Analytische Sterbealtersbestimmung von Skelettfunden: Möglichkeiten und Grenzen bei der Bearbeitung von historischem und rezentem Skelettmaterial

The aim of the present work is the research in age specific changes at human skeletal remains. Thereby references for the application of the methods for age estimation should be developed. With the optimized method the remains from the medieval graveyard Dresden-Briesnitz should be estimated. Based on the single age estimations the age structure of this population should be reconstructed. For the research skeletal remains with known age and sex from the 20th century were available. The recent series consists of Crania (n=300), Clavicles (n=41), Ossa coxae (n=50) and the Femora (n=83). From the medieval graveyard Dresden-Briesnitz up to 827 individuals were used. From this 411 adult individuals became part of the present work. For the methodological approach the age specific changes at the sutures of the skull, at the medial end of the Clavicle, at the Os coxae the Facies symphysialis, Facies auricularis and the Acetabulum, at the Os sacrum the Facies auricularis were compared with the chronological age at the recent material. Furthermore at the Femur and Humerus the changes in the proximal part and the microstructure in Femur, Tibia, Fibula and Humerus were observed. At the historical material the comparison was done with the changes at the Facies symphysialis and the histo-morphological changes in the Femur. The research in the age-specific changes showed, that the application of the morphological methods implied an extensive practice at remains with known age. The best results were achieved by the changes at the Facies symphysialis and the developed histo-morphologic method at the femur with the highest correspondence between the chronological and the estimated biological age. The histo-morphologic approach allows close estimates over the whole adolescent period. The methodological part of this approach, developed at the femur, is transferable to the tibia and the humerus. The Transition analysis, with the combination of the closure of the skull-sutures, the changes at the Facies symphysialis as well as auricularis at the hipbone is one of the most preferable methods in age estimation. The suture closure at the Tabula interna of the skull and the age specific changes at the Facies auricularis of the ilia can provide good information about age. But it is indispensible to consider the variability of the morphological characteristics and the wide age-ranges. Even the changes at the Acetabulum can give useful information to age at death. In the opposite, the changes at the obliteration at the Tabula externa of the skull especially the application of the lower sutures of the Neurocranium and the Viscerocranium shouldn’t be used for age estimation as single traits. After the orientation at the methods for age estimation with the recent material and the research in the age specific changes at the medieval material, age at death of the skeletons of Dresden-Briesnitz was estimated. The age structure of this graveyard was reconstructed with the single data of the skeletal individuals. A very low life expectancy of 26 years for the population of Dresden-Briesnitz was estimated. This low life span is correlated with the high rates of infant mortality. 50% of the individuals haven’t reached the adulthood. After overcoming the infant period the life span was growing. So many people reached the senile age cohort. Nearly the same number of men (n=115) and women (n=104) were buried at this graveyard. With the examination of Dresden-Briesnitz it was possible to close a gap in the anthropological reconstruction of the 10th – 13th century, which was an important period at the transition of the late Slavic to the early German settlement. A higher life span in the younger archaeological horizon (11th – 13th century) could be indicated for an optimization of the living conditions

First outline and baseline data of a randomized, controlled multicenter trial to evaluate the health economic impact of home telemonitoring in chronic heart failure — CardioBBEAT

Background: Evidence that home telemonitoring for patients with chronic heart failure (CHF) offers clinical benefit over usual care is controversial as is evidence of a health economic advantage. Methods: Between January 2010 and June 2013, patients with a confirmed diagnosis of CHF were enrolled and randomly assigned to 2 study groups comprising usual care with and without an interactive bi-directional remote monitoring system (Motiva$^{®}$). The primary endpoint in CardioBBEAT is the Incremental Cost-Effectiveness Ratio (ICER) established by the groups' difference in total cost and in the combined clinical endpoint "days alive and not in hospital nor inpatient care per potential days in study" within the follow-up of 12 months. Results: A total of 621 predominantly male patients were enrolled, whereof 302 patients were assigned to the intervention group and 319 to the control group. Ischemic cardiomyopathy was the leading cause of heart failure. Despite randomization, subjects of the control group were more often in NYHA functional class III-IV, and exhibited peripheral edema and renal dysfunction more often. Additionally, the control and intervention groups differed in heart rhythm disorders. No differences existed regarding risk factor profile, comorbidities, echocardiographic parameters, especially left ventricular and diastolic diameter and ejection fraction, as well as functional test results, medication and quality of life. While the observed baseline differences may well be a play of chance, they are of clinical relevance. Therefore, the statistical analysis plan was extended to include adjusted analyses with respect to the baseline imbalances. Conclusions: CardioBBEAT provides prospective outcome data on both, clinical and health economic impact of home telemonitoring in CHF. The study differs by the use of a high evidence level randomized controlled trial (RCT) design along with actual cost data obtained from health insurance companies. Its results are conducive to informed political and economic decision-making with regard to home telemonitoring solutions as an option for health care. Overall, it contributes to developing advanced health economic evaluation instruments to be deployed within the specific context of the German Health Care System

The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice

Fracture healing is impaired in aged and osteoporotic individuals. Because adequate mechanical stimuli are able to increase bone formation, one therapeutical approach to treat poorly healing fractures could be the application of whole-body vibration, including low-magnitude high-frequency vibration (LMHFV). We investigated the effects of LMHFV on fracture healing in aged osteoporotic mice. Female C57BL/6NCrl mice (n=96) were either ovariectomised (OVX) or sham operated (non-OVX) at age 41 weeks. When aged to 49 weeks, all mice received a femur osteotomy that was stabilised using an external fixator. The mice received whole-body vibrations (20 minutes/day) with 0.3 G: peak-to-peak acceleration and a frequency of 45 Hz. After 10 and 21 days, the osteotomised femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, micro-computed tomography (μCT), histology and gene expression analyses. LMHFV disturbed fracture healing in aged non-OVX mice, with significantly reduced flexural rigidity (-81%) and bone formation (-80%) in the callus. Gene expression analyses demonstrated increased oestrogen receptor β (ERβ, encoded by Esr2) and Sost expression in the callus of the vibrated animals, but decreased β-catenin, suggesting that ERβ might mediate these negative effects through inhibition of osteoanabolic Wnt/β-catenin signalling. In contrast, in OVX mice, LMHFV significantly improved callus properties, with increased flexural rigidity (+1398%) and bone formation (+637%), which could be abolished by subcutaneous oestrogen application (0.025 mg oestrogen administered in a 90-day-release pellet). On a molecular level, we found an upregulation of ERα in the callus of the vibrated OVX mice, whereas ERβ was unaffected, indicating that ERα might mediate the osteoanabolic response. Our results indicate a major role for oestrogen in the mechanostimulation of fracture healing and imply that LMHFV might only be safe and effective in confined target populations

Autologous Mesenchymal Stroma Cells Are Superior to Allogeneic Ones in Bone Defect Regeneration

The application of autologous mesenchymal stem cells (MSC) for the treatment of bone defects requires two invasive procedures and several weeks of ex vivo cell expansion. To overcome these limitations, the administration of allogeneic MSC may be attractive, because they are anticipated to be immunoprivileged. Because preclinical studies using various animal models are conflicting with respect to the efficacy of allogeneic MSC, we investigated whether autologous and allogeneic human MSC (hMSC) are equally effective in regenerating bone in a humanized mouse model resembling the human immune system. Applying autologous and allogeneic hMSC in critically sized femoral defects, we found that allogeneic hMSC elicited a mild immune response early after implantation, whereas early angiogenic processes were similar in both treatments. At later healing time points, the transplantation of allogeneic hMSC resulted in less bone formation than autologous hMSC, associated with a reduced expression of the osteogenic factor Runx2 and impaired angiogenesis. We found by species-specific staining for collagen-type-1α2 that MSCs of either source did not synthesize new bone matrix, indicating an indirect contribution of transplanted hMSC to bone regeneration. In conclusion, our data suggest that the application of autologous hMSC is superior to that of allogeneic cells for bone defect treatment

Modulation of fixation stiffness from flexible to stiff in a rat model of bone healing

Constant fixator stiffness for the duration of healing may not provide suitable mechanical conditions for all stages of bone repair. Therefore, we investigated the influence of stiffening fixation on callus stiffness and morphology in a rat diaphyseal osteotomy model to see if healing time was shortened and callus stiffness increased through modulation of fixation from flexible to stiff. An external unilateral fixator was applied to the osteotimised femur and stiffened by decreasing the offset of the inner fixator bar at 3, 7, 14, and 21 days post-operation. After 5 weeks the rats were killed and healing was evaluated with mechanical, histological and micro-computed tomography methods. Constant fixation stiffness control groups with either stiff or flexible fixation were included for comparison. The callus stiffness of the stiff group and all 4 experimental groups was greater than in the flexible group. The callus of the flexible group was larger but contained a higher proportion of unmineralized tissue and cartilage. The stiff and modulated groups (3, 7, 14, and 21 days) all showed bony bridging at 5 weeks, as well as signs of callus remodeling. Stiffening fixation at 7 and 14 days post-osteotomy produced the highest degree of callus bridging. Bone mineral density in the fracture gap was highest in animals where the fixation was stiffened after 14 days. The predicted benefit of a large robust callus formed through early flexible fixation could not be shown, however the benefits of stabilizing a flexible construct to achieve timely healing was demonstrated at all time points

Fracture Healing Is Delayed in Immunodeficient NOD/scid‑IL2Rγcnull Mice.

