An altered heparan sulfate structure in the articular cartilage protects against osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression. METHODS: To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1e2fl/e2fl). To study the impact of the HS sulfation pattern, OA was surgically induced in mice with a heterozygous (Ndst1+/-) or chondrocyte-specific (Col2-Cre;Ndst1fl/fl) loss-of-function allele of the sulfotransferase Ndst1. OA progression was evaluated using the OARSI scoring system. To investigate expression and activity of cartilage degrading proteases, femoral head explants of Ndst1+/- mutants were analyzed by qRT-PCR, Western Blot and gelatin zymography. RESULTS: All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1e2fl/e2fl: 0.83; 95% HDI 0.72-0.96; Ndst1+/-: 0.83, 95% HDI 0.74-0.9; Col2-Cre;Ndst1fl/fl: 0.87, 95% HDI 0.76-1). Using cartilage explant cultures of Ndst1 animals, we detected higher amounts of aggrecan degradation products in wildtype samples (NITEGE 4.24-fold, 95% HDI 1.05-18.55; VDIPEN 1.54-fold, 95% HDI 1.54-2.34). Accordingly, gelatin zymography revealed lower Mmp2 activity in mutant samples upon RA-treatment (0.77-fold, 95% HDI: 0.60-0.96). As expression of major proteases and their inhibitors was not altered, HS seems to regulate cartilage degeneration by affecting protease activity. CONCLUSION: A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression.

[Stimulation of fracture healing by growth factors and cell-based technologies]. / Stimulation der Frakturheilung durch Wachstumsfaktoren und zellbasierte Technologien.

Bone has the special capability to completely regenerate after trauma and to re-establish its original geometry and biomechanical stability corresponding to the pretrauma conditions. Nevertheless, in daily clinical practice impaired fracture healing and nonunions are regular complications as a result of inadequate mechanical stability and/or insufficient biological processes around the fracture region. Since the beginning of the millennium, intensive research on the physiological processes in bone healing as well as the production and clinical administration of growth factors have enabled the possibility to improve the local biological processes during fracture healing by osteoinduction. Although the initial clinical results, particularly of bone morphogenetic proteins, in fracture healing were promising, growth factors did not become established for unrestricted use in the clinical application. Currently, additional growth factors are being investigated with respect to the potential supportive and osteoinductive characteristics for enhancement of fracture healing and possible clinical applications. Furthermore, the development of cell-based technologies is another promising approach to positively stimulate fracture healing. In addition to the gold standard of autologous bone grafting, harvesting of mesenchymal stroma cells by aspiration has gained in importance in recent years. Allogeneic bone cell transplantation procedures and in particular gene therapy are promising new strategies for the treatment of disorders of fracture healing. This review gives an overview of present and future possibilities for modulation of fracture healing by growth factors and cell-based technologies.

[Interpersonal competence in orthopedics and traumatology : Why technical and procedural skills alone are not sufficient]. / Interpersonelle Kompetenz in Orthopädie und Unfallchirurgie : Warum technische und prozedurale Fähigkeiten alleine nicht ausreichen.

Patient safety has increasingly gained significance as criterion which clinics and doctors will be measured against in terms of ethics and finances. The "human factor" moved into focus regarding the question of how to reduce treatment errors in clinical daily routine. Nevertheless, systematic mediation of interpersonal competences only plays a minor role in the catalogue of requirements for medical specialization and professional training. This is the case not only in orthopedics and traumatology, but in other medical fields as well. At the insistence of DGOU and in cooperation with Lufthansa Flight Training, a training model was initiated, comparable to training models used in aviation. In aviation, apart from the training of procedural and technical abilities, regular soft skills training has become standard in the training of all Lufthansa staff. Several studies confirm that by improving communication, interaction, and teamwork skills not only a reduction of intolerable incidents is observed, but also a positive economic effect. Interpersonal competences should be firmly anchored in orthopedics and traumatology and thus be implemented as third post in specialist training.

[Further training in the faculty of orthopedics and trauma surgery. Outstanding, average or insufficient?]. / Weiterbildung im Fach Orthopädie und Unfallchirurgie. Mustergültig, mittelmäßig oder mangelhaft?

A well structured and executed and practical residency program is important to secure a sufficient number of well trained orthopedic surgeons in the future. Some of the residents, however, see substantial shortcomings here. Additionally, orthopedic residency programs struggle to be a valid alternative for graduated medical students when comparing them to residency programs in other medical specialities or alternative job options. In improving the current situation program directors as well as residents must play a key role. A rapid improvement of structural shortcomings of German residency programs does not only provide an advantage in recruiting new residents now, but may also help to maintain the high quality in orthopedic health care in the future.

