Optimising treatment of younger, active knee osteoarthritis patients:Surgical options and functional outcomes

The main objective of this thesis is to facilitate the shared-decision making for the best surgical treatment strategy in relatively young and active knee osteoarthritis (OA) patients, based on their individual expectations and activity goals. We investigated three topics: I) current functional outcomes, including participation in sports and work, of joint preserving alternatives to knee arthroplasty (KA), II) prognostic factors for patient relevant outcomes, such as return to sport and work, after knee osteotomy and KA, and III) strategies to optimize outcomes like goal attainment and patient satisfaction in this relatively young and active group of KA patients. The results reported in this thesis support the use of knee joint sparing alternatives to KA in the treatment of relatively young, active patients. Individual activity goals, and prognostic factors for patient relevant outcomes, such as preoperative sports participation and being the family’s breadwinner, should be taken into account when deciding which treatment option is best for each specific patient. Finally, if patients go on to require a knee arthroplasty, goal-oriented and personalized rehabilitation should be offered

Arrhythmogenic cardiomyopathy - beyond monogenetic disease

Interpreting genetic variants, describing their associated clinical characteristics, and identifying new genetic loci involved in arrhythmogenic cardiomyopathy (ACM) is the focus of this thesis. By investigating various aspects of these genetic variants, we were able to correctly classify two variants occurring in the lamin A/C (LMNA) and titin (TTN) gene. We demonstrated that the reduced force generation seen in cardiomyocytes with the LMNA variant (LMNA c.992G>A) is due to remodelling within the cardiomyocytes and that patients with this specific variant have a milder phenotype compared to what is known from other pathogenic LMNA variants. By extensive phenotyping of carriers of a truncating TTN variant (TTN c.59926+1G>A) we were the first to show that (paroxysmal) atrial fibrillation is an important clinical feature in carriers of truncated TTN variants, even in the absence of dilated cardiomyopathy, atrial enlargement or generally accepted risk factors for atrial fibrillation. Thanks to extensive international collaboration it was possible to compile one of the largest cohorts of patients carrying truncating variants in desmoplakin (DSP). We showed that the location of such a genetic variant within the gene is associated with disease severity. Moreover, these studies show that enrichment of truncating genetic variants in specific regions of DSP variants in ACM patients, when compared to controls, facilitating interpretation of such variants. The multifactorial nature of ACM was underscored in a systematic analysis of the clinical outcome of patients from ACM cohorts carrying multiple variants in ACM related genes, showing that carrying multiple variants influences disease severity. Finally, by analysing genes encoding the sarcomere, the contractile unit of the heart muscle and the plectin (PLEC) gene for rare variants in ACM patients, we showed that these genes do not have a major role in the development of ACM

Primary angioplasty: Preprocedural pharmacological therapy

Primary coronary angioplasty has been shown to be an effective reperfusion therapy for patients with acute myocardial infarction, not only for those who present to PTCA centres but also for patients who present to hospitals without angioplasty facilities. With the increasing use of primary angioplasty more patients will be transferred to a (tertiary) PTCA centre. An increase in treatment delay is associated with a worse clinical outcome. The importance of an open infarct-related vessel at acute angiography is becoming clear. Pharmacological pretreatment of patients during transportation to a PTCA centre with the aim to open the infarct-related vessel in advance might be beneficial. Glycoprotein IIb/IIIa receptor blockers seem to be the agents of choice for facilitated PTCA. The safety and (cost) effectiveness of this pretreatment of patients transported to undergo primary angioplasty remain to be evaluatedPrimary coronary angioplasty has been shown to be an effective reperfusion therapy for patients with acute myocardial infarction, not only for those who present to PTCA centres but also for patients who present to hospitals without angioplasty facilities. With the increasing use of primary angioplasty more patients will be transferred to a (tertiary) PTCA centre. An increase in treatment delay is associated with a worse clinical outcome. The importance of an open infarct-related vessel at acute angiography is becoming clear. Pharmacological pretreatment of patients during transportation to a PTCA centre with the aim to open the infarct-related vessel in advance might be beneficial. Glycoprotein IIb/IIIa receptor blockers seem to be the agents of choice for facilitated PTCA. The safety and (cost) effectiveness of this pretreatment of patients transported to undergo primary angioplasty remain to be evaluate

Intervensi Koroner Perkutan Primer untuk Infark Miokard Elevasi ST di Pusat Jantung Pemula di Indonesia: 100 pasien pertama

