Cycad Palm Toxicosis in 14 Dogs from Texas.

The goal of this study is to report clinical information, diagnostic findings, and treatment modalities; assess variables that may help distinguish survivors from nonsurvivors; and review the outcome of cycad palm toxicosis in dogs. Fourteen client-owned dogs with confirmed cycad palm ingestion were identified by reviewing the medical record database at Gulf Coast Veterinary Specialists. Information on signalment, time of ingestion to presentation, clinical signs, physical examination findings, initial and peak/nadir laboratory abnormalities, radiographic and ultrasonographic findings, treatment modalities, liver histopathology, and clinical outcome was retrieved. Of the 14 dogs, nine (64%) died as a direct result of cycad palm intoxication, and three survivors had persistently elevated liver enzymes, signifying residual liver damage. Despite decontamination, patients continued to display evidence of illness, indicating rapid absorption of toxins. When evaluating initial and peak/nadir laboratory values, nadir serum albumin levels and nadir platelet counts were significantly lower in nonsurvivors compared to survivors (1.25 g/dL [0.4-2.1 g/dL] versus 2.6 g/dL [1.7-3.4 g/dL] and 21 × 103 [0-64 × 103] versus 62 × 103 [6-144 × 103], respectively). In this cohort of dogs, the case fatality rate was higher than previously reported. Nadir serum albumin levels and nadir platelet counts may help distinguish potential survivors from nonsurvivors.

Retargeting FX-binding-ablated HAdV-5 to vascular cells by inclusion of the RGD-4C peptide in hexon hypervariable region 7 and the HI loop.

Recent studies have generated interest in the function of human adenovirus serotype 5 (HAdV-5) hexon: factor X (FX) binding and subsequent hepatocyte transduction and interaction with the immune system. Here, we retargeted adenovirus serotype 5 vectors, ablated for FX interaction, by replacing amino acids in hexon HVR7 with RGD-4C or inserting the peptide into the fibre HI loop. These genetic modifications in the capsid were compatible with virus assembly, and could efficiently retarget transduction of the vector via the αvß3/5 integrin-mediated pathway, but did not alter immune recognition by pre-existing human neutralizing anti-HAdV-5 antibodies or by natural antibodies in mouse serum. Thus, FX-binding-ablated HAdV-5 can be retargeted but remain sensitive to immune-mediated attack. These findings further refine HAdV-5-based vectors for human gene therapy and inform future vector development.

G-Protein-Coupled Receptor 35 Mediates Human Saphenous Vein Vascular Smooth Muscle Cell Migration and Endothelial Cell Proliferation.

Vascular smooth muscle cell (VSMC) migration and proliferation is central to neointima formation in vein graft failure following coronary artery bypass. However, there are currently no pharmacological interventions that prevent vein graft failure through intimal occlusion. It is hence a therapeutic target. Here, we investigated the contribution of GPR35 to human VSMC and endothelial cell (EC) migration, using a scratch-wound assay, and also the contribution to proliferation, using MTS and BrdU assays, in in vitro models using recently characterized human GPR35 ortholog-selective small-molecule agonists and antagonists. Real-time PCR studies showed GPR35 to be robustly expressed in human VSMCs and ECs. Stimulation of GPR35, with either the human-selective agonist pamoic acid or the reference agonist zaprinast, promoted VSMC migration in the scratch-wound assay. These effects were blocked by coincubation with either of the human GPR35-specific antagonists, CID-2745687 or ML-145. These GPR35-mediated effects were produced by inducing alterations in the actin cytoskeleton via the Rho A/Rho kinase signaling axis. Additionally, the agonist ligands stimulated a proliferative response in ECs. These studies highlight the potential that small molecules that stimulate or block GPR35 activity can modulate vascular proliferation and migration. These data propose GPR35 as a translational therapeutic target in vascular remodeling.

Regulation of cardiovascular remodeling by the counter-regulatory axis of the renin-angiotensin system.

The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease.