CRAE and CRVE, respectively) and arterio-venous ratio (AVR). Retinal arteriolar bifurcation geometry was expressed as arteriolar bifurcation angles (BA), arterial branching coefficient (BC), and sub-optimality (degree of deviation from optimality) of the retinal arteriolar angles. The statistical analyses were based on the 1,044 study participants who had both gradable retinal images and cognitive testing. Both general cognition, as indexed by a general cognitive factor reflecting the variance common to all the cognitive tests used, and most of the individual cognitive tests were negatively affected in participants with diabetic retinopathy relative to those without. These cognitive measures also showed a significant relationship with increasing severity of diabetic retinopathy (none, mild, and moderate-severe). Those with moderate-severe diabetic retinopathy had worst performances on general cognitive function, executive function, information processing speed, non-verbal memory and mental flexibility. When lifetime decline was estimated from peak, prior cognitive level, severity of diabetic retinopathy was significantly associated with a greater decline in information processing speed, non-verbal memory and mental flexibility and, in men for general cognition and executive function. The associations of severity of diabetic retinopathy with general cognition, executive function and information processing speed were independent of socio-demographic characteristics, cardiovascular risk factors, macrovascular disease, mood and hyperglycaemia. The associations with estimated decline in specific cognitive measures resulted principally from the impact of diabetic retinopathy on general cognitive ability. The study also showed that larger retinal arteriolar and venular calibres were both significantly associated with lower test scores on verbal memory in men. Multiple linear regression analyses demonstrated larger retinal arteriolar calibre was associated with a significantly greater decline in verbal memory after possible confounding by retinal venular calibre and vascular risk factors and disease was taken into account. In contrast, the study did not support an independent association between retinal venular calibre and cognitive decline in men or in women with Type 2 diabetes. Parameters of retinal arteriolar bifurcation geometry were not associated with cognitive outcome. Overall, these findings support the hypothesis that cerebral microvascular disease associated with Type 2 diabetes, reflected by the presence and severity of diabetic retinopathy, may exacerbate the effects of ageing on cognitive function. In particular, alterations in the blood-brain barrier may be an important pathophysiological mechanism in the occurrence of cognitive dysfunction in diabetic patients. They further may be added to the knowledge that gained from previous pathologic and brain imaging investigations demonstrating a relationship between markers of cerebral microvascular disease and cognitive dysfunction in diabetes. The role of quantitative parameters of retinal vascular network geometry in diabetes-related cognitive impairment is less clear. Prospective studies are required to clarify the temporal sequence of these associations and the eventual clinical significance of these small, early cognitive function changes. Such a follow-up project involving the present study population is underway. From a clinical perspective, if the above findings are substantiated, diabetes-associated cognitive dysfunction may be amenable to treatment and preventive strategies specifically targeted at protecting the cerebral microvasculature and reducing the risk of developing even mild microvascular disease in an ageing diabetic population.

Heme oxygenase (HO) is an enzyme that facilitates the oxidative breakdown of free heme into equi-molar concentrations of carbon monoxide (CO), the bile pigment biliverdin IX and free iron. These products have immuno-modulatory and antioxidative properties, which may be useful in the treatment of diseases characterised by low-grade inflammation and oxidative stress, such as insulin resistance and hyperglycaemia in type 2 diabetes. In fact, HO-1 protein levels and carbon monoxide generation are down-regulated in murine models of obesity and type 2 diabetes. Two independent research teams have reported that pharmacological induction of HO activity by protoporphyrin-based compounds, such as hemin and cobalt (III) protoporphyrin IX chloride (CoPP), exerts anti-diabetic effects, including protection from weight gain, systemic inflammation and peripheral insulin resistance, in various experimental models of type 2 diabetes. However, the relative insolubility and instability of hemin in solution and the multiple side-effects of CoPP, including weight loss, preclude their use for the treatment of patients in clinic. Heme arginate (HA) is a stable and soluble composition of hemin and L-arginine (LA) in a solution containing propylene glycol, ethanol and water. Furthermore, HA is licensed for the treatment of acute porphyria in several European countries. Therefore, HA may potentially be used in clinical trials. The current PhD thesis tests the hypothesis that the heme component of HA ameliorates hyperglycaemia via induction of HO activity in the leptin receptor deficient db/db (db/db) mouse model of type 2 diabetes. A preliminary in vivo study demonstrates that the heme but not the LA component of HA exerts an anti-hyperglycaemic effect in db/db mice. In a separate in vivo study, concomitant treatment of HA with stannous (IV) mesoporphyrin IX dichloride (SM), an inhibitor of HO activity, further improves the glycaemic control despite complete abrogation of the HA-mediated increase in HO activity in db/db mice. This result is in contrast to the above stated hypothesis, and demonstrates that the antihyperglycaemic effect of HA is due to a HO activity independent mechanism. Furthermore, the ameliorative effect of HA and HA+SM treatment on hyperglycaemia in db/db mice coincides with a gain in body and visceral fat weight, a reduction in islet β-cell inflammation and the preservation of islet β-cell function. Subsequent in vitro experiments demonstrate that HA exerts anti-inflammatory effects by a HO activity independent mechanism in pro-inflammatory in vitro models such as in cytokine mix-stimulated MIN6 β-cells and in classically activated bone marrow derived macrophages (BMDMs). In conclusion, the current thesis demonstrates the novel finding that the heme component of HA can exert anti-inflammatory and anti-diabetic effects via a HO activity independent mechanism. Future work should focus on studies to test the hypothesis that the interaction of heme with the nuclear receptor Rev-erb-α is responsible for the anti-inflammatory and anti-diabetic effects of HA.

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.