Pharmacokinetics of nicorandil in dogs with mild mitral regurgitation

The aim of this study was to examine the pharmacokinetics of nicorandil, a hybrid of an adenosine triphosphate-sensitive potassium channel opener and a nitrate, and to estimate its clinical doses in dogs with mild mitral valve regurgitation (MR). Nicorandil (0.1, 0.3, and 1.0 mg/kg) was administered orally to normal dogs and those with experimentally-induced MR, and its plasma concentrations were analyzed using high-performance liquid chromatography. Plasma concentrations increased dose-dependently after the administration of nicorandil, and were not different between normal dogs and those with MR. Similar to the effective plasma values obtained in cardiac disease in humans, the findings of this pharmacokinetic study may indicate that a dose of 0.3-1.0 mg/kg has the same effectiveness in dogs with cardiac dysfunction.     

Glucocorticoid sensitivity depends on expression levels of glucocorticoid receptors in canine neoplastic mast cells

Glucocorticoid (GC) administration with or without other chemotherapeutic reagents is a commonly used option in the treatment of mast cell malignancies. However, the responsiveness of mast cell tumors to GC treatment varies in individuals, and the regulatory mechanisms determining the GC sensitivity of malignant mast cells remain unclear. Since the expression of the GC receptor (GR) has been reported to be associated with GC sensitivity in human neoplastic lymphocytes, we attempted to investigate the relationship between GR levels and GC sensitivity by using neoplastic mast cells derived from canine mast cell tumors (MCTs). To elucidate the regulatory mechanisms involved in GC responsiveness, we analyzed various canine MCT cell lines and tissue samples from dogs with MCT. While the proliferation of canine MCT cells was suppressed by the addition of GC to the culture, we found that MCT cells derived from humans and rodents, as well as canine lymphoma cells, responded poorly to GC. However, there were also some variations in responsiveness to GC treatment among canine MCT cell lines used in this study. Using real-time polymerase chain reaction and Western blot analysis, we elucidated the relationship between GR expression and responsiveness to GC in canine MCT cells. Furthermore, to assess the involvement of GR expression in GC sensitivity in vivo, clinical investigations were conducted on dogs with cutaneous MCT. Written informed consent was obtained from owners, and the affected dogs were treated with prednisolone (0.5-2.0 mg kg(-1)day(-1), administered orally) 1 or 2 weeks prior to the surgical removal of the tumors. Tumor volume was measured according to WHO criteria both before and after prednisolone treatment, and the GC sensitivity of each MCT was determined on the basis of the reduction in tumor volume. Of the 15 dogs with MCT, 11 responded to treatment with prednisolone completely or partially, whereas 4 dogs showed no response. Examination of clinical samples obtained by surgical removal revealed that GR expression levels were significantly lower in GC-resistant MCT tissues than in GC-sensitive MCT tissues. Thus, these results strongly indicate that GR expression may contribute to GC sensitivity in canine MCT.     

Patient-side assay of lipase activity correlating with pancreatic lipase immunoreactivity in the dog

Pancreatitis is a common exocrine pancreatic disease in dogs, and the pancreatic lipase immunoreactivity (PLI) test is used for diagnosis. Enzyme catalytic assay is thought to have low specificity, but a lipase activity assay with increased specificity has been developed in human clinical chemistry. We measured serum lipase activity of 65 client-owned dogs using the newly developed FUJI DRI-CHEM slide and compared the results with their PLI concentrations. The results showed a good correlation (r = 0.91), and the normal and pancreatitis dogs identified based on the PLI values were correctly separated based on lipase activity. The present study suggests that FUJI DRI-CHEM lipase activity would be helpful for diagnosis of pacreatitis in dogs and, in particular, that it can be used as a patient-side assay and contributes to immediate treatment.     

Postnatal development of hypoplastic thymus in semi-lethal dwarf pet/pet males

The petit rat (pet/pet) is a new semi-lethal dwarf mutant with anomalies in the thymus and testes, defects inherited as a single autosomal recessive trait. At birth, these pet/pet rats show low birth weight and extremely small thymuses; at 140 days of age, their thymuses show abnormal involution. In the present study, we examined early postnatal development of hypoplastic pet/pet thymuses. In addition to being hypoplastic at birth, pet/pet thymus growth was almost completely impaired during the early postnatal period. As shown by cellular incorporation of BrdU, the mitotic activity was lower in pet/pet than in normal thymuses, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that apoptosis occurred more often in pet/pet than in normal thymus cells during the first few days after birth. These results indicate that postnatal development of the hypoplastic pet/pet thymus is defective due to the reduced proliferation and increased apoptosis of thymic cells.     

Histopathology and distribution of cells harboring bovine leukemia virus (BLV) proviral sequences in ovine lymphosarcoma induced by BLV inoculation.

Six sheep with lymphosarcoma induced by hypodermic inoculation of bovine leukemia virus (BLV) materials were examined to elucidate the relation between pathologic lesions and integration of BLV provirus in cellular DNAs. Antibodies to BLV gp-antigens had been detected since the 3rd week after the inoculation, and BLV was positive when checked 3 months later. Lymphosarcomas followed the leukemic phase in 4 sheep. The other 2 sheep showed initial lesions of lymphosarcoma and were aleukemic clinically. Five animals were killed by enthanasia and autopsied at 2.5 to 3.5 years postinoculation (pi) because of their diseased condition. One animal died 10 years pi following the 4th leukemic episode. Sarcomatous lesions were confirmed grossly and histologically, and the proliferating neoplastic cells were classified into lymphocytic, prolymphocytic, lymphoblastic and histiocytic types. Integration of BLV provirus in cellular DNAs of the peripheral blood lymphocytes (PBL) and neoplastic cells of sarcomatous lesions was examined by Southern blotting technique. BLV provirus was demonstrated in the PBL of all infected animals and in most of the sarcomatous lesions of the spleen, kidney and lymph nodes except 4 lymph nodes showing slight neoplastic infiltration. The results indicated that ovine lymphosarcoma could be caused by BLV and the cells carrying proviral information seemed to be disseminated and proliferate in the lesions.     

Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells in vivo and in vitro

Anti-copper treatments have been investigated to determine whether they suppress angiogenesis and tumor development since Cu is widely accepted as being required for angiogenesis. We examined the effects of treatment with trientine, a copper-chelating agent, on tumor development in a murine xenograft model using fibrosarcoma-derived transplantable QRsp-11 cells and C57BL/6 mice and induction of apoptosis in tumor cells and endothelial cells in vivo and in vitro. The tumor volumes increased more slowly in trientine-treated mice than in untreated mice. Tumor volumes in the treated mice were significantly smaller than those in the untreated mice at 24 days postinoculation (d.p.i.) of tumor cells. A cluster of pyknotic tumor cells and morphological abnormalities in capillary endothelial cells were observed in the tumors of trientine-treated mice but not in the tumors of untreated mice. The proportions of apoptotic and necrotic cells in the tumors of treated mice were approximately 3.5-fold higher than those in the tumors of untreated mice at 14 d.p.i. When the cells were treated with trientine in vitro, mouse endothelial cells and bovine primary endothelial cells showed an approximately 10-fold higher sensitivity to trientine than QRsp-11 cells in terms of D37. However, the proportion of apoptotic cells in endothelial cells was significantly lower than that in QRsp-11 cells after treatment with trientine. These results show that apoptosis was induced in tumor cells by treatment with trientine in vivo and in vitro.     

Cesium radioactivity in peripheral blood is linearly correlated to that in skeletal muscle: Analyses of cattle within the evacuation zone of the Fukushima Daiichi Nuclear Power Plant

The accident at the Fukushima Daiichi Nuclear Power Plant (FNPP) released a large amount of radioactive substances into the environment. Furthermore, beef contaminated with radioactive cesium above the 500 Bq/kg safety standard was circulated in the food chain in 2011. Japanese consumers remain concerned about the safety of radioactively contaminated food. In our previous study, we detected a linear correlation between radioactive cesium (¹³⁷Cs) activity in blood and muscle around 500 to 2500 Bq/kg in cattle. However, it was unclear whether the correlation was maintained at a lower radioactivity close to the current safety standard of 100 Bq/kg. In this study, we evaluated 17 cattle in the FNPP evacuation zone that had a ¹³⁷Cs blood level less than 10 Bq/kg. The results showed a linear correlation between blood ¹³⁷Cs and muscle ¹³⁷Cs (Y = 28.0X, R² = 0.590) at low radioactivity concentration, indicating that cesium radioactivity in the muscle can be estimated from blood radioactivity. This technique would be useful in detecting high‐risk cattle before they enter the market, and will contribute to food safety.     

Electrical manipulation of magnetization reversal in a ferromagnetic semiconductor

We report electrical manipulation of magnetization processes in a ferromagnetic semiconductor, in which low-density carriers are responsible for the ferromagnetic interaction. The coercive force HC at which magnetization reversal occurs can be manipulated by modifying the carrier density through application of electric fields in a gated structure. Electrically assisted magnetization reversal, as well as electrical demagnetization, has been demonstrated through the effect. This electrical manipulation offers a functionality not previously accessible in magnetic materials and may become useful for reversing magnetization of nanoscale bits for ultrahigh-density information storage.     

Evaluation of plant bed filter ditches for the removal of T-N and T-P from eutrophic pond water containing particulate N and P

Cultivation of useful terrestrial and aquatic plant species in plant bed filter ditches enables to treat domestic wastewater in addition to resource recycling and amenity functions. We reported previously that a ditch planted with papyrus removed Nand P most effectively from artificial wastewater. We evaluated the effectiveness of plant bed filter ditches in the treatment of eutrophic pond water, which unlike artificial wastewater, contains particulate Nand P. Experimental ditches were planted with papyrus, African marigold, peppermint, and impatience. These plant species were effective in removing N and P from artificial wastewater and could be used by rural communities for the production of handicrafts, cut flowers, and ornamental purposes. The control ditch did not contain plants (plant-free ditch). Pond water was continuously supplied to the ditches at a loading rate of 0.6–0.9 g m^-2 d^-1 for Nand 0.2–0.35 g m^-2 d^-1 for P. In the plant-free ditch, particulate Nand P in the influent were removed by passage through the bed filter, unlike NO³-N and PO⁴-P. A larger amount of PO⁴-P was dissolved from particulate P in the bed filter. The planted ditches effectively removed NO³-N, PO⁴-P as well as particulate Nand P. The planted ditches were able to purify eutrophic pond water, resulting in clear water with a concentration below 0.3 mg L^-1 for N and 0.02 mg L^-1 for P, concentrations at which water bloom does not occur. The average removal rate of pollutants by the planted ditches during the experiment, except for the first 2 weeks, was 0.67 g m^-2 d^-1 for total N and 0.03 g m^-2 d^-1 for total P. We recommend that plant bed filter ditches containing papyrus and flowers be used for ornamental purposes and removal of N and P from pond water along with the supply of clear water as ornamental streams.