Background: The benefits of Primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI) have been demon-strated, but most studies were conducted in experienced centres in western world. Experience, logistics and patient characteristics may differ in other parts of the world, particularly in a starting center.Methods: Data on all consecutive STEMI patients treated with primary PCI in Cinere hospital, Jakarta, Indonesia were collected in a prospective database.Results:,Between July 2006 and December 2008, a total of 100 patients with STEMI were treated by primary PCI. Mean age was 56.9 ±10.4 years (range 37-82), 88% was male. Mean time between onset of chest pain and admission was 369 ± 388 minutes. The mean time between admission and balloon inflation was 258 minutes. Before PCI, 50% of patients had TIMI 0 flow. After primary PCI 94% of patients had TIMI 2/3 flow. There were no deaths in the catheterisation room, and no emergency coronary bypass surgery was needed as a result of PCI complications. Mean left ventricular ejection fraction as measured by echocardiography after 1 day was 48 ± 12 %.Conclusions: Outcome after primary PCI at a starting center is excellent in this series. Primary PCI was effective in restoration of TIMI flow, without complications. Time delay between symptom onset, admission and balloon inflation was long and all efforts should be encouraged to shorten this.Latar belakang: Manfaat Intervensi perkutan primer (IKP) untuk Infark Miokard Elevasi ST (IMEST) telah terbukti, namun-demikian kebanyakan penelitian mengenai ini di laksanakan dipusat layanan jantung yang berpengalaman di dunia barat, Pengalaman , logistik dan karakteristik pasien mungkin berbeda di belahan dunia ini, terutama di pusat yang baru mulai.Metode: Seluruh data pasien konsekutif dengan IMEST yang ditangani dengan IKP primer di pusat jantung Cinere , Jakarta, Indonesia dihimpun melalui seperangkat data yang dilaksanakan secara propekstif.Hasil: Antara Juli 2006 dan Desember 2008, dari seluruh jumlah 100 pasien dengan IMEST yang ditangani dengan IKP primer. Rerata usia adalah 56,9 tahun ± 10,4 tahun (berkisar 37-82 tahun), 88 % diantaranya adalah pria. Rerata waktu antara onset nyeri dada dan masuk rumah sakit adalah 369 ± 388 menit. Rerata waktu antara masuk rumah sakit dengan inflasi balon adalah 258 menit. Sebelum IKP, 50 % pasien dengan aliran TIMI 0. Setelah IKP primer 94 % pasien memperoleh aliran TIMI 2/3. Tidak ada kematian didalam ruang kateterisasi maupun diperlukan tindakan bedah graft pintas arteri koroner yang gawat akibat komplikasi dari IKP. Rerata fraksi ejeksi yang diukur dengan ekokardiografi setelah 1 hari adalah 48±12 %.Kesimpulan: Hasil akhir yang diperoleh setelah IKP primer pada pusat jantung yang baru dimulai adalah baik pada serial ini. IKP primer efektif dalam memeperbaiki aliran TIMI, tanpa komplikasi. Keterlambatan waktu antara permulaan gejala, saat masuk dan inflasi balon masih panjang dan segala usaha harus diupayakan untuk memendekan waktu ini

Structural Studies of Lanthanide Double Perovskites

This project focuses on the examination of the structures of lanthanide containing double perovskites of the type Ba2LnB'O6-d (Ln = lanthanide or Y3+ and B' = Nb5+, Ta5+, Sb5+ and/or Sn4+) using synchrotron X-ray and neutron powder diffraction. The first part of this project examined the relative stability of R3 rhombohedral and I4/m tetragonal structures as the intermediate phase adopted by the series Ba2LnB'O6 (Ln = lanthanide (III) or Y3+ and B' = Nb5+, Ta5+ or Sb5+). It was found that I4/m tetragonal symmetry was favoured when B' was a transition metal with a small number of d electrons, such as Nb5+ or Ta5+. This is due to the presence of p-bonding in these compounds. In the Ba2LnNbO6 and Ba2LnTaO6 series R3 rhombohedral symmetry was, however, favoured over I4/m tetragonal symmetry when Ln = La3+ or Pr3+ due to the larger ionic radius of these cations. The incompatibility of the d0 and d10 B'-site cations in this family of compounds was indicated by significant regions of phase segregation in the two series Ba2Eu1-xPrxNb1-xSbxO6 and Ba2NdNb1-xSbxO6. In the second part of this project the compounds in the series Ba2LnSnxB'1-xO6-d (Ln = Pr, Nd or Tb and B' = Nb5+ or Sb5+) were examined to understand the relative stability of oxygen vacancies in these materials compared to the oxidation of the lanthanide cations and to determine if any oxygen vacancy ordering occurred. It was found, using a combination of structural characterisation, X ray Absorption Near Edge Structure and Ultra-Violet, Visible and Near Infrared spectroscopies, that with Ln = Pr or Tb increased Sn4+ doping results in a change in the oxidation state of the Ln3+ cations to Ln4+. This leads to those series containing little or no oxygen vacancies. A loss of B site cation ordering was found to accompany this oxidation state change and phase segregation was found to occur in the Ba2PrSnxSb1-xO6-d series most likely due to the Pr3+ and Pr4+ cations segregating into different phases. The Nd3+ cations in the series Ba2NdSnxSb1-xO6-d, however, can not oxidise to the tetravalent state so the number of oxygen vacancies rises with increasing x. It was found that oxygen vacancies concentrate onto the axial site of the compounds with x = 0.6 and 0.8 at ambient temperature. In Ba2Sn0.6Sb0.4O5.7 the oxygen vacancies were found to change to concentrating on the equatorial site at higher temperatures and it is suggested that this oxygen vacancy ordering plays a role in the adoption of I2/m monoclinic symmetry