Förderzeitraum 2014
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Sonstige beteiligte Institutionen
- Clinical Trial Center (CTC) / Zentrale für Klinische Studien Würzburg (ZKSW) (2)
- Röntgen Center for Complex Material Systems (RCCM), Am Hubland, 97074 W¨urzburg, Germany (2)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (1)
- Comprehensive Hearing Center, Department of ORL, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Würzburg, Germany (1)
- DNA Analytics Core Facility, Biocenter, University of Würzburg, Würzburg, Germany (1)
- Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany (1)
- Department of Paediatric Radiology, Institute of Diagnostic and Interventional Radiology, Josef-Schneider-Straße 2, Wuerzburg 97080, Germany (1)
- Interdisziplinäres Zentrum für Klinische Forschung (ZIKF), Würzburg (1)
- Research Center for Infectious Diseases (ZINF), University of Würzburg, Würzburg, Germany (1)
- Research Center for Infectious Diseases, University of Wuerzburg, Wuerzburg 97080, Germany (1)
- Würzburg Fabry Center for Interdisciplinary Therapy (FAZIT), University of Würzburg, Würzburg, Germany (1)
Background
Health-related and disease-specific quality of life (HRQoL) has been increasingly valued as relevant clinical parameter in cystic fibrosis (CF) clinical care and clinical trials. HRQoL measures should assess – among other domains – daily functioning from a patient’s perspective. However, validation studies for the most frequently used HRQoL questionnaire in CF, the Cystic Fibrosis Questionnaire (CFQ), have not included measures of physical activity or fitness. The objective of this study was, therefore, to determine the cross-sectional and longitudinal relationships between HRQoL, physical activity and fitness in patients with CF.
Methods
Baseline (n = 76) and 6-month follow-up data (n = 70) from patients with CF (age ≥12 years, FEV1 ≥35%) were analysed. Patients participated in two multi-centre exercise intervention studies with identical assessment methodology. Outcome variables included HRQoL (German revised multi-dimensional disease-specific CFQ (CFQ-R)), body composition, pulmonary function, physical activity, short-term muscle power, and aerobic fitness by peak oxygen uptake and aerobic power.
Results
Peak oxygen uptake was positively related to 7 of 13 HRQoL scales cross-sectionally (r = 0.30-0.46). Muscle power (r = 0.25-0.32) and peak aerobic power (r = 0.24-0.35) were positively related to 4 scales each, and reported physical activity to 1 scale (r = 0.29). Changes in HRQoL-scores were directly and significantly related to changes in reported activity (r = 0.35-0.39), peak aerobic power (r = 0.31-0.34), and peak oxygen uptake (r = 0.26-0.37) in 3 scales each. Established associates of HRQoL such as FEV1 or body mass index correlated positively with fewer scales (all 0.24 < r < 0.55).
Conclusions
HRQoL was associated with physical fitness, especially aerobic fitness, and to a lesser extent with reported physical activity. These findings underline the importance of physical fitness for HRQoL in CF and provide an additional rationale for exercise testing in this population.
CCN family member 1 (CCN1), also known as cysteine-rich angiogenic inducer 61 (CYR61), belongs to the extracellular matrix-associated CCN protein family. The diverse functions of these proteins include regulation of cell migration, adhesion, proliferation, differentiation and survival/apoptosis, induction of angiogenesis and cellular senescence. Their functions are partly overlapping, largely non-redundant, cell-type specific, and depend on the local microenvironment. To elucidate the role of CCN1 in the crosstalk between stromal cells and myeloma cells, we performed co-culture experiments with primary mesenchymal stem cells (MSC) and the interleukin-6 (IL-6)-dependent myeloma cell line INA-6. Here we show that INA-6 cells display increased transcription and induction of splicing of intron-retaining CCN1 pre-mRNA when cultured in contact with MSC. Protein analyses confirmed that INA-6 cells co-cultured with MSC show increased levels of CCN1 protein consistent with the existence of a pre-mature stop codon in intron 1 that abolishes translation of unspliced mRNA. Addition of recombinant CCN1-Fc protein to INA-6 cells was also found to induce splicing of CCN1 pre-mRNA in a concentration-dependent manner. Only full length CCN1-Fc was able to induce mRNA splicing of all introns, whereas truncated recombinant isoforms lacking domain 4 failed to induce intron splicing. Blocking RGD-dependent integrins on INA-6 cells resulted in an inhibition of these splicing events. These findings expand knowledge on splicing of the proangiogenic, matricellular factor CCN1 in the tumor microenvironment. We propose that contact with MSC-derived CCN1 leads to splicing and enhanced transcription of CCN1 which further contributes to the translation of angiogenic factor CCN1 in myeloma cells, supporting tumor viability and myeloma bone disease.
Background
Fatty acid binding protein (FABP) is an intracellular transport protein associated with myocardial damage size in patients undergoing cardiac surgery. Furthermore, elevated FABP serum concentrations are related to a number of common comorbidities, such as heart failure, chronic kidney disease, diabetes mellitus, and metabolic syndrome, which represent important risk factors for postoperative acute kidney injury (AKI). Data are lacking on the association between preoperative FABP serum level and postoperative incidence of AKI.
