Biomechanical Properties of Repair Cartilage Tissue Are Superior Following Microdrilling Compared to Microfracturing in Critical Size Cartilage Defects.

BACKGROUND/AIM: Common surgical treatment options for large focal chondral defects (FCDs) in the knee include microfracturing (MFX) and microdrilling (DRL). Despite numerous studies addressing MFX and DRL of FDCs, no in vivo study has focused on biomechanical analysis of repair cartilage tissue in critical size FCDs with different amounts of holes and penetration depths. MATERIALS AND METHODS: Two round FCDs (d=6 mm) were created on the medial femoral condyle in 33 adult merino sheep. All 66 defects were randomly assigned to 1 control or 4 different study groups: 1) MFX1, 3 holes, 2 mm depth; 2) MFX2, 3 holes, 4 mm depth; 3) DRL1, 3 holes, 4 mm depth; and 4) DRL2, 6 holes, 4 mm depth. Animals were followed up for 1 year. Following euthanasia, quantitative optical analysis of defect filling was performed. Biomechanical properties were analysed with microindentation and calculation of the elastic modulus. RESULTS: Quantitative assessment of defect filling showed significantly better results in all treatment groups compared to untreated FCDs in the control group (p<0.001), with the best results for DRL2 (84.2% filling). The elastic modulus of repair cartilage tissue in the DRL1 and DRL2 groups was comparable to the adjacent native hyaline cartilage, while significantly inferior results were identified in both MFX groups (MFX1: p=0.002; MFX2: p<0.001). CONCLUSION: More defect filling and better biomechanical properties of the repair cartilage tissue were identified for DRL compared to MFX, with the best results for 6 holes and 4 mm of penetration depth. These findings are in contrast to the current clinical practice with MFX as the gold standard and suggest a clinical return to DRL.

Pharmacokinetics of metamizole (dipyrone) as an add-on in calves undergoing umbilical surgery.

This preliminary clinical investigation of the pharmacokinetic behavior of the main metamizole (dipyrone) metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) in calves undergoing umbilical surgery is part of an already published main study. A single intravenous dose of metamizole was added to ketamine/xylazine/isoflurane anesthesia. Eight Simmental calves weighing 90 ± 10.8 kg and aged 47.6 ± 10.4 days received 40 mg/kg metamizole intravenously 10 minutes prior to general anesthesia. Blood samples were collected over 24 hours and analyzed for 4-MAA and 4-AA. Meloxicam was additionally given twice: 2.5 hours pre- and 20.5 hours postsurgically. The pharmacokinetic profile of 4-MAA was best fitted to a two-compartment model and was characterized by a fast distribution half-life and slow elimination half-life (t½alpha = 5.29 minutes, t½beta = 9.49 hours). The maximum concentration (Cmax 101.63 µg/mL) was detected at the first measurement time point 15 minutes after administration. In contrast, 4-AA showed fast, high and biphasic plasma peak concentration behavior in five calves (2.54-2.66 µg/mL after 15-30 minutes, and 2.10-2.14 µg/mL after 2-3.5 hours) with a t½beta of 8.87 hours, indicating a rapid distribution and subsequent redistribution from well-perfused organs. Alternatively, three calves exhibited a slower and lower monophasic plasma peak concentration (1.66 µg/mL after 6.5 hours) with a t½beta of 6.23 hours, indicating slow accumulation in the intravascular compartment. The maximum concentration and area under the plasma concentration curve (AUC) of 4-AA were lower than those of 4-MAA. This metabolic behavior supports our already published data on clinical monitoring and plasma cortisol concentrations (PCCs). Compared to those of saline controls, lower PCCs correspond to the t½alpha of 4-MAA. Data on Tmax and t½beta also match these clinical observations. However, further studies are required to assess the exact analgesic mechanism and potency of the metamizole metabolites in calves.

Animal Models of Neointimal Hyperplasia and Restenosis: Species-Specific Differences and Implications for Translational Research.

The process of restenosis is based on the interplay of various mechanical and biological processes triggered by angioplasty-induced vascular trauma. Early arterial recoil, negative vascular remodeling, and neointimal formation therefore limit the long-term patency of interventional recanalization procedures. The most serious of these processes is neointimal hyperplasia, which can be traced back to 4 main mechanisms: endothelial damage and activation; monocyte accumulation in the subintimal space; fibroblast migration; and the transformation of vascular smooth muscle cells. A wide variety of animal models exists to investigate the underlying pathophysiology. Although mouse models, with their ease of genetic manipulation, enable cell- and molecular-focused fundamental research, and rats provide the opportunity to use stent and balloon models with high throughput, both rodents lack a lipid metabolism comparable to humans. Rabbits instead build a bridge to close the gap between basic and clinical research due to their human-like lipid metabolism, as well as their size being accessible for clinical angioplasty procedures. Every different combination of animal, dietary, and injury model has various advantages and disadvantages, and the decision for a proper model requires awareness of species-specific biological properties reaching from vessel morphology to distinct cellular and molecular features.

Use of metamizole as an additional analgesic during umbilical surgery in calves.

