Ultrasonography of portosystemic shunting in dogs : Doppler studies before, during and after surgery

Portosystemic shunting occurs when anomalous veins allow the portal blood to enter the systemic veins directly without first flowing through the hepatic sinusoids. Portosystemic shunting can occur via acquired portosystemic collaterals or via congenital portosystemic shunts and may result in clinical signs of hepatic encephalopathy due to high blood ammonia levels. It is necessary to differentiate congenital portosystemic shunts non-invasively from other conditions that cause hyperammonemia, since congenital portosystemic shunts require surgical treatment while the other conditions do not. Portography, ultrasonography, scintigraphy, CT and MRI have been used to diagnose portal vein disorders. Although Doppler ultrasonography is the only technique that does not require the use of anesthesia, and can provide detailed anatomic and hemodynamic information about the abdominal vasculature, its accuracy in detecting congenital portosystemic shunts was reported to be insufficient. In the present studies, gray scale ultrasonography with color Doppler mode appeared to be an accurate method to: diagnose a congenital portosystemic shunt, specify its type, distinguish it from acquired portosystemic collaterals and rule it out. The definitive therapy for congenital portosystemic shunts would ideally be complete occlusion of the shunt. However, in most dogs, only partial shunt ligation can be performed because attenuating the shunt vessel results in post-ligation portal hypertension. Acute portal hypertension can usually be successfully avoided, though development of chronic portal hypertension remains a frequent complication. Regardless of the technique used for shunt attenuation and for assessing post-ligation portal hypertension, the clinical outcome remains unpredictable. This is largely because there is no method currently available to determine the optimal degree of shunt narrowing. As a consequence of an exaggerated shunt closure, dogs may develop postoperative complications related to acute or chronic portal hypertension. To help avoid this problem, intraoperative ultrasonography greatly increases the likelihood of determining the optimal shunt diameter. Congenital extrahepatic portosystemic shunts do not have to, and actually should not, be completely occluded. Once the flow becomes hepatopetal in the entire portal vein and in the shunt adjacent to the portal vein, further narrowing of the shunt is unnecessary. Complete occlusion of a congenital extrahepatic portosystemic shunt has been suggested to result in a better clinical outcome compared to partial ligation. Several surgeons propose that a second surgery should be performed in every dog whose shunt has partially been attenuated in order to occlude their shunt completely. We have shown that dogs that underwent a partial ligation of a congenital portosystemic shunt do not have to be routinely re-operated on. Color Doppler ultrasonography performed at least one month after surgical ligation of a shunt can reveal whether a persisting hyperammonemia is the result is of a functional shunt, acquired portosystemic collaterals, or both. Dogs that have developed acquired portosystemic collaterals and dogs, whose extrahepatic portosystemic shunt was partially ligated and the flow direction in the entire portal vein and in the shunt adjacent to the portal vein became hepatopetal should not be re-operated on

Impact of copper and iron binding properties on the anticancer activity of 8-hydroxyquinoline derived Mannich bases.

The anticancer activity of 8-hydroxyquinolines relies on complex formation with redox active copper and iron ions. Here we employ UV-visible spectrophotometry and EPR spectroscopy to compare proton dissociation and complex formation processes of the reference compound 8-hydroxyquinoline (Q-1) and three related Mannich bases to reveal possible correlations with biological activity. The studied derivatives harbor a CH2-N moiety at position 7 linked to morpholine (Q-2), piperidine (Q-3), and chlorine and fluorobenzylamino (Q-4) substituents. Solid phase structures of Q-3, Q-4·HCl·H2O, [(Cu(HQ-2)2)2]·(CH3OH)2·Cl4·(H2O)2, [Cu(Q-3)2]·Cl2 and [Cu(HQ-4)2(CH3OH)]·ZnCl4·CH3OH were characterized by single-crystal X-ray diffraction analysis. In addition, the redox properties of the copper and iron complexes were studied by cyclic voltammetry, and the direct reaction with physiologically relevant reductants (glutathione and ascorbic acid) was monitored. In vitro cytotoxicity studies conducted with the human uterine sarcoma MES-SA/Dx5 cell line reveal the significant cytotoxicity of Q-2, Q-3, and Q-4 in the sub- to low micromolar range (IC50 values 0.2-3.3 μM). Correlation analysis of the anticancer activity and the metal binding properties of the compound series indicates that, at physiological pH, weaker copper(ii) and iron(iii) binding results in elevated toxicity (e.g.Q4: pCu = 13.0, pFe = 6.8, IC50 = 0.2 μM vs.Q1: pCu = 15.1, pFe = 13.0 IC50 = 2.5 μM). Although the studied 8-hydroxyquinolines preferentially bind copper(ii) over iron(iii), the cyclic voltammetry data revealed that the more cytotoxic ligands preferentially stabilize the lower oxidation state of the metal ions. A linear relationship between the pKa (OH) and IC50 values of the studied 8-hydroxyquinolines was found. In summary, we identify Q-4 as a potent and selective anticancer candidate with significant toxicity in drug resistant cells

