Introduction: Inflammation and angiogenesis are hallmarks of rheumatoid arthritis (RA) that contribute largely to the formation of pannus tissue and joint destruction in patients suffering from RA. We have recently shown that intravenously applied cationic liposomes target efficiently angiogenic endothelial cells in the synovial vasculature of rheumatoid joints and therefore may also serve as potent vehicles for systemic drug delivery and therapy in RA. Therefore the aim of our study was to quantify the antiangiogenic and antiinflammatory properties of EndoTAG-1^® (paclitaxel formulated in cationic liposomes) in the inflamed joints of murine models of RA and to compare the therapeutical efficacy of EndoTAG-1^® to Taxol^® (paclitaxel in Cremophor EL).

Materials and Methods: Targeting of fluorescently labelled cationic liposomes to the synovial vasculature in mice with antigen-induced arthritis (AIA) was analysed by intravital microscopy. Density of functional vessels and adhesion of fluorescently labelled platelets or leukocytes were determined after treatment with EndoTAG-1^®. Knees were subjected to clinical scoring and histopathological analysis.

Results: EndoTAG-1^® treatment of AIA mice with developing or in established disease showed a strong attenuation of the course of the disease as well as a potent anti-inflammatory effect. Histological analysis of knee sections demonstrated a dramatic reduction of the pannus and infiltration of inflammatory cells. Enrichment of EndoTAG at the synovial vasculature of AIA mice was observed when compared with healthy mice. Treatment of AIA mice with EndoTAG-1^® concomitant to disease induction showed a complete remission of the course of the disease as shown by a significant decrease of clinical scores compared to both control and Taxol^® treated groups. A complete inhibition (98%) of neo-vascularisation was observed in the synovial vasculature of mice with AIA that were treated with EndoTAG-1^® whereas Taxol^® alone showed only 50% inhibitory effect. Rolling and adhesion of platelets were reduced to 53% (paclitaxel 5%) and 98% (paclitaxel 57%), respectively.

Discussion: Our in vivo data clearly demonstrates that anti-angiogenic and anti-inflammatory activity of Endo-TAG-1^® contribute to the therapeutical efficacy of this drug in RA. Notably, therapeutic efficacy with Endo-TAG-1^® was superior to Taxol^®. This strongly suggests that systemic delivery of cationic liposomes is very well suited to enrich compounds to rheumatoid joints for therapy and could be a promising treatment option for RA.

Introduction: With the advent of thoracoscopy, anterior release procedures in adolescent idiopathic scoliosis (AIS) have come into more frequent use, however, the indication criteria for an anterior release in thoracic AIS are still controversial in the literature. The aim is to achieve a better coronal correction but the benefit as compared to a single posterior approach is not yet clarified.

Material and Methods: Two groups of 15 patients each were matched for sex, age and cobb angle. Patients of group 1 were operated with a staged procedure of an anterior release followed by posterior instrumentation (anterior-posterior spinal fusion, APSF) and patients of group 2 were operated by a single posterior spinal fusion (PSF) with performance of concave sided rib osteotomies (concave thoracoplasty, CTP).

Results: Mean age: 16.2 y (APSF), 17.6 y (PSF). Mean preop curve: 81.7° ± 10.1° (APSF), 84.2° ± 14.1° (PSF). Mean postop curve: 34.9° ± 15.5° (APSF), 34.3° ± 12.2° (PSF) (p=0,49).

Conclusion: The single posterior approach gave the same coronal correction rate as compared to patients operated with a two stage procedure with preceding anterior release. A posterior release with CTP is more effective in increasing spinal flexibility than disc excision. According to our clinical experience, an anterior release prior to posterior instrumentation in AIS should only be considered in hyperkyphosis, coronal imbalance or massive curves.

Background: The healthy endothelium consists of quiescent endothelial cells that, under appropriate stimulation, can undergo profound changes leading to an activated phenotype. Activated endothelial cells of the synovial vasculature play a major role in the inflammatory process occurring in rheumatoid arthritis (RA) and enhanced angiogenesis contributes to the development and maintenance of RA. Thus, the endothelium can be used as an gateway for drug delivery and therapy. Cationic liposomes have been shown to target angiogenic endothelial cells in chronic inflammation in mice, also shown in tumors. They may also serve as potent vehicles for drug delivery to the synovial vasculature of rheumatoid joints.

Methods: To test whether cationic liposomes can serve as vehicles for drug delivery in RA we investigated the targeting of fluorescently labelled cationic liposomes (LipoRed) to the activated synovial vasculature of knees from arthritic mice. In a second step we used cationic liposomes carrying the compound MDG-12 (Endo-MDG-12) to study the effects of a targeted delivery of this drug to the inflamed joints in Antigen induced Arthritis (AIA). Targeting of LipoRed to the synovial vasculature was analysed by intravital microscopy (IVM) in mice with AIA. Synovial tissue was investigated at day 8 after AIA induction. Time resolved binding of liposomes was quantified at functional vessels of the microvasculature. Mice with AIA were intravenously treated with EndoMDG-12 in a therapeutic setting. Knee joints were subjected to clinical scoring and histopathology analysis.

