Microsurgical Aneurysm Model in Rats and Mice: Development of Endovascular Treatment and Optimization of Magnetic Resonance Imaging

The rupture of a cerebral artery aneurysm causes a devastating subarachnoid hemorrhage (SAH), with a mortality of almost 50% during the first month. Each year, 8-11/100 000 people suffer from aneurysmal SAH in Western countries, but the number is twice as high in Finland and Japan. The disease is most common among those of working age, the mean age at rupture being 50-55 years. Unruptured cerebral aneurysms are found in 2-6% of the population, but knowledge about the true risk of rupture is limited. The vast majority of aneurysms should be considered rupture-prone, and treatment for these patients is warranted. Both unruptured and ruptured aneurysms can be treated by either microsurgical clipping or endovascular embolization. In a standard microsurgical procedure, the neck of the aneurysm is closed by a metal clip, sealing off the aneurysm from the circulation. Endovascular embolization is performed by packing the aneurysm from the inside of the vessel lumen with detachable platinum coils. Coiling is associated with slightly lower morbidity and mortality than microsurgery, but the long-term results of microsurgically treated aneurysms are better. Endovascular treatment methods are constantly being developed further in order to achieve better long-term results. New coils and novel embolic agents need to be tested in a variety of animal models before they can be used in humans. In this study, we developed an experimental rat aneurysm model and showed its suitability for testing endovascular devices. We optimized noninvasive MRI sequences at 4.7 Tesla for follow-up of coiled experimental aneurysms and for volumetric measurement of aneurysm neck remnants. We used this model to compare platinum coils with polyglycolic-polylactic acid (PGLA) -coated coils, and showed the benefits of the latter in this model. The experimental aneurysm model and the imaging methods also gave insight into the mechanisms involved in aneurysm formation, and the model can be used in the development of novel imaging techniques. This model is affordable, easily reproducible, reliable, and suitable for MRI follow-up. It is also suitable for endovascular treatment, and it evades spontaneous occlusion.

Evidence in European Asylum Procedures

This thesis explores the particular framework of evidentiary assessment of three selected appellate national asylum procedures in Europe and discusses the relationship between these procedures, on the one hand, and between these procedures and other legal systems, including the EU legal order and international law, on the other. A theme running throughout the thesis is the EU strivings towards approximation of national asylum procedures and my study analyses the evidentiary assessment of national procedures with the aim of pinpointing similarities and differences, and the influences which affect these distinctions. The thesis first explores the frames construed for national evidentiary solutions by studying the object of decision-making and the impact of legal systems outside the national. Second, the study analyses the factual evidentiary assessment of three national procedures - German, Finnish and English. Thirdly, the study explores the interrelationship between these procedures and the legal systems influencing them and poses questions in relation to the strivings of EU and methods of convergence. The thesis begins by stating the framework and starting points for the research. It moves on to establish keys of comparison concerning four elements of evidentiary assessment that are of importance to any appellate asylum procedure, and that can be compared between national procedures, on the one hand, and between international, regional and national frameworks, on the other. Four keys of comparison are established: the burden of proof, demands for evidentiary robustness, the standard of proof and requirements for the methods of evidentiary assessment. These keys of comparison are then identified in three national appellate asylum procedures, and in order to come to conclusions on the evidentiary standards of the appellate asylum procedures, relevant elements of the asylum procedures in general are presented. Further, institutional, formal and procedural matters which have an impact on the evidentiary standards in the national appellate procedures are analysed. From there, the thesis moves on to establish the relationship between national evidentiary standards and the legal systems which affect them, and gives reasons for similarities and divergences. Further, the thesis studies the impact of the national frameworks on the regional and international level. Lastly, the dissertation makes a de lege ferenda survey of the relationship between EU developments, the goal of harmonization in relation to national asylum procedures and the particular feature of evidentiary standards in national appellate asylum procedures. Methodology The thesis follows legal dogmatic methods. The aim is to analyse legal norms and legal constructions and give them content and context. My study takes as its outset an understanding of the purposes for legal research also regarding evidence and asylum to determine the contents of valid law through analysis and systematization. However, as evidentiary issues traditionally are normatively vaguely defined, a strict traditional normative dogmatic approach is not applied. For the same reason a traditionalist and strict legal positivism is not applied. The dogmatics applied to the analysis of the study is supported by practical analysis. The aim is not only to reach conclusions concerning the contents of legal norms and the requirements of law, but also to study the use and practical functioning of these norms, giving them a practcial context. Further, the study relies on a comparative method. A functionalist comparative method is employed and keys of comparison are found in evidentiary standards of three selected national appellate asylum procedures. The functioning equivalences of German, Finnish and English evidentiary standards of appellate asylum procedures are compared, and they are positioned in an European and international legal setting. Research Results The thesis provides results regarding the use of evidence in national appellate asylum procedures. It is established that evidentiary solutions do indeed impact on the asylum procedure and that the results of the procedure are dependent on the evidentiary solutions made in the procedures. Variations in, amongst other things, the interpretation of the burden of proof, the applied standard of proof and the method for determining evidentiary value, are analysed. It is established that national impacts play an important role in the adaptation of national appellate procedures to external requirements. Further, it is established that the impact of national procedures on as well the international framework as on EU law varies between the studied countries, partly depending on the position of the Member State in legislative advances at the EU level. In this comparative study it is, further, established that the impact of EU requirements concerning evidentiary issues may be have positive as well as negative effects with regard to the desired harmonization. It is also concluded that harmonization using means of convergence that primaly target legal frameworks may not in all instances be optimal in relation to evidentiary standards, and that more varied and pragmatic means of convergence must be introduced in order to secure harmonization also in terms of evidence. To date, legal culture and traditions seem to prevail over direct efforts at procedural harmonization.

