Cardiac output affects the response to pulsed inhaled nitric oxide in mechanically ventilated anesthetized ponies determined by CT angiography of the lung.

Objective: To measure changes in regional lung perfusion using CT angiography in mechanically ventilated, anesthetized ponies administered pulsed inhaled nitric oxide (PiNO) during hypotension and normotension.

Animals: 6 ponies for anesthetic 1 and 5 ponies for anesthetic 2.

Procedures: Ponies were anesthetized on 2 separate occasions, mechanically ventilated, and placed in dorsal recumbency within the CT gantry.

Strategies for extended lifetime of implantable intraperitoneal insulin catheters.

Implantable insulin infusion systems using the intra-peritoneal route have dramatically changed the management of diabetes paving the way toward the realization of the potential "holy grail" of a fully implantable artificial pancreas. However, the wear duration of delivery catheters is compromised by the foreign body-mediated immune response. Both occlusion material present at the distal catheter tip end and fibrotic encapsulation surrounding the catheters influence the controlled and precise delivery of insulin, which eventually leads to the need for surgical intervention.

Effects of pulsed inhaled nitric oxide delivery on the distribution of pulmonary perfusion in spontaneously breathing and mechanically ventilated anesthetized ponies.

Objective: To measure changes in pulmonary perfusion during pulsed inhaled nitric oxide (PiNO) delivery in anesthetized, spontaneously breathing and mechanically ventilated ponies positioned in dorsal recumbency.

Animals: 6 adult ponies.

Procedures: Ponies were anesthetized, positioned in dorsal recumbency in a CT gantry, and allowed to breathe spontaneously.

Development of a method to measure regional perfusion of the lung in anesthetized ponies using computed tomography angiography and the maximum slope model.

Objective: To develop a method based on CT angiography and the maximum slope model (MSM) to measure regional lung perfusion in anesthetized ponies.

Animals: 6 ponies.

Procedures: Anesthetized ponies were positioned in dorsal recumbency in the CT gantry.

Root cause determination of intraperitoneal catheter obstructions: Insulin amyloid aggregates vs foreign body reaction.

Continuous intraperitoneal insulin infusion, from an implanted insulin pump connected to a catheter that delivers insulin directly to the peritoneal cavity has many clinical advantages for patients with Type 1 diabetes. However, the ongoing incidence of catheter obstructions remains a barrier to the widespread use of this therapy. To date, the root cause of these obstructions remains unknown.

Fibrotic Encapsulation Is the Dominant Source of Continuous Glucose Monitor Delays.

Continuous glucose monitor (CGM) readings are delayed relative to blood glucose, and this delay is usually attributed to the latency of interstitial glucose levels. However, CGM-independent data suggest rapid equilibration of interstitial glucose. This study sought to determine the loci of CGM delays.

A New Animal Model of Insulin-Glucose Dynamics in the Intraperitoneal Space Enhances Closed-Loop Control Performance.

Current artificial pancreas systems (AP) operate via subcutaneous (SC) glucose sensing and SC insulin delivery. Due to slow diffusion and transport dynamics across the interstitial space, even the most sophisticated control algorithms in on-body AP systems cannot react fast enough to maintain tight glycemic control under the effect of exogenous glucose disturbances caused by ingesting meals or performing physical activity. Recent efforts made towards the development of an implantable AP have explored the utility of insulin infusion in the intraperitoneal (IP) space: a region within the abdominal cavity where the insulin-glucose kinetics are observed to be much more rapid than the SC space.

Release of (and lessons learned from mining) a pioneering large toxicogenomics database.

Aim: We release the Janssen Toxicogenomics database. This rat liver gene-expression database was generated using Codelink microarrays, and has been used over the past years within Janssen to derive signatures for multiple end points and to classify proprietary compounds.

Materials & Methods: The release consists of gene-expression responses to 124 compounds, selected to give a broad coverage of liver-active compounds.

Effects of pulse-delivered inhaled nitric oxide administration on pulmonary perfusion and arterial oxygenation in dorsally recumbent isoflurane-anesthetized horses.

Objective: To image the spatial distribution of pulmonary blood flow by means of scintigraphy, evaluate ventilation-perfusion (VA/Q) matching and pulmonary blood shunting (Qs/Qt) by means of the multiple inert gas elimination technique (MIGET), and measure arterial oxygenation and plasma endothelin-1 concentrations before, during, and after pulse-delivered inhaled nitric oxide (PiNO) administration to isoflurane-anesthetized horses in dorsal recumbency.

Animals: 3 healthy adult Standardbreds.

Procedures: Nitric oxide was pulsed into the inspired gases in dorsally recumbent isoflurane-anesthetized horses.

Effects of hydration on scintigraphic glomerular filtration rate measured using integral and plasma volume methods in dogs with suspected renal disease.

The current standard scintigraphic method for estimating glomerular filtration rate (GFR) in dogs is the integral method, which normalizes renal GFR to body weight. The plasma volume method, that is normalizing GFR to plasma volume, has been reported to be more physiologically correct. The aim of this prospective study was to test the effect of hydration status on GFR measured by these two methods in a group of dogs with suspected renal disease.

Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants.

Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression.

Integrating omic technologies into aquatic ecological risk assessment and environmental monitoring: hurdles, achievements, and future outlook.

Background: In this commentary we present the findings from an international consortium on fish toxicogenomics sponsored by the U.K. Natural Environment Research Council (Fish Toxicogenomics-Moving into Regulation and Monitoring, held 21-23 April 2008 at the Pacific Environmental Science Centre, Vancouver, BC, Canada).

Radiographic features of cardiogenic pulmonary edema in dogs with mitral regurgitation: 61 cases (1998-2007).

Objective: To evaluate radiographic distribution of pulmonary edema (PE) in dogs with mitral regurgitation (MR) and investigate the association between location of radiographic findings and direction of the mitral regurgitant jet (MRJ).

Design: Retrospective case series.

Animals: 61 dogs with cardiogenic PE and MR resulting from mitral valve disease (MVD; 51 dogs), dilated cardiomyopathy (9), and hypertrophic cardiomyopathy (1).

Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat.

The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the U.S. Food and Drug Administration, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints.

Effects of measurement of plasma activity input on normalization of glomerular filtration rate to plasma volume in dogs.

Glomerular filtration rate (GFR) normalized to body fluid volumes to adjust for differing body size and conformation is more physiologically correct than a relationship with body weight (BW). GFR can be normalized to plasma volume by a renographic method that uses the Rutland-Patlak plot with plasma activity and kidney activity inputs. A plasma