Methods
This prospective cohort study investigated the association between preoperative h-FABP serum concentrations and postoperative incidence of AKI, hospitalization time and length of ICU treatment. Blood samples were collected according to a predefined schedule. The AKI Network definition of AKI was used as primary endpoint. All associations were analysed using descriptive and univariate analyses.
Results
Between 05/2009 and 09/2009, 70 patients undergoing cardiac surgery were investigated. AKI was observed in 45 patients (64%). Preoperative median (IQR) h-FABP differed between the AKI group (2.9 [1.7–4.1] ng/ml) and patients without AKI (1.7 [1.1–3.3] ng/ml; p = 0.04), respectively. Patients with AKI were significantly older. No statistically significant differences were found for gender, type of surgery, operation duration, CPB-, or X-Clamp time, preoperative cardiac enzymes, HbA1c, or CRP between the two groups. Preoperative h-FABP was also correlated with the length of ICU stay (rs = 0.32, p = 0.007).
Conclusions
We found a correlation between preoperative serum h-FABP and the postoperative incidence of AKI. Our results suggest a potential role for h-FABP as a biomarker for AKI in cardiac surgery.
Background
Reliable central venous access (CVC) is essential for hematology–oncology patients since frequent puncture of peripheral veins—e.g., for chemotherapy, antibiotic administration, repeated blood sampling, and monitoring—can cause unacceptable pain and psychological trauma, as well as severe side effects in cases of extravasation of chemotherapy drugs. However, CVC lines still carry major risk factors, including thrombosis, infection (e.g., entry site, tunnel, and luminal infections), and catheter dislocation, leakage, or breakage.
Methods
Here we performed a retrospective database analysis to determine the incidence of CVC-associated thrombosis in a single-center cohort of 448 pediatric oncologic patients, and to analyze whether any subgroup of patients was at increased risk and thus might benefit from prophylactic anticoagulation.
Results
Of the 448 patients, 269 consecutive patients received a CVC, and 55 of these 269 patients (20%) also had a thrombosis. Of these 55 patients, 43 had at least one CVC-associated thrombosis (total number of CVC-associated thrombosis: n = 52). Among all patients, the median duration of CVC exposure was 464 days. Regarding exposure time, no significant difference was found between patients with and without CVC-associated thrombosis. Subclavia catheters and advanced tumor stages seem to be the main risk factors for the development of CVC-associated thrombosis, whereas pharmacologic prophylaxis did not seem to have a relevant impact on the rate of thrombosis.
Conclusions
We conclude that pediatric surgeons and oncologists should pay close attention to ensuring optimal and accurate CVC placement, as this appears the most effective tool to minimize CVC-associated complications.
Background
To examine whether lack of measurement invariance (MI) influences mean comparisons among different disease groups, this paper provides (1) a systematic review of MI in generic constructs across chronic conditions and (2) an empirical analysis of MI in the Health Education Impact Questionnaire (heiQ™).
Methods
(1) We searched for studies of MI among different chronic conditions in online databases. (2) Multigroup confirmatory factor analyses were used to study MI among five chronic conditions (orthopedic condition, rheumatism, asthma, COPD, cancer) in the heiQ™ with N = 1404 rehabilitation inpatients. Impact on latent and composite mean differences was examined.
Results
(1) A total of 30 relevant studies suggested that about one in three items lacked MI. However, only four studies examined impact on latent mean differences. Scale means were only affected in one of these three studies. (2) Across the eight heiQ™ scales, seven scales had items with lack of MI in at least one disease group. However, in only two heiQ™ scales were some latent or composite mean differences affected.
Conclusions
Lack of MI among disease groups is common and may have a relevant influence on mean comparisons when using generic instruments. Therefore, when comparing disease groups, tests of MI should be implemented. More studies of MI and according impact on mean differences in generic questionnaires are needed.
Background
Barbed suture material offers the possibility of knotless flexor tendon repair, as suggested in an increasing number of biomechanical studies. There are currently two different absorbable barbed suture products available, V-Loc™ and Stratafix™, and both have not been compared to each other with regard to flexor tendon repair. The purpose of this study was to evaluate both suture materials for primary stability under static and cyclic loading in a biomechanical ex vivo model.
Methods
Forty fresh porcine flexor digitorum profundus tendons were randomized in two groups. A four-strand modified Kessler suture technique was used to repair the tendon either with a 3–0 V-Loc™ or 3–0 Stratafix™ without a knot. Parameters of interest were mode of failure, 2-mm gap formation force, displacement, stiffness and maximum load under static and cyclic testing.
Results
The maximum load was 42.3 ± 7.2 for the Stratafix™ group and 50.7 ± 8.8 N for the V-Loc™ group. Thus, the ultimate tensile strength was significantly higher for V-Loc™ (p < 0.05). The 2-mm gap occurred at 24.8 ± 2.04 N in the Stratafix™ group in comparison to 26.5 ± 2.12 N in the V-Loc™ group (n.s.). Displacement was 2.65 ± 0.56 mm in the V-Loc™ group and 2.71 ± 0.59 mm in the Stratafix™ group (n.s.). Stiffness was 4.24 ± 0.68 (N/mm) in the V-Loc™ group and 3.85 ± 0.55 (N/mm) the Stratafix™ group (n.s.). Those measured differences were not significant.