Results: In a time dependent manner, intravenously applied LipoRed enriched more then three fold in the synovial vasculature of AIA mice when compared with healthy mice. In AIA animals maximum binding measured as relative fluorescence (Fmax=142 RFU) was already achieved 5 min after LiopoRed application (tmax) and dropped to the half maximum after 100 min (tmax/2)compared with healthy mice with a Fmax=48 RFU, tmax=15 min and tmax/2=60 min. Treatment of AiA animals with EndoMDG-12 showed a clear attenuation of the course of the disease. Analysis of the clinical score and thickness of knee joints showed a significant decrease of both parameters compared with the control group.

Conclusion: Based on our in vivo data, cationic liposomes seem to be very well suited to deliver compounds to rheumatoid joints for diagnosis and/or therapy. Furthermore, our results from animal experiments suggest that cationic liposomes like EndoMDG-12 could be a promising treatment option for RA.

Objectives: Platelets are suggested to participate in the pathogenesis of rheumatoid arthritis. We showed for the first time in vivo an increase of platelet-endothelial cell interactions in mice with Antigen-induced-Arthritis (AiA). However, underlying mechanisms are not clear so far. Therefore, the aim of the present study was to investigate first the impact of P-selectin on AiA and second the influence of platelet P-Selectin on the endothelial damage and activation of leukocytes by means of intravital microscopy.

Methods: In the first part C57/Bl6 and P-selectin deficient mice were disposed in four groups (n=7; control/AiA per strain). In the second part ex-vivo labelled platelets were transferred between different strains in AiA. The extent of AiA was assessed by knee joint swelling and by histological scoring. Platelet- and leukocyte-endothelium interactions were investigated.

Results: In arthritic P-selectin deficient mice compared to arthritic C57/Bl6 mice, platelet interaction was significantly reduced and reached the level of both control groups without AiA. In addition interaction of leukocytes in P-selectin deficient arthritic animals was significantly decreased in comparison to arthritic C57/Bl6 animals. Swelling of the knee joint and histological score was reduced in arthritic P-selectin deficient mice compared to arthritic C57/Bl6 mice. In the second part a significant increase of leukocyte-endothelial cell interaction in P-selectin deficient arthritic recipients was shown if P-selectin sufficient platelets were donated. If P-selectin deficient platelets were donated, the number of adherent leukocytes was significantly reduced.

Conclusion: We demonstrated for the first time in vivo a significant decrease of the interaction of platelets and leukocytes with the endothelium in P-selectin deficient mice with AiA and a reduction of clinical and histological symptoms of arthritis. Furthermore we showed that platelets provide storage of P-selectin for the recruitment of leukocytes in P-selectin deficient animals and therefore platelets seem to play a critical role in leukocyte-endothelial cell interaction. These findings suggest that P-Selectin is involved in the development and maintenance of arthritis and it could be at least partly responsible for the leukocyte tissue damage in AiA. Therefore, a reduced presence of P-selectin due to inhibition of platelets could be a new option for treatment of rheumatoid arthritis.

Introduction: There are few long-term studies after Zielke ventral derotation spondylodesis (VDS). We present a minimum 17 year follow-up study to assess factors predicting distal adjacent disc degeneration.

Material/Methods: Twenty-eight patients with thora-columbar AIS operated in 1982 have been retrospectively evaluated. Mean age 16,3 years, minimum follow-up 15 years. Anterior fusion was performed with rib graft.

Results: Mean pre-op Cobb angle was 65 ± 23°, post-op correction rate was 61,2 ± 12,4%. Mean angulation of end vertebra was 32 ± 10°, post-op corrected to a mean of 8° (correction rate 79%). Mean post-op Th10/L2 kyphosis was 10°. Rod breakage was seen in 17 patients.

Conclusion: Thoracolumbar kyphosis was associated both with proximal implant breakage and with segmental lordosis and degeneration of the distal adjacent segment. Disc angulation in the AP plane seems to be good tolerated. Anterior support with iliac bone graft or cages is expected to overcome these complications.

Introduction: In rigid AIS, the main resistance for thoracic derotation are the anteriorly rotated ribs on the concavity. This study presents clinical and radiographic long term results of the CTP, which is a routine surgical procedure at the authors’ institution.

Material and Methods: Between 1996 and 1997 we have operated on 466 cases of scoliosis. 36 patients with thoracic AIS were evaluated. Technique: The ribs on the concave side are osteotomised close to the costo-transverse joint and elevated over the bended rod.

Results: Mean follow up was 6.4 y. Mean preoperative side bending flexibility was 21%. Mean correction rate was 68%, mean rib hump correction was 3cm. Mean loss of correction 4°. There was no neurological complication, and pulmonary morbidity was not increased.

Conclusion: In rigid thoracic scoliosis, a release of the concave ribs by means of the CTP can both significantly increase the extent of correction and contributes to an excellent cosmetic result.