Combined use of an epidural cooling catheter and systemic moderate hypothermia enhances spinal cord protection against ischemic injury in rabbits

BackgroundEpidural placement of a cooling catheter can protect against ischemic spinal cord injury. With the use of rabbits, we investigated whether this epidural cooling technique, when combined with systemic moderate hypothermia, can protect the spinal cord against ischemic metabolic stress.MethodsNew Zealand white rabbits (n = 28) were assigned to 1 of 4 different groups. Animals underwent abdominal aortic occlusion for 30 minutes using a 3F balloon catheter. Group 1 (n = 7) underwent epidural cooling by the catheter and systemic moderate hypothermia (35°C) induced with a cooling blanket. Group 2 (n = 7) underwent epidural cooling under systemic normothermia (38.5°C). Group 3 (n = 7) underwent systemic moderate hypothermia (35°C) without epidural cooling. Group 4 (n = 7) underwent neither epidural nor blanket cooling as a negative control. Neurologic status of their hind limbs was graded according to the modified Tarlov scale at 1, 2, and 7 days after surgery.ResultsDuring infrarenal aortic ischemia, epidural temperature was significantly lower in group 1 (18.5°C ± 0.8°C) than in group 2 (28.6°C ± 1.0°C; P = .0001), group 3 (34.2°C ± 0.06°C; P = .0001), or group 4 (38.5°C ± 0.2°C; P = .0001). Hind limb function recovery was greater in group 1 (mean Tarlov score, 4.9 ± 0.057) than in group 2 (2.6 ± 0.3; P = .0028), group 3 (2.1 ± 0.34; P = .0088), or group 4 (0.0 ± 0.0; P = .0003).ConclusionsEpidural cooling catheter combined with systemic moderate hypothermia produced additive cooling ability and protected the spinal cord against ischemia in rabbits more effectively than either intervention alone

Anti-neoplastic effects of topoisomerase inhibitors in canine mammary carcinoma, melanoma, and osteosarcoma cell lines

Numerous topoisomerase inhibitors with proven efficacy have been used extensively to treat various human neoplasms. However, among these, only doxorubicin has been used and studied extensively in veterinary oncology. The current study was performed to evaluate the responsiveness of canine osteosarcoma (cOSA), mammary gland tumour (cMGT), and malignant melanoma (cMM) cell lines to several topoisomerase inhibitors. In addition, the correlation between the sensitivity to treatment and multi-drug resistant (MDR) factors was investigated. cOSA cell lines exhibited higher sensitivity than cMGT and cMM cell lines to all the topoisomerase inhibitors tested in vitro; this was associated with the levels of multi-drug resistance protein 1 (MDR1) gene expression in the cOSA cell lines. Treatment of cOSA (HMPOS) and cMGT cell line (CHMp) xenograft mouse models with etoposide markedly delayed tumour progression in HMPOS xenografts, but failed to elicit lasting anti-tumour effects on CHMp xenograft mice. The present findings suggest that MDR1 represents a molecular signature for prediction of treatment efficacy of topoisomerase inhibitors, especially that of etoposide, which may be a clinically useful anti-tumour agent for cOSA; however, further study is necessary to refine the treatment protocol

Evaluation of immunohistochemical staining with PMab-38, an anti-dog podoplanin monoclonal antibody, in various canine tumor tissues

Podoplanin (PDPN) is a type I transmembrane sialoglycoprotein with O-glycosylation and a high content of sialic acid. PDPN has been reported to be expressed in various human tumors and promote tumor progression, epithelial-mesenchymal transition, and distant metastasis. PDPN is also expressed in cancer-associated fibroblasts (CAFs), which promote tumor growth. We have developed novel tumor specific anti-PDPN antibodies. PMab-38, which is an anti-dog PDPN monoclonal antibody, recognized PDPN expression in canine squamous cell carcinoma (SCC) and malignant melanoma. However, there has been no research into PMab-38 recognition of other types of tumors and systemic normal tissue. The objective of this study was to evaluate the staining positivity of PMab-38 by immunohistochemical staining of various paraffin-embedded canine tumor and systemic normal tissues. Immunohistochemical analysis revealed that PMab-38 positively stained tumor cells in 9/11 (82%) SCC and 9/11 (82%) pulmonary adenocarcinoma tissues. In the tumor stroma, large spindle-shaped mesenchymal cells, which were suspected to be CAFs, were stained by PMab-38 in almost all tumor types: 9/10 (90%) for anal sac adenocarcinoma and 11/12 (92%) for transitional cell carcinoma tissues. Almost all normal tissues were negatively stained with PMab-38 except part of the kidney glomerulus. Taken together, our findings provide evidence that various types of tumor cells were strongly stained by PMab-38, but most normal cells were not stained. These results indicate that PDPN recognized by PMab-38 might be a target for tumor antigen targeting therapy. Further studies are required to investigate the anti-tumor effect in various canine tumors by antibody therapy using PMab-38

Evaluation of the proper dosage of lapatinib and its safety in dogs

Lapatinib is a low-molecular-weight agent targeting the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). It is one of the antitumor agents used against advanced breast cancer in human. We intended to apply it against canine mammary gland tumors (cMGTs). To this end, we evaluated the tolerated dosage and the side effects of lapatinib in healthy dogs. In this study, we conducted a dose-escalation toxicity test starting from 30 mg/kg to determine the maximum tolerated dose. Grade 3 toxicity, which was apparent as weight loss, was observed at the dose of 40 mg/kg/day. We then performed a long-term administration test and found that the dose of 35 mg/kg/day was well-tolerated within 7 weeks but caused grade 3 hepatic toxicity by the eighth week. In conclusion, our findings reveal that the dose of 35 mg/kg/day administered for no more than 8 weeks is fairly safe for use in healthy dogs. This dose is higher than the recommended dose for humans; thus, further studies evaluating the effective dose against canine tumors are needed

Numerical analysis of blood flow distribution in 4- and 3-branch vascular grafts

Trifurcated arch grafts (3-branch grafts) are now being used to repair the thoracic aorta in addition to conventional arch grafts (4-branch grafts). The anatomical shape of the 3-branch graft is different from the original vessel, so it is necessary for clinical application to evaluate blood flow distribution in the graft to assess whether there is adequate blood flow to the target organs. To achieve this, we developed a computational fluid dynamics (CFD) method to evaluate blood flow distribution in the grafts. Aortic blood flow was measured by phase-contrast magnetic resonance imaging (PC-MRI), and flow distribution into the branched vessels was obtained. The MRI image was used to create a patient-specific image model that represents the geometry of the aortic arch. The CFD analysis method was employed to determine a boundary condition of the blood flow analysis in the aorta using a patient-specific image model. We also created simplified models of 4-branch and 3-branch grafts and used our CFD analysis method to compare blood flow distribution among simplified models. It was found that blood flow distribution in the descending aorta was 71.3 % for the 4-branch graft and 67.7 % for the 3-branch graft, indicating that a sum of branching flow in the 3-branch graft was almost the same as the one in the 4-branch graft. Therefore, there is no major concern about implanting a new 3-branch graft. Our CFD analysis method may be applied to estimate blood flow distribution of a newly developed vascular graft prior to its clinical use and provide useful information for safe use of the graft.7 page(s