Conclusion
V-Loc™ demonstrates a higher maximum load in tendon reconstruction. The differences in 2-mm gap formation force, displacement and stiffness were not significant. Hereby, the V-Loc™ has an advantage when used as unidirectional barbed suture for knotless flexor tendon repair.
Background
It is hypothesized that because of higher mast cell numbers and mediator release, mastocytosis predisposes patients for systemic immediate-type hypersensitivity reactions to certain drugs including non-steroidal anti-inflammatory drugs (NSAID).
Objective
To clarify whether patients with NSAID hypersensitivity show increased basal serum tryptase levels as sign for underlying mast cell disease.
Methods
As part of our allergy work-up, basal serum tryptase levels were determined in all patients with a diagnosis of NSAID hypersensitivity and the severity of the reaction was graded. Patients with confirmed IgE-mediated hymenoptera venom allergy served as a comparison group.
Results
Out of 284 patients with NSAID hypersensitivity, 26 were identified with basal serum tryptase > 10.0 ng/mL (9.2%). In contrast, significantly (P = .004) more hymenoptera venom allergic patients had elevated tryptase > 10.0 ng/mL (83 out of 484; 17.1%). Basal tryptase > 20.0 ng/mL was indicative for severe anaphylaxis only in venom allergic subjects (29 patients; 4x grade 2 and 25x grade 3 anaphylaxis), but not in NSAID hypersensitive patients (6 patients; 4x grade 1, 2x grade 2).
Conclusions
In contrast to hymenoptera venom allergy, NSAID hypersensitivity do not seem to be associated with elevated basal serum tryptase levels and levels > 20 ng/mL were not related to increased severity of the clinical reaction. This suggests that mastocytosis patients may be treated with NSAID without special precautions.
Introduction
Spindle cell rhabdomyosarcoma of the head and neck is a very rare tumor in adults. We report on one case with long-term survival.
Case presentation
A 41-year-old nonsmoking Caucasian man presented in June 2007 with a painless swelling under his tongue. A diagnosis of a soft tissue sarcoma, and a myofibrosarcoma in particular, was made via biopsy. After multimodal treatment, including local and systemic therapy, our patient remained disease-free until September 2010. The local recurrence was treated unsuccessfully with various chemotherapy regimens. In September 2011, our patient underwent surgical resection again, and a spindle cell rhabdomyosarcoma was diagnosed. To analyze the mismatch between the original diagnosis of a myofibrosarcoma and the second diagnosis, the two specimens were reassessed, and a final diagnosis of a spindle cell rhabdomyosarcoma was made. In 2012 and 2013, our patient suffered further recurrences that were surgically treated, and he is still alive with disease six years and 10 months after the initial diagnosis in June 2007.
Conclusions
In adults, the spindle cell rhabdomyosarcoma tumor is very rare in the head and neck region. In contrast to childhood tumors, spindle cell rhabdomyosarcoma in adulthood is often associated with a poor prognosis. In the present case, the radical surgical treatment might have helped to prolong the patient’s overall survival, which has lasted more than six years. To our knowledge, this is the longest overall survival reported so far for this tumor entity in the head and neck region.
Background
The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host’s liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood.
Results
Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite’s glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin.
Conclusions
Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.
Premature implant loosening following total knee arthroplasty (TKA) can have several causes. In this article we report on a rare case of a 74 year old male patient suffering tibial component loosening 14 month after primary TKA. The patient did neither have any malignancies nor joint arthroplasty before. Upon clinical examination the range of motion in the diseased knee was painfully restricted to 80° of knee flexion, with the patient increasingly suffering sleeping and resting pain, and also at weight bearing. In standard radiographs, loosening of the TKA due to a large osteolysis at the tibial component was evident. Local computed tomography (CT) of the right knee revealed loosening of the tibial component due to a presumably malign bone tumor. For determination of the final diagnosis a representative biopsy of the tumor was taken by open surgery prior to the tumor resection. Histopathologic evaluation of the biopsy revealed a periprosthetic myxoid chondrosarcoma of the proximal tibia. Pre-operative staging examination included CT scans of lung and abdomen, as well as a bone scintigraphy which revealed no signs of tumor metastasis in the body. Surgical management comprised wide tumor resection and implantation of a hinged tumor knee arthroplasty with replacements of the distal femur and proximal tibia, as well as a patella tendon replacement using a synthetic ligament. Revision surgery was necessary twice due to impaired wound healing and critical soft tissue coverage, and treatment included a gastrocnemius muscle flap with skin mesh graft covering. Unfortunately long-term follow-up examinations could not be obtained, as the patient deceased due to an alveolitis during rehabilitation. In summary, the specifics of this rare case of aseptic TKA loosening, and the unusual circumstances of chondrosarcoma diagnosis and treatment are informative for those providing surgical treatment of similar cases.