The effectiveness of infrainguinal percutaneous transluminal angioplasty in the treatment of critical limb ischaemia

Critical chronic lower limb ischaemia (CLI) is the most severe form of peripheral arterial disease. Even though the treatment of CLI has evolved during the last decade, CLI is still associated with considerable morbidity, mortality and a decreased quality of life, in addition to a large financial impact on society. ---- Bypass surgery has traditionally been considered the approach of choice to treat CLI patients in order to avoid amputation. However, there are increasing data on the efficacy of endovascular revascularization procedures, such as percutaneous transluminal angioplasty (PTA), to achieve good leg salvage rates as well. Data gathered on all the 2,054 CLI patients revascularized at the Helsinki University Central Hospital between 2000 and 2007 were retrospectively analyzed. This patient cohort was used to compare the results of infrainguinal PTA and bypass surgery as well as to investigate predictors of failure after PTA. This study showed that infrainguinal PTA and bypass surgery yielded rather similar results in terms of survival, amputation-free survival and freedom from any re-intervention. When the femoropoliteal segment was treated, leg salvage was significantly better in the bypass surgery group, whereas no significant difference was observed between the two treatment methods when the revascularization extended to the infrapopliteal segment. PTA resulted in a significantly lower freedom from surgical re-interventions when compared to surgical revascularization. In this study the most important predictors of poor outcome after PTA for CLI were cardiac morbidity, nonambulatory status upon hospital arrival, and gangrene as a manifestation of CLI. Thus, when feasible, PTA seems to be a valid alternative for bypass surgery in the treatment of CLI provided that active redo-surgery is utilized. The optimal revascularization strategy should always be sought for each CLI patient individually considering the clinical state of the leg, the occlusive lesions to be treated, co-morbidities, life-expectancy, and the availability of a suitable vein for bypass.

High-risk patients and high-risk grafts in infrainguinal bypass for critical limb ischaemia

The main purpose of revascularization procedures for critical limb ischaemia (CLI) is to preserve the leg and sustain the patient s ambulatory status. Other goals are ischaemic pain relief and healing of ischaemic ulcers. Patients with CLI are usually old and have several comorbidities affecting the outcome. Revascularization for CLI is meaningless unless both life and limb are preserved. Therefore, the knowledge of both patient- and bypass-related risk factors is of paramount importance in clinical decision-making, patient selection and resource allocation. The aim of this study was to identify patient- and graft-related predictors of impaired outcome after infrainguinal bypass for CLI. The purpose was to assess the outcome of high-risk patients undergoing infrainguinal bypass and to evaluate the usefulness of specific risk scoring methods. The results of bypasses in the absence of optimal vein graft material were also evaluated, and the feasibility of the new method of scaffolding suboptimal vein grafts was assessed. The results of this study showed that renal insufficiency - not only renal failure but also moderate impairment in renal function - seems to be a significant risk factor for both limb loss and death after infrainguinal bypass in patients with CLI. Low estimated GFR (PIENEMPI KUIN 30 ml/min/1.73 m2) is a strong independent marker of poor prognosis. Furthermore, estimated GFR is a more accurate predictor of survival and leg salvage after infrainguinal bypass in CLI patients than serum creatinine level alone. We also found out that the life expectancy of octogenarians with CLI is short. In this patient group endovascular revascularization is associated with a better outcome than bypass in terms of survival, leg salvage and amputation-free survival especially in presence of coronary artery disease. This study was the first one to demonstrate that Finnvasc and modified Prevent III risk scoring methods both predict the long-term outcome of patients undergoing both surgical and endovascular infrainguinal revascularization for CLI. Both risk scoring methods are easy to use and might be helpful in clinical practice as an aid in preoperative patient selection and decision-making. Similarly than in previous studies, we found out that a single-segment great saphenous vein graft is superior to any other autologous vein graft in terms of mid-term patency and leg salvage. However, if optimal vein graft is lacking, arm vein conduits are superior to prosthetic grafts especially in infrapopliteal bypasses for CLI. We studied also the new method of scaffolding suboptimal quality vein grafts and found out that this method may enable the use of vein grafts of compromised quality otherwise unsuitable for bypass grafting. The remarkable finding was that patients with the combination of high operative risk due to severe comorbidities and risk graft have extremely poor survival, suggesting that only relatively fit patients should undergo complex bypasses with risk grafts. The results of this study can be used in clinical practice as an aid in preoperative patient selection and decision-making. In the future, the need of vascular surgery will increase significantly as the elderly and diabetic population increases, which emphasises the importance of focusing on those patients that will gain benefit from infrainguinal bypass. Therefore, the individual risk of the patient, ambulatory status, outcome expectations, the risk of bypass procedure as well as technical factors such as the suitability of outflow anatomy and the available vein material should all be assessed and taken into consideration when deciding on the best revascularization strategy.