Evaluation of Macrophage-Targeting PET Tracers for Imaging Inflammation in Atherosclerosis

Atherosclerosis is an inflammatory disease which is characterized by accumulation of lipids in the vascular wall. The rupture of atherosclerotic plaque is often behind the leading causes of death in the Western world: myocardial infarction and stroke. Plaques prone to rupture are often inflamed and contain large numbers of immune cells, especially macrophages. The detection of inflammation has been studied by new imaging techniques, such as positron emission tomography (PET). The aim of this thesis was to evaluate macrophage-targeting PET tracers for the imaging of inflammation in atherosclerosis and to evaluate responses to interventions using an established PET tracer. The studies were conducted in two mouse models. In vivo imaging, ex vivo biodistribution and aortic autoradiography were utilized to assess the tracer uptake in atherosclerotic arteries. Plasma biomarker measurements and histological stainings were conducted to assess the inflammation and the presence of tracer targets. The effects of dietary and atorvastatin interventions on aortic inflammation and uptake of an established tracer, 18F-FDG, were studied. Of the studied tracers, 18F-FMCH showed the highest potential. 18F-FEMPA, 68Ga-DOTANOC, and 68 Ga-DOTATATE also showed suitable characteristics for in vivo imaging with certain limitations, whereas 18F-FDR-NOC was not suitable. Compared to mice on high-fat food, dietary intervention led to attenuated aortic inflammation and lower 18F-FDG uptake, whereas atorvastatin alone had no effect. In conclusion, the macrophage-targeting tracers showed potential for the imaging of inflammation in atherosclerosis, especially 18F-FMCH, which will be further studied in a clinical setting. The therapy responses could be assessed in a mouse model with 18F-FDG.Siirretty Doriast

Perianestetisk omvårdnad av häst

This work is a combination of a literature study and a practical pilotstudy. In the literature study essential physiological reasons of why anaesthesia of horses is so risky are explained. Diffrent methods of induction and recovery are brought up, together with significant aspects of positioning the horse on the operating table and perianaesthetic complications such as myopathy, neuropathy and limb fractures. The pilotstudy had the purpose of examine the bodytemperature of horses undergoing general anaesthesia and to control the perianaesthetic temperature measurements performed in Swedish horseclinics and veterinary hospitals. Our hypothesis was that the bodytemperature of the horses would decrease but not enough to cause a problem. The purpose of this work has been to gather more profound knowledges in the subject of perianaesthetic nursing of horses which is an important part of the assignment of a veterinary nurse.Detta examensarbete är en kombination av en litteraturstudie och en praktisk pilotstudie. I litteraturstudien tas grundläggande fysiologiska orsaker till varför det är så riskfyllt att söva en häst upp samt olika metoder vid induktion och uppvak. Där tas även upp viktiga aspekter som bör tas i beaktande då hästen positioneras på operationsbordet och några av de komplikationer som kan tillstöta i samband med anestesin, varav myopati är den vanligast förekommande. Med pilotstudien ville vi kontrollera om det sker någon temperatursänkning hos de hästar som genomgår en generell anestesi samt hur kliniker och djursjukhus i Sverige genomför temperaturmätningar i samband med en sådan. Syftet med detta arbete har varit att få fördjupade kunskaper inom den perianestetiska omvårdnaden på häst som är en viktig del av djursjukvårdarens arbetsuppgifter

Type 2 diabetes enhances arterial uptake of choline in atherosclerotic mice: an imaging study with positron emission tomography tracer 18F-fluoromethylcholine

Additional file 1. Supplemental data

Positron Emission Tomography Imaging of Macrophages in Atherosclerosis with F-18-GE-180, a Radiotracer for Translocator Protein (TSPO)

Intraplaque inflammation plays an important role in the progression of atherosclerosis.) The 18 kDa translocator protein (TSPO) expression is upregulated in activated macrophages, representing a potential target to identify inflamed atherosclerotic plaques. We preclinically evaluated F-18-GE-180, a novel third-generation TSPO radioligand, in a mouse model of atherosclerosis. Methods. Nine hypercholesterolemic mice deficient in low density lipoprotein receptor and apolipoprotein B48 (LDLR(-/-)ApoB(100/100)) and six healthy C57BL/6N mice were injected with 10 MBq of F-18-GE-180. Specificity of binding was demonstrated in three LDLR(-/-)ApoB(100/100) mice by injection of nonradioactive reference compound of F-18-GE-180 before F-18-GE-180. Dynamic 30-minute PET was performed followed by contrast-enhanced CT, and the mice were sacrificed at 60 minutes after injection. Tissue samples were obtained for ex vivo biodistribution measurements, and aortas were cut into serial cryosections for digital autoradiography. The presence of macrophages and TSPO was studied by immunohistochemistry. The F-18-GE-180 retention in plaque areas with different macrophage densities and lesion-free vessel wall were compared. Results. The LDLR-/-ApoB(100/100) mice showed large, inflamed plaques in the aorta. Autoradiography revealed significantly higher 18F-GE-180 retention in macrophage-rich plaque areas than in noninflamed areas (count densities 150 +/- 45 PSL/mm(2) versus 51 +/- 12 PSL/mm2, p Conclusion. F-18-GE-180 shows specific uptake in macrophage-rich areas of atherosclerotic plaques in mice. However, retention in atherosclerotic lesions does not exceed that in lesion-free vessel wall. The third-generation TSPO radioligand F-18-GE-180 did not show improved characteristics for imaging atherosclerotic plaque inflammation compared to previously studied TSPO-targeting tracers.</div

VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart

Peer reviewe

Effects of dipeptidyl peptidase 4 inhibition on inflammation in atherosclerosis: A 18F-fluorodeoxyglucose study of a mouse model of atherosclerosis and type 2 diabetes

Background and aims: Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic inflammation using histology and 2-deoxy-2-[18F]-fluoro-d-glucose (18F-FDG), a positron emission tomography tracer of inflammation, in a mouse model of hypercholesterolemia and type 2 diabetes.Methods: Igf2/Ldlr-/-Apob100/100 mice were fed a high-fat diet (HFD) for 8 weeks and then randomly allocated to receive HFD (n = 14), or HFD with added linagliptin (n = 15) for additional 12 weeks. Five mice fed a chow diet were studied as an additional control. At the end of the study, glucose tolerance, aortic and liver uptake of 18F-FDG, and histology were studied.Results: Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar 18F-FDG uptake by atherosclerotic plaques in linagliptin and HFD groups (plaque-to-wall ratio: 1.7 ± 0.25 vs. 1.6 ± 0.21; p = 0.24). In the liver, linagliptin reduced the histologic inflammation score but had no effect on 18F-FDG uptake. Compared with chow diet, uptake of 18F-FDG was similar in the aorta, but higher in the liver after HFD.Conclusions: Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and 18F-FDG uptake, in atherosclerotic mice with type 2 diabetes.   </p

Amyloid-Targeting PET Tracer [18F]Flutemetamol Accumulates in Atherosclerotic Plaques

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [ 18 F]Flutemetamol in atherosclerotic plaques. The binding of [ 18 F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR − / − ApoB 100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [ 18 F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR − / − ApoB 100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [ 18 F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients. </p

Therapeutic Antibody Against Phosphorylcholine Preserves Coronary Function and Attenuates Vascular 18F-FDG Uptake in Atherosclerotic Mice

This study showed that treatment with a therapeutic monoclonal immunoglobulin-G1 antibody against phosphorylcholine on oxidized phospholipids preserves coronary flow reserve and attenuates atherosclerotic inflammation as determined by the uptake of 18F-fluorodeoxyglucose in atherosclerotic mice. The noninvasive imaging techniques represent translational tools to assess the efficacy of phosphorylcholine-targeted therapy on coronary artery function and atherosclerosis in clinical studies.</p

Translating pragmatic markers : or whatever you want to call them

This study analyses the translation of pragmatic markers from English into Swedish. The source text that was translated and used as a basis for the study is an article called “Black Books”, which was published in the British music magazine Prog in January 2013. The study is limited to question tags, general extenders and single-word pragmatic markers. It aims to investigate how these types of pragmatic markers can be translated in a dynamic and natural way, as well as how a careful analysis can facilitate the search for appropriate translation equivalents. Previous research and theories were used to determine the functions of the pragmatic markers in the source text, and the translation choices made on the basis of these findings were supported by corpus searches in the English-Swedish Parallel Corpus and Korp. The study revealed that because of the different ways in which pragmatic functions are expressed in English and Swedish, almost none of the pragmatic markers in the source text could be translated directly into Swedish. Formally equivalent solutions such as tja as a translation of well were generally considered too unnatural. While the study is too small to provide any general guidelines, it shows how a careful analysis may help the translator find more dynamically equivalent and natural solutions in the form of, for instance, other Swedish pragmatic markers, modal particles, adverbs and conjunctions

The ocean of loneliness : Experiences of loneliness among the elderly

Antalet äldre ökar både nationellt och internationellt. Ensamhet har rapporterats vara vanligare hos den äldre generationen och kan komma att bli ett växande hälsoproblem. Sjuksköterskan bör ha förmåga att stödja de äldre så att de kan bilda en meningsfull tillvaro både individuellt och i samspel med andra människor. Syftet med studien var att belysa upplevelsen av ensamhet hos äldre personer över 65 år. Studien genomfördes som en litteraturstudie med 12 vetenskapliga artiklar. Resultatet mynnade ut i fem kategorier: att sakna samhörighet, att vara lämnad kvar, att uppleva begränsningar, att uppleva den stora ensamheten och att uppleva ensamhetens föränderlighet. De äldre upplevde ensamheten som att vara uteslutna och övergivna. Upplevelsen av ensamhet kunde vara stor och skrämmande men även resultera i känslor av frihet. Ensamheten kunde upplevas som föränderlig och var inte alltid en konstant känsla. Ytterligare forskning om äldres upplevelser av ensamhet är betydande för att öka kunskapen om ensamhet vilket kan förbättra omvårdnaden av äldre i klinisk verksamhet.The elderly population is increasing both internationally and nationally. Loneliness has been reported to be more common in the older generation and could become a growing health problem. The nurse should have the ability to support older people so that they can form a meaningful existence, both individually and in interaction with other people. The aim of the study was to highlight the experience of loneliness in elderly people 65 years and over. The study was conducted as a literature review of 12 scientific articles. The results culminated in five categories: lack of togetherness, to be left behind, to experience limitations, to experience the great solitude and to experience the changeable solitude. The elderly experienced loneliness as being excluded and abandoned. The experience of loneliness could be huge and frightening but also result in a feeling of freedom. Loneliness could be perceived as changeable and was not always a constant feeling. Further research in elderly people's experiences of loneliness is important to increase knowledge of loneliness which can improve the care of the elderly in clinical practice