Distribution of myofibroblasts, smooth muscle-like cells, macrophages, and mast cells in mitral valve leaflets of dogs with myxomatous mitral valve disease

Objective—To map the cellular distribution and phenotypic alteration of the predominant stromal cell population throughout the entire valve length of dogs with myxomatous mitral valve disease (MMVD).<p></p> Sample Population—31 mitral valve complexes (ie, mitral valve leaflets) collected from 4 clinically normal dogs and 27 dogs with MMVD of varying severity.<p></p> Procedures—A combination of standard histologic and immunohistochemical techniques was used to identify pathologic changes, the presence of mast cells, and the density and distribution of cells expressing vimentin, desmin, A-smooth muscle actin (A-SMA), smooth muscle myosin, and the macrophage marker MAC387.<p></p> Results—Vimentin-positive cells predominated in the mitral valve leaflets from clinically normal dogs and were located throughout the leaflet, but cell density was appreciably decreased with disease progression, and minimal cell numbers were found in distinct myxomatous areas. Cells that were positive for A-SMA were uncommon in the mitral valve leaflets from clinically normal dogs and only seen in appreciable numbers in mitral valves of dogs with severe late-stage disease, in which cells were typically located close to the ventricularis valve surface. A slight increase in mast cell numbers was observed in the distal zone of affected leaflets.<p></p> Conclusions and Clinical Relevance—Activated-myofibroblasts (α-SMA–positive cells) were increased and inactive-myofibroblasts (vimentin-positive cells) were reduced in mitral valve leaflets of dogs with MMVD, compared with that of clinically normal dogs.<p></p> Impact on Human Medicine—This is the first description of spatial and temporal alterations in mitral valve cells of any species with MMVD and has clinical importance in the understanding of disease development in dogs and humans

Expression of receptors for verotoxin 1 from <i>Escherichia coli</i> O157 on bovine intestinal epithelium.

Human enterohaemorrhagic &lt;i&gt;Escherichia coli&lt;/i&gt; (EHEC) infection most commonly arises, either directly or indirectly, from cattle, which act as a reservoir host for these bacteria. In man, EHEC disease can be severe, whereas EHEC do not normally cause disease in cattle. Verotoxins (VTs) are the main virulence factors in human disease but no role for VT has been ascribed in cattle; however, this study shows for the first time that VT receptor is expressed by the bovine intestinal tract. VT bound to crypt epithelial cells of the small (ileum and jejunum) and large (caecum and colon) intestine independently of the animals' age. VT also bound to discrete cell subsets in the bovine kidney and to submucosal lymphoid cells but not to vasculature. Analysis of tissues for isoforms of the VT receptor, Gb3, confirmed the presence of the receptor in the bovine intestinal epithelium and kidney. A distinct pattern of Gb3 receptor isoform mixtures was observed in the bovine kidney. This, together with the general absence of receptors on vasculature, could contribute to the apparent resistance of cattle to systemic effects of VT. Expression of Gb3 on the bovine intestinal epithelium, together with previously described effects, may affect EHEC colonisation in its reservoir hosts and hence the potential for distribution to man

Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds

Novel ruthenium(II) organo-metallic compounds are active in ovarian cancer models [Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE, Chen H, et al. In vitro and in vivo activity and cross resistance profiles of novel ruthenium(II) organometallic arene complexes in human ovarian cancer. BrJ Cancer 2002;86(10):1652-7]. [(eta(6)-C6H5C6H5)Ru(en)Cl](+) (as a PF6 salt, where en = ethylenediamine (RM175)) has been evaluated in a 13-cell line panel. Particular sensitivity (similar to 10-fold lower than mean IC50) was noted in breast cancer and non-small cell lung cancer cell lines. In addition, IC50 in the A549 was 2 mu M and RM175 (25 mg kg(-1), days 1 and 5, i.p.) caused a significant (p = 0.004) growth delay in a xenograft model. HC11 [(eta(6)-tetrahydroanthracene)Ru(en)Cl]PF6 was more potent in the A549 cell line (IC50 0.5 eta M). HC11 (25 mg kg-1, days 1, 8 and 15, i.p.) was also active in vivo. Following RM175 25 mg kg-1, days 1 and 5, and 15 mg kg(-1), days 1-5, HC11 25 and 40 mg kg(-1), day 1, elevated alanine transaminase levels were detected, suggesting hepatotoxicity. No changes were observed in kidney or haematological parameters. In liver sections, multi-focal hepatic necrosis was seen, becoming confluent at high doses of HC11. In vitro studies confirmed that HC11 was more toxic than RM175 to fresh human hepatocytes and equitoxic to mithramycin. Liver toxicity may be related to the arene ligand and modification may reduce the potential for hepatic toxicity, while maintaining the anti-tumour activity seen. (c) 2005 Elsevier Inc. All rights reserved

Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds

Novel ruthenium(II) organo-metallic compounds are active in ovarian cancer models [Aird RE, Cummings J, Ritchie AA, Muir M, Morris RE, Chen H, et al. In vitro and in vivo activity and cross resistance profiles of novel ruthenium(II) organometallic arene complexes in human ovarian cancer. BrJ Cancer 2002;86(10):1652-7]. [(eta(6)-C6H5C6H5)Ru(en)Cl](+) (as a PF6 salt, where en = ethylenediamine (RM175)) has been evaluated in a 13-cell line panel. Particular sensitivity (similar to 10-fold lower than mean IC50) was noted in breast cancer and non-small cell lung cancer cell lines. In addition, IC50 in the A549 was 2 mu M and RM175 (25 mg kg(-1), days 1 and 5, i.p.) caused a significant (p = 0.004) growth delay in a xenograft model. HC11 [(eta(6)-tetrahydroanthracene)Ru(en)Cl]PF6 was more potent in the A549 cell line (IC50 0.5 eta M). HC11 (25 mg kg-1, days 1, 8 and 15, i.p.) was also active in vivo. Following RM175 25 mg kg-1, days 1 and 5, and 15 mg kg(-1), days 1-5, HC11 25 and 40 mg kg(-1), day 1, elevated alanine transaminase levels were detected, suggesting hepatotoxicity. No changes were observed in kidney or haematological parameters. In liver sections, multi-focal hepatic necrosis was seen, becoming confluent at high doses of HC11. In vitro studies confirmed that HC11 was more toxic than RM175 to fresh human hepatocytes and equitoxic to mithramycin. Liver toxicity may be related to the arene ligand and modification may reduce the potential for hepatic toxicity, while maintaining the anti-tumour activity seen. (c) 2005 Elsevier Inc. All rights reserved

Cutaneous alternaria infectoria infection in a dog in association with therapeutic immunosuppression for the management of immune-mediated haemolytic anaemia

A 4-year-old, ovariohysterectomized, English springer spaniel on immunosuppressive therapy was re-examined for the review of its immune-mediated haemolytic anaemia and the recent development of skin lesions. For the 3 months since hospital discharge, the dog had been receiving 1.3 mg/kg prednisolone and 2.6 mg/kg ciclosporin, both administered orally twice daily. Physical examination revealed hepatomegaly and multiple, purulent, crusting, erosive to ulcerative lesions over different body areas. Onychorrhexis had occurred on one digit and the underlying corium had blackened. There were two proliferative and one plaque-like lesions in the mouth. Thick walled fungal hyphae were detected in impression smears from all skin lesions and staining with periodic acid–Schiff’s stain confirmed the presence of multiple fungal hyphae and spores in all biopsies examined. Fungal culture isolated a heavy, pure growth of an Alternaria sp. which was identified as A. infectoria by sequencing the internal transcribed spacer 1 region of the rRNA gene. The animal’s condition prevented detailed investigation of the oral lesions. Withdrawal of the ciclosporin and reduction of the prednisolone dosage resulted in spontaneous resolution of the skin lesions within 40 days. Further gradual decrements in the prednisolone dosage to zero were carried out without recurrence of the immune-mediated haemolytic anaemia. After 12 months, there has been no recurrence of either the skin lesions or the anaemia. To the authors’ knowledge, this is the first reported case of A. infectoria infection in a dog