Anticancer 8-hydroxyquinoline-amino acid hybrids and their half-sandwich Ru and Rh complexes : solution chemistry and interaction with biomolecules

Development of novel chemotherapeutic agents aims to obtain more effective and selective compounds. Platinum(II)-containing chemotherapeutics have been widely used for decades in cancer therapy against solid tumors due to their effectiveness; although, their use is accompanied by drawbacks such the serious side-effects and resistance [1]. To overcome these problems, efforts have been made to find better alternatives such as the complexes of other platinum metals. 8-hydroxyquinolines and their metal complexes are widely investigated due to their anticancer properties [2,3]; however, they often have limited water solubility. In this work two novel water-soluble 8-hydroxyquinoline-D-amino acid hybrids, [(R)-1-((5-chloro-8- hydroxyquinolin-7-yl)methyl)pyrrolidine-2-carboxylic acid (8HQCl-D-Pro) and its homologue 8HQCl-D-hPro (Chart 1), and their [Ru(η6 -p-cymene)(H2O)3] 2+ and [Rh(η5 -C5Me5)(H2O)3] 2+ complexes were developed

Prevalence of Echocardiographic Evidence of Trace Mitral and Aortic Valve Regurgitation in 50 Clinically Healthy, Young Adult Labrador Retrievers without Heart Murmur

Background-Though physiologic regurgitation of the right-sided cardiac valves is well recognized in dogs and other mammals, the prevalence of trace insufficiency of the mitral and aortic valves in clinically healthy, young adult dogs is unknown. Methods-In this observational cross-sectional study, 50 clinically healthy, young adult Labrador retrievers without an audible heart murmur were enrolled. All dogs were bred and owned by a single organization. Cardiac screening was requested for all dogs that were intended for breeding. These dogs underwent a cardiac auscultation and transthoracic echocardiography by a veterinary cardiology specialist. If mitral or aortic valve regurgitation was noticed, the jet size was subjectively assessed on color Doppler echocardiography. Pedigree analysis was performed to reveal a possible hereditary background of mitral valve regurgitation. Results-The prevalence of trivial mitral valve regurgitation was 52% with no significant predisposition to gender ( p = 0.86) or haircoat color ( p = 0.68). The prevalence of aortic valve regurgitation was 4%. Pedigree analysis for mitral valve regurgitation showed familial clustering, suggesting a hereditary background of the trait. Conclusions-The prevalence of silent trace mitral valve regurgitation in young adult Labrador retrievers was high. Because the regurgitant jet was trivial in all dogs, it is probably physiologic

Genetic Basis of Dilated Cardiomyopathy in Dogs and Its Potential as a Bidirectional Model

Cardiac disease is a leading cause of death for both humans and dogs. Genetic cardiomyopathies, including dilated cardiomyopathy (DCM), account for a proportion of these cases in both species. Patients may suffer from ventricular enlargement and systolic dysfunction resulting in congestive heart failure and ventricular arrhythmias with high risk for sudden cardiac death. Although canine DCM has similar disease progression and subtypes as in humans, only a few candidate genes have been found to be associated with DCM while the genetic background of human DCM has been more thoroughly studied. Additionally, experimental disease models using induced pluripotent stem cells have been widely adopted in the study of human genetic cardiomyopathy but have not yet been fully adapted for the in-depth study of canine genetic cardiomyopathies. The clinical presentation of DCM is extremely heterogeneous for both species with differences occurring based on sex predisposition, age of onset, and the rate of disease progression. Both genetic predisposition and environmental factors play a role in disease development which are identical in dogs and humans in contrast to other experimental animals. Interestingly, different dog breeds have been shown to develop distinct DCM phenotypes, and this presents a unique opportunity for modeling as there are multiple breed-specific models for DCM with less genetic variance than human DCM. A better understanding of DCM in dogs has the potential for improved selection for breeding and could lead to better overall care and treatment for human and canine DCM patients. At the same time, progress in research made for human DCM can have a positive impact on the care given to dogs affected by DCM. Therefore, this review will analyze the feasibility of canines as a naturally occurring bidirectional disease model for DCM in both species. The histopathology of the myocardium in canine DCM will be evaluated in three different breeds compared to control tissue, and the known genetics that contributes to both canine and human DCM will be summarized. Lastly, the prospect of canine iPSCs as a novel method to uncover the contributions of genetic variants to the pathogenesis of canine DCM will be introduced along with the applications for disease modeling and treatment