[Compatibility of science and clinical aspects. Between realism and utopia]. / Vereinbarkeit von Wissenschaft und Klinik. Zwischen Realismus und Utopie.

The working environment for young residents in orthopedic surgery has changed tremendously over the past 10 years. Due to cumulative clinical requirements and increasing demands on work-life balance research activity has become less attractive. Successful incorporation of research into the career of residents is a challenging project for the future. The young forum of the German Association for Orthopedics and Traumatology (DGOU) provides different approaches to enhance the quality of research and to help young orthopedists and trauma surgeons.

[How many generalists and how many specialists does orthopedics and traumatology need?]. / Wie viel Generalist und wie viel Spezialist braucht die Orthopädie und Unfallchirurgie?

The training in orthopedic and trauma surgery has changed significantly with the introduction of the new residency program. The contents taught have already been reduced in breadth and the current developments in the outpatient and particularly in the clinical landscape also contribute to increasing specialization. This trend favors structures in which comprehensive medical care for the population in Germany in orthopedic and trauma surgery appears to be endangered and in which the future efforts for e.g. polytraumatised patients need to be questioned. The Young Forum of the German Society for Orthopedics and Traumatology actively accompanies a discussion about the necessity and value of generalists to ensure the level of care in Germany in addition to the specialists.

Local delivery of growth factors using coated suture material.

The optimization of healing processes in a wide range of tissues represents a central point for surgical research. One approach is to stimulate healing processes with growth factors. These substances have a short half-life and therefore it seems useful to administer these substances locally rather than systemically. One possible method of local delivery is to incorporate growth factors into a bioabsorbable poly (D, L-lactide) suspension (PDLLA) and coat suture material. The aim of the present study was to establish a procedure for the local delivery of growth factors using coated suture material. Sutures coated with growth factors were tested in an animal model. Anastomoses of the colon were created in a rat model using monofilament sutures. These were either untreated or coated with PDLLA coating alone or coated with PDLLA incorporating insulin-like growth factor-I (IGF-I). The anastomoses were subjected to biomechanical, histological, and immunohistochemical examination. After 3 days the treated groups showed a significantly greater capacity to withstand biomechanical stress than the control groups. This finding was supported by the results of the histomorphometric. The results of the study indicate that it is possible to deliver bioactive growth factors locally using PDLLA coated suture material. Healing processes can thus be stimulated locally without subjecting the whole organism to potentially damaging high systemic doses.

[Treatment of periprosthetic and peri-implant fractures : modern plate osteosynthesis procedures]. / Versorgung periprothetischer und periimplantärer Frakturen : Moderne Plattenosteosyntheseverfahren.

Periprosthetic fractures are increasing not only due to the demographic development with high life expectancy, the increase in osteoporosis and increased prosthesis implantation but also due to increased activity of the elderly population. The therapeutic algorithms are manifold but general valid rules for severe fractures are not available. The most commonly occurring periprosthetic fractures are proximal and distal femoral fractures but in the clinical routine fractures of the tibial head, ankle, shoulder, elbow and on the borders to other implants (peri-implant fractures) and complex interprosthetic fractures are being seen increasingly more. It is to be expected that in the mid-term further options, such as cement augmentation of cannulated polyaxial locking screws will extend the portfolio of implants for treatment of periprosthetic fractures. The aim of this review article is to present the new procedures for osteosynthesis of periprosthetic fractures.

[Periprosthetic fractures. An interdisciplinary challenge]. / Periprothetische Frakturen. Eine interdisziplinäre Herausforderung.

Demographic changes and rising numbers of implanted prostheses accompanied by increasing demands on mobility and activities of the elderly will lead to an increasing number of periprosthetic fractures in the future. Poor bone quality, geriatric comorbidities and multiple prostheses result in an increased risk for this type of fracture in the old patient. Management of these patients is challenging and demanding and needs an interdisciplinary approach. The present work describes the different aspects of periprosthetic fractures in the geriatric patient with regard to epidemiology, risk factors, prevention and treatment options.

[Pelvic ring fractures in the elderly. Underestimated osteoporotic fracture]. / Beckenringfrakturen im Alter. Die unterschätzte osteoporotische Fraktur.

The incidence of pelvic fractures at 0.3-8% is low compared to all fractures. Nevertheless, the number of pelvic fractures in the elderly is increasing. Due to the increased age of the patient differences in trauma mechanism, fracture pattern and therapy occur. Most pelvic fractures in the elderly are caused by low-energy trauma. This makes it difficult to find the right diagnosis especially in insufficiency fracture of the pelvis. The time until the right treatment is started is prolonged significantly. Elderly patients who suffer from a high-energy fracture have a significantly higher risk of haemorrhage. At the same time emergency stabilisation of the pelvis using a C-clamp is dangerous due to the special fracture morphology with transiliac instabilities and the combination with osteoporosis. Low-energy trauma leads to simple fractures of the pubis, which often can be treated without operation. In these cases fractures of the dorsal pelvic ring need to be excluded using CT scan. Fracture of the dorsal part of the pelvic ring such as insufficiency fractures of the sacrum should be stabilized by 3D-guided percutaneous iliosacral screw fixation to reduce pain and allow early mobilisation.

[Safety culture in orthopedics and trauma surgery : Course concept: interpersonal competence by the German Society for Orthopaedics and Trauma (DGOU) and Lufthansa Aviation Training]. / Sicherheitskultur in Orthopädie und Unfallchirurgie : Kurskonzept: Interpersonal Competence by Deutsche Gesellschaft für Orthopädie und Unfallchirurgie (DGOU) and Lufthansa Aviation Training.

Patient safety has become a central and measurable key factor in the routine daily medical practice. The human factor plays a decisive role in safety culture and has moved into focus regarding the reduction of treatment errors and undesired critical incidents. Nonetheless, the systematic training in communication and interpersonal competences has so far only played a minor role. The German Society of Orthopaedics and Trauma (DGOU) in cooperation with the Lufthansa Aviation Training initiated a course system for interpersonal competence. Several studies confirmed the reduction of critical incidents and costs after implementation of a regular and targeted human factor training. The interpersonal competence should be an essential component of specialist training within the framework of a 3­column model.

[The Summer School of the German Society for Orthopaedics and Traumatology - A Success Story]. / Die Summer School der Deutschen Gesellschaft für Orthopädie und Unfallchirurgie ­ eine Erfolgsgeschichte.

Background: It has been known for several years that orthopaedic and trauma clinics suffer from a shortage of young people, due to the substantial loss in attractiveness. The Youth Forum OU has been addressing this problem for many years, by initiating many projects such as the Summer School to counteract this trend. The purpose of this research is to evaluate the success of Summer Schools since 2009. Methods: The Youth Forum OU performed a survey in December 2014 to answer the research question on the basis of an internet-based poll of the student participants in all Summer Schools between 2009 and 2014. Following data cleansing, 121 students and former students were included in the survey. Results: Seventy-two completed questionnaires were collected and included in the evaluation. The survey included 40 % of Summer School participants, with a mean age of 27.3 years (SD ± 2.95); 50 % were female. Participation in the Summer School helped 50 % of the respondents to decide to start advanced study in orthopaedics and/or traumatology (OU). One third of these Summer School participants had already finished a university degree; 100 % are now residents in orthopaedics and/or traumatology. Regardless of prior plans, 87.2 % of participants are now residents in OU. Thirty-three are still students: 78.8 % have already decided to work in OU. The survey also served to identify the factors positively and negatively associated with OU. Unfavourable factors included the reputation of OU, and the difficulty of reconciling family and work. Favourable factors included surgical work and personal experience during university studies. Discussion: The aim of this study was to evaluate whether the efforts of the Youth Forum OU, the German Society for Orthopaedics and Traumatology (DGOU) and the local hospitals lead to increased interest in OU. The answer to this question is positive. This is particularly true for those students who did not plan to become an orthopaedic or trauma surgeon before participating in a Summer School. In conclusion, the efforts to recruit residents for OU by using Summer Schools were successful. Moreover, this research offers approaches to counteract the loss of attractiveness of OU.

Effects of thymic peptides, in vitro, on the impaired immunocytotoxicity of peripheral blood mononuclear cells from tumor patients.

The effects of a thymic peptide preparation (TP) on the immunocytotoxicity and cytokine secretion of peripheral blood lymphocytes and monocytes from patients with colorectal tumors, breast tumors and melanoma were studied in vitro. On average, breast tumor and melanoma patients showed significantly lower natural killer (NK) cell activities than colorectal tumor patients and normal controls. In contrast, the generation of lymphokine (IL-2) activated killer (LAK) cells was found to be comparable within the different tumor diseases (24% cytotoxicity), but lower than in the group of normal controls. TP, being without any effects on NK cell activity in all groups, increased the deficient LAK cell activity of breast tumor and melanoma patients, as well as of normal controls? without significant effects on PBL from colorectal tumor patients. This increase was found to be associated with an increase of the IL-2 induced IFN-gamma and, on a lower level, TNF-alpha secretion, especially from breast tumor and melanoma patients. In addition, monocytes from these patients showed a deranged tumoristatic activity, compared to colorectal tumor patients and normal controls. The stimulation of monocytes by IFN-gamma greatly elevated the mean of the antitumor activity in all groups studied. TP being slightly effective on monocytes from melanoma patients, did not further enhance monocyte-mediated cytotoxicity when applied alone or in combination with IFN-gamma. Reduced basal monocytic chemokine levels were only found in the groups of melanoma (IL-8) and colorectal tumor patients (MCP-1), whereas RANTES secretion was increased, compared to normal controls. TP was active only in reducing the IL-8 secretion of monocytes from colon tumor patients. The results indicate that selected functions of peripheral blood mononuclear cells can be partially improved by the thymic peptide preparation.

Acidolysis and hot water extraction provide new insights into the composition of the induced "lignin-like" material from squash fruit.

Accumulation of "lignin-like" material (L-LM) by plant tissues in response to injury or disease has been observed in a wide variety of plant taxa. The most intensively studied L-LM is that produced by members of the Cucurbitaceae; this material is thought to be an unusual lignin rich in p-coumaryl alcohol derived subunits. Employing acidolysis we found the primary degradation product of L-LM from squash fruit was p-coumaryl aldehyde. These findings conflict with the current concept of L-LM, but would be consistent with L-LM being a polymer derived directly from p-coumaryl aldehyde or a gum containing this compound. Results of hot water extraction support the latter possibility. Further, we report on a simple TLC method useful for rapid qualitative characterization of acidolysis degradation products.

Low molecular thymic peptides improve the deficient immunocytotoxicity of mononuclear cells from tumor patients in vitro.

We studied, in vitro, the stimulating effects of a commercial preparation of low molecular thymic peptides (TP) on the immunocytotoxicity of peripheral blood lymphocytes and monocytes from patients with breast tumors, melanoma and colorectal tumors. On average, tumor patients showed a lower natural killer (NK), lymphokine (IL-2) activated killer (LAK) cell and basic tumoristatic activity of monocytes, compared with healthy donors. There was no correlation between the NK-cell number and the NK-cell activity of the tumor patients. The TP showed no effects on the NK-cell activity in any group, yet elevated the deficient LAK-cell activity of tumor patients and that of healthy donors. On monocytes, TP enhanced the deranged tumoristatic activity only in tumor patients, while being slightly inhibitory on control monocytes. Dividing the donors on the basis of the TP effects on cytotoxicity of the mononuclear cells into TP-nonresponders and TP-responders, a higher number of TP-responders was found among tumor patients, compared with healthy donors. Moreover, a higher number of TP-nonresponders were observed with lymphocytes from colorectal tumor patients at advanced tumor stage. Therefore, on the basis of the applied immunocytotoxic assays, these results may provide a basis for selecting tumor patients, who may respond to TP in immunotherapy protocols.

Effects of oral bromelain administration on the impaired immunocytotoxicity of mononuclear cells from mammary tumor patients.

The protease bromelain from pineapple was suggested for adjuvant therapy of malignant diseases. We studied immunological effects of an orally applied bromelain drug on 16 breast cancer patients in comparison with healthy donors. Bromelain was applied for 10 days with a daily dose of 3000 F.I.P. units and the immunocytotoxicity of blood monocytes and lymphocytes against the leukemic K562 and MDA-MB-231 mammary carcinoma target cells was determined in vitro. In addition, the expression of the cell surface markers CD44, CD16, CD11a and CD62L on lymphocytes and the secretion of IL-2 and IL-1beta from monocytes was measured. Patients leukocytes expressed lower bMAK-, MAK-, NK- and LAK-cell activities, compared with those from healthy donors. Orally applied bromelain increased the reduced bMAK- and MAK-cell activity of patients monocytes about 2-fold. When the patients were classified on the basis of bromelain effects on the monocytic cytotoxicity into bromelain responders and nonresponders, about 40% of the patients responded to bromelain with an increase of cytotoxicity from 7.8% to 54% (bMAK-cell activity) and from 16% to 47% (MAK-cell activity). Bromelain was less effective on the higher cytotoxicity of monocytes from healthy donors, but stimulated the secretion of IL-1beta from monocytes. In contrast, patient monocytes secreted no detectable IL-1beta, before, during and after bromelain treatment. Bromelain had no effects on the impaired patients NK- and LAK-cell activity, but reduced the LAK-cell activity of healthy donors. No IL-2 was found in the supernatants of untreated and treated lymphocytes from healthy donors. Bromelain reduced the expression of CD44, but weakly increased CD11a and CD62L expression on patient lymphocytes, whereas CD16 remained unchanged. In vitro bromelain application to lymphocytes had similar effects, with greater reduction rates of CD44 and CD16 expression. As to coagulation parameters in plasma of healthy donors, the activated partial thromboplastin time was increased from 38 to 46 sec, leaving prothrombin time and plasminogen unchanged. These data suggest, that orally applied bromelain stimulates the deficient monocytic cytotoxicity of mammary tumor patients, which may partially explain its proposed antitumor activity.

