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Malnutrition is a worldwide problem which can result in prolonged hospitalization from complications such as poor wound healing and increased morbidity. There is increasing evidence of the effect of risk of malnutrition (ROM) on outcomes in orthopedic surgical patients. However, there is little data on the effect of nutritional status on clinical outcomes in orthopedic trauma patients with surgical site infections (SSI). Therefore, our aim was to investigate how malnutrition risk affects clinical outcomes in a prospective cohort of orthopedic trauma patients with SSI.The study included 345 patients who underwent surgery due to SSI at a level 1 trauma center. All patients were evaluated on their nutritional status as assessed by the Nutritional Risk Screening in 2014/15 and 2017/18. 238 (69.0%) datasets were available for the follow-up analysis. Twenty patients (8.4%) had died, resulting in 218 patients. Outcomes investigated included comorbidities, medication intake, destination of discharge, degree of mobility, support for procuring food, mortality risk and quality of life.32.8% were at risk of malnutrition (ROM) at EXAM1. Female patients had a higher ROM than males (p 0.05). Patients with ROM had more comorbidities (p 0.001), an increased need for medication intake (p 0.001), a decreased level of mobility (p 0.001) and increased need of support in procuring food (p 0.001). The destination of discharge was independent of the nutritional status (p = 0.641). Twenty (8.4%) of the available 238 patients had died during follow-up time period, resulting in a 6.2-times higher risk of mortality in patients with ROM. EQ-5D revealed that mobility, self-supply and usual activities of daily living were increased in well-nourished patients (p 0.001).ROM in orthopedic trauma patients with SSI is associated with an increased number of comorbidities and need for medication intake, a decrease in mobility and a higher dependency for food acquisition. Patients at ROM exhibited a 6.2-times higher mortality rate than well-nourished patients. EQ-5D evaluation showed better mobility, self-supply, and activity of daily living in well-nourished patients. We therefore strongly recommend supplementing patients with ROM with a specific diet during and after discharge from the hospital in order to reduce postoperative complications and long-term mortality.

Despite growing knowledge about the mechanisms of fracture healing, non-union formation still represents a major complication in trauma and orthopedic surgery. Non-union models in mice gain increasing interest, because they allow investigating the molecular and cellular mechanisms of failed fracture healing. These models often use segmental defects to achieve non-union formation. Alternatively, failed fracture healing can be induced by transverse fractures with additional periosteal injury. The present study systematically compared the reliability of these two approaches to serve as non-union model. A 0.6 mm K-wire was inserted into the femora of CD-1 mice in a retrograde fashion and a closed transverse femoral fracture was created. Subsequently, the fracture site was exposed and the periosteum was cauterized. This approach was compared with a well-established non-union model involving the pin-clip fixation of a 1.8 mm segmental defect. The callus tissue was analyzed by means of radiography, biomechanics, histology and Western blotting. At 10 weeks after surgery 10 out of 12 femora (83.3 %) of the K-wire group showed a non-union formation. The pin-clip model resulted in 100 % non-union formation. The K-wire group showed increased bone formation, osteoclast activity and bending stiffness when compared to the group with pin-clip fixation. This was associated with a higher expression of bone formation markers. However, the number of CD31-positive microvessels was reduced in the K-wire group, indicating an impaired angiogenic capacity after periosteal cauterization. These findings suggest that the pin-clip model is more reliable for the study of non-union formation in mice. The K-wire model including periosteal injury by cauterization however, may be particularly applied in preclinical studies which explore the effects of damaged periosteum and reduced angiogenic capacity to trauma-induced fractures.

Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4−/−), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD. Furthermore, we investigated the influence of vitamin D on bone quality in this model. The bone morphology analyses revealed reduced bone mineral contents as well as changes in trabecular bone architecture and decreased cortical bone densities in Abcb4−/− mice with severe liver fibrosis. We observed dysregulation of genes involved in bone remodeling (osteoprotegerin, osteocalcin, osteopontin) and vitamin D metabolism (7-dehydrocholesterol reductase, Gc-globulin, Cyp2r1, Cyp27a1) as well as alterations in calcium and vitamin D homeostasis. In addition, serum RANKL and TGF-β levels were increased in Abcb4−/− mice. Vitamin D dietary intervention was only partially able to restore the bone phenotypes of Abcb4−/− animals. We conclude that the Abcb4−/− mouse provides an experimental framework and a preclinical model to gain further insights into the molecular pathobiology of HOD and to study the systemic effects of therapeutic interventions.

Gold standard for in vitro toxicity tests and drug screenings is primary human hepatocytes (hHeps). Because of their limited availability efforts have been made to provide alternatives, e.g., monocyte-derived NeoHepatocytes. In the past years it has been critically discussed if gaining hepatocyte features is associated with trans-differentiation of monocytes or their activation towards a macrophage phenotype. Generating NeoHepatocytes in the presence of six different human AB sera, fetal calf serum (FCS) or autologous serum showed that yield and quality of NeoHepatocytes is inversely correlated to macrophage activation. Using autologous serum constantly the highest amount of cells with the best metabolic capacity was obtained. Focus of this study was to further analyze bio-transformation capacity of the optimized NeoHepatocytes for use as in vitro toxicity test-system. Treatment of the optimized NeoHepatocytes with two different pro-teratogenic substances with corresponding metabolites and eight known hepatotoxins showed comparable toxicity to hHeps. Bio-transformation rates, assessed by testosterone metabolism, were comparable in both cell types. Our data reveal that use of autologous serum reduced macrophage activation which improved yield and function of NeoHepatocytes resulting in bio-transformation and toxicity profiles comparable to hHeps. Thus, their easy accessibility makes them an ideal candidate for in vitro toxicity studies.

Background & Aims Adverse alcohol effects in the liver involve oxidative metabolism, fat deposition and release of fibrogenic mediators, including TGF-β. The work presents an assessment of liver damaging cross-talk between ethanol and TGF-β in hepatocytes. Methods To investigate TGF-β effects on hepatocytes, microarray analyses were performed and validated by qRT-PCR, Western blot analysis and immunohistochemistry. The cellular state was determined by assessing lactate dehydrogenase, cellular glutathione, reactive oxygen species, lipid peroxidation and neutral lipid deposition. RNA interference was used for gene silencing in vitro . Results TGF-β is induced in mouse livers after chronic ethanol insult, enhances ethanol induced oxidative stress and toxicity towards cultured hepatocytes plus induces lipid-, oxidative stress metabolism- and fibrogenesis-gene expression signatures. Interestingly, TGF-β down-regulates alcohol metabolizing enzyme Adh1 mRNA in cultured hepatocytes and liver tissue from TGF-β transgenic mice via the ALK5/Smad2/3 signalling branch, with Smad7 as a potent negative regulator. ADH1 deficiency is a determining factor for the increased lipid accumulation and Cyp2E1 dependent toxicity in liver cells upon alcohol challenge. Further, ADH1 expression was decreased during liver damage in an intragastric ethanol infusion mouse model. Conclusion In the presence of ethanol, TGF-β displays pro-steatotic action in hepatocytes via decreasing ADH1 expression. Low ADH1 levels are correlated with enhanced hepatocyte damage upon chronic alcohol consumption by favoring secondary metabolic pathways.