OBJECTIVE: To investigate the effect of metamizole on physiologic variables in calves undergoing surgical extirpation of the navel during anaesthesia using xylazine, ketamine and isoflurane. STUDY DESIGN: Double-blind, randomized trial. ANIMALS: A total of 26 calves. METHODS: Calves with uncomplicated umbilical hernias and otherwise clinically healthy were randomly allocated to one of two groups: the control group (CG) and metamizole group (MG). All calves were administered meloxicam (0.5 mg kg-1) intravenously (IV) 150 minutes before skin incision (SI). Animals were premedicated with xylazine (0.2 mg kg-1) intramuscularly 50 minutes before SI. Anaesthesia was induced with ketamine (2 mg kg-1) IV 30 minutes before SI and maintained with isoflurane in oxygen. MG calves were given metamizole (40 mg kg-1) IV 60 minutes before SI. CG calves were administered an equivalent volume of saline. Heart rate (HR) and mean arterial blood pressure (MAP) were recorded from 5 minutes before SI until the end of anaesthesia (60 minutes after SI). Blood samples for determination of the plasma cortisol concentration (PCC) were drawn 60 minutes before SI and at 5, 30, 60, 150, and 510 minutes after SI. RESULTS: In both groups, PCC increased during surgery and decreased after surgery. PCC was consistently lower in MG than in CG and was significantly (p = 0.0026) lower at 150 minutes after SI in the MG. Overall, the mean PCC in MG was 10.9 nmol L-1 lower than that in CG (p = 0.01). In both groups, HR decreased during anaesthesia, whereas MAP increased, albeit with no statistically significant (p > 0.05) differences between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Our study results suggest that a single preoperative dose of metamizole may have a positive impact on intra- and immediate postoperative analgesia by reducing PCC when used as an indicator of nociception.

Evaluation of an ADVanced Organ Support (ADVOS) system in a two-hit porcine model of liver failure plus endotoxemia.

BACKGROUND: Novel extracorporeal procedures are constantly being developed and evaluated for use in patients with sepsis. Preclinical evaluation of such procedures usually requires testing in large animal models. In the present work, the safety and efficacy of a recently developed ADVanced Organ Support (ADVOS) system in a newly developed large animal two-hit model of liver failure combined with endotoxemia were tested. METHODS: After establishing the model in more than 50 animals, a randomized study was performed. An inflammatory cholestatic liver injury was initially provoked in pigs. Three days after surgery, endotoxin was gradually administered during 7½ h. Animals were randomized to receive standard medical treatment either with (ADVOS group, n = 5) or without ADVOS (control group, n = 5). The ADVOS treatment was started 2½ h after endotoxemia and continued for 7 h. Survival, cardiovascular, respiratory, renal, liver, coagulation, and cerebral parameters were analyzed. RESULTS: Three days after surgery, cholestatic injury resulted in hyperbilirubinemia [5.0 mg/dl (IQR 4.3-5.9 mg/dl)], hyperammonemia [292 µg/dl (IQR 291-296 µg/dl)], leukocytosis [20.2 103/µl (IQR 17.7-21.8 103/µl)], and hyperfibrinogenemia [713 mg/dl (IQR 654-803 mg/dl)]. After endotoxemia, the ADVOS procedure stabilized cardiovascular, respiratory, and renal parameters and eliminated surrogate markers as bilirubin [2.3 (IQR 2.3-3.0) vs. 5.5 (IQR 4.6-5.6) mg/dl, p = 0.001] and creatinine [1.4 (IQR 1.1-1.7) vs. 2.3 (IQR 2.1-3.1) mg/dl, p = 0.01]. Mortality: All animals in the ADVOS group survived, while all animals in the control group expired during the 10-h observation period (p = 0.002). No adverse events related to the procedure were observed. CONCLUSIONS: The ADVOS procedure showed a promising safety and efficacy profile and improved survival in a sepsis-like animal model with dysfunction of multiple organs. An amelioration of major organ functions (heart and lung) combined with removal of markers for kidney and liver function was observed.

Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.

Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.

Comparative Oncology: Evaluation of 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) Positron Emission Tomography/Computed Tomography (PET/CT) for the Staging of Dogs with Malignant Tumors.

INTRODUCTION: 2-Deoxy-2-[18F]fluoro-D-glucose PET/CT is a well-established imaging method for staging, restaging and therapy-control in human medicine. In veterinary medicine, this imaging method could prove to be an attractive and innovative alternative to conventional imaging in order to improve staging and restaging. The aim of this study was both to evaluate the effectiveness of this image-guided method in canine patients with spontaneously occurring cancer as well as to illustrate the dog as a well-suited animal model for comparative oncology. METHODS: Ten dogs with various malignant tumors were included in the study and underwent a whole body FDG PET/CT. One patient has a second PET-CT 5 months after the first study. Patients were diagnosed with histiocytic sarcoma (n = 1), malignant lymphoma (n = 2), mammary carcinoma (n = 4), sertoli cell tumor (n = 1), gastrointestinal stromal tumor (GIST) (n = 1) and lung tumor (n = 1). PET/CT data were analyzed with the help of a 5-point scale in consideration of the patients' medical histories. RESULTS: In seven of the ten dogs, the treatment protocol and prognosis were significantly changed due to the results of FDG PET/CT. In the patients with lymphoma (n = 2) tumor extent could be defined on PET/CT because of increased FDG uptake in multiple lymph nodes. This led to the recommendation for a therapeutic polychemotherapy as a treatment. In one of the dogs with mammary carcinoma (n = 4) and in the patient with the lung tumor (n = 1), surgery was cancelled due to the discovery of multiple metastasis. Consequently no treatment was recommended. CONCLUSION: FDG PET/CT offers additional information in canine patients with malignant disease with a potential improvement of staging and restaging. The encouraging data of this clinical study highlights the possibility to further improve innovative diagnostic and staging methods with regard to comparative oncology. In the future, performing PET/CT not only for staging but also in therapy control could offer a significant improvement in the management of dogs with malignant tumors.