[Scatter tomography - dosimetry and radiographic technique with diagnostic x-rays (author's transl)]. / Streutomographie - Dosimetrie und Aufnahmetechnik mit diagnostischen Röntgenstrahlen.

Scatter tomography (ST) is a method to acquire information about biological structures using Compton scattered photons. In contrast to previously published methods high resolution in ST is achieved by using conventional x-ray energies. From a general model for the calculation of the radiation exposure, a minimum of the x-ray dosis relative to the spatial resolution is predicted at 60 keV. A simple experimental set-up for recording scatter tomograms is described. First measurements on bovine lungs seem to confirm the expected advantages of the proposed method.

Cell proliferation and differentiation during fracture healing are influenced by locally applied IGF-I and TGF-beta1: comparison of two proliferation markers, PCNA and BrdU.

Growth factors IGF-I and TGF-beta1 are known to stimulate fracture healing. The purpose of this study was to investigate the role of locally applied IGF-I and TGF-beta1 during the early phase of fracture healing (Days 5, 10, and 15 after fracture) on cellular processes like proliferation and differentiation in a rat model. Two different immunohistochemical markers were used to analyze cell proliferation: (1) injection of the thymidine analogue BrdU and subsequent immunohistochemical staining for BrdU-positive nuclei, and (2) the antibody against the "proliferating cell nuclear antigen" (PCNA). In comparison, both methods revealed similar results concerning the types of proliferating cells at the different time points and the two groups. Labeling indices of both methods showed very good correlation (e.g., r(s): 0.887 and p < 0.001 at day 10 in the control group without growth factors). Comparison of the callus morphology and the proliferation rate showed differences during fracture healing due to the local application of IGF-I and TGF-beta1 from coated implants. At Day 5 the callus of the group treated with growth factors displayed an earlier appearance of cartilage compared to the control group. This was accompanied by an onset of cell proliferation in chondrocytes. Likewise, at the later time points an enhanced maturation of the callus tissue and the proliferation pattern were detectable in the growth-factor group. These results indicate that local application of IGF-I and TGF-beta1 accelerates early cellular processes during fracture healing.

Validation of questionnaires from several medical fields regarding the constitution of patients.

INTRODUCTION: To consider or determine an individual's 'warm and cold' constitution is common part of traditional Chinese medicine (TCM), Indian medicine (Ayurveda), anthroposophic medicine and classical natural medicine. OBJECTIVE: Common psychometric characteristics of 4 questionnaires should be examined. METHODS: 110 cancer patients and 110 non-cancer patients were asked to answer these questionnaires twice 4 weeks apart. Subsequent validation of the questionnaires included psychometrical qualities of item acceptability, sensitivity to change, construct validity (homogeneity), re-test reliability and group comparison. RESULTS: The Ayurveda questionnaire was considered suitable after reducing the questions from 22 to 8 (internal construct validity kappa = 0.64). The TCM questionnaire was considered unsuitable in our model because of the absence of construct validity. The questionnaire on anthroposophic medicine was considered a suitable and reliable tool with alpha = 0.57 (Cronbach's alpha) and r = 0.61 (re-test reliability) after reducing the questions from 6 to 4. The questionnaire on sensitivity to temperatures based on classical natural medicine was considered suitable after reducing the questions from 10 to 8 (alpha = 0.58; r = 0.73). Cancer and non-cancer patients differ in only one item, i.e. in their sensitivities to cold. CONCLUSION: The questionnaires for anthroposophic medicine, Ayurveda medicine and sensitivity to temperatures are in part suitable and reliable for determining individual constitutions according to their medical philosophy. The questionnaire based on traditional Chinese medicine failed these criteria. A difference between patients with or without malignant disease was only observed for sensitivity to temperatures. The anthroposophic hypothesis that cancer either changes an individual's thermic constitution or is caused by such a change could not be confirmed in this study.