Following bone fracture, the repair process starts with an inflammatory reaction at the fracture site. Fracture healing is disturbed when the initial inflammation is increased or prolonged, whereby, a balanced inflammatory response is anticipated to be crucial for fracture healing, because it may induce down-stream responses leading to tissue repair. However, the impact of the immune response on fracture healing remains poorly understood. Here, we investigated bone healing in NOD/scid-IL2Rγcnull mice, which exhibit severe defects in innate and adaptive immunity, by biomechanical testing, histomorphometry and micro-computed tomography. We demonstrated that NOD/scid-IL2Rγcnull mice exhibited normal skeletal anatomy and a mild bone phenotype with a slightly reduced bone mass in the trabecular compartment in comparison to immunocompetent Balb/c mice. Fracture healing was impaired in immunodeficient NOD/scid-IL2Rγcnull mice. Callus bone content was unaffected during the early healing stage, whereas it was significantly reduced during the later healing period. Concomitantly, the amount of cartilage was significantly increased, indicating delayed endochondral ossification, most likely due to the decreased osteoclast activity observed in cells isolated from NOD/scid-IL2Rγcnull mice. Our results suggest that--under aseptic, uncomplicated conditions--the immediate immune response after fracture is non-essential for the initiation of bone formation. However, an intact immune system in general is important for successful bone healing, because endochondral ossification is delayed in immunodeficient NOD/scid-IL2Rγcnull mice

The Wnt serpentine receptor Frizzled-9 regulates new bone formation in fracture healing.

Wnt signaling is a key regulator of bone metabolism and fracture healing. The canonical Wnt/β-catenin pathway is regarded as the dominant mechanism, and targeting this pathway has emerged as a promising strategy for the treatment of osteoporosis and poorly healing fractures. In contrast, little is known about the role of non-canonical Wnt signaling in bone. Recently, it was demonstrated that the serpentine receptor Fzd9, a Wnt receptor of the Frizzled family, is essential for osteoblast function and positively regulates bone remodeling via the non-canonical Wnt pathway without involving β-catenin-dependent signaling. Here we investigated whether the Fzd9 receptor is essential for fracture healing using a femur osteotomy model in Fzd9(-/-) mice. After 10, 24 and 32 days the fracture calli were analyzed using biomechanical testing, histomorphometry, immunohistochemistry, and micro-computed tomography. Our results demonstrated significantly reduced amounts of newly formed bone at all investigated healing time points in the absence of Fzd9 and, accordingly, a decreased mechanical competence of the callus tissue in the late phase of fracture healing. In contrast, cartilage formation and numbers of osteoclasts degrading mineralized matrix were unaltered. β-Catenin immunolocalization showed that canonical Wnt-signaling was not affected in the absence of Fzd9 in osteoblasts as well as in proliferating and mature chondrocytes within the fracture callus. The expression of established differentiation markers was not altered in the absence of Fzd9, whereas chemokines Ccl2 and Cxcl5 seemed to be reduced. Collectively, our results suggest that non-canonical signaling via the Fzd9 receptor positively regulates intramembranous and endochondral bone formation during fracture healing, whereas it does not participate in the formation of cartilage or in the osteoclastic degradation of mineralized matrix. The finding that Fzd9, in addition to its role in physiological bone remodeling, regulates bone repair may have implications for the development of treatments for poorly or non-healing fractures

C5aR-antagonist significantly reduces the deleterious effect of a blunt chest trauma on fracture healing

ABSTRACT: Confirming clinical evidence, we recently demonstrated that a blunt chest trauma considerably impaired fracture healing in rats, possibly via the interaction of posttraumatic systemic inflammation with local healing processes, the underlying mechanisms being unknown. An important trigger of systemic inflammation is the complement system, with the potent anaphylatoxin C5a. Therefore, we investigated whether the impairment of fracture healing by a severe trauma resulted from systemically activated complement. Rats received a blunt chest trauma and a femur osteotomy stabilized with an external fixator. To inhibit the C5a-dependent posttraumatic systemic inflammation, half of the rats received a C5aR-antagonist intravenously immediately and 12 h after the thoracic trauma. Compared to the controls (control peptide), the treatment with the C5aR-antagonist led to a significantly increased flexural rigidity (three-point-bending test), an improved bony bridging of the fracture gap, and a slightly larger and qualitatively improved callus (mCT, histomorphometry) after 35 days. In conclusion, immunomodulation by a C5aR-antagonist could abolish the deleterious effects of a thoracic trauma on fracture healing, possibly by influencing the function of inflammatory and bone cells locally at the fracture site. C5a could possibly represent a target to prevent delayed bone healing in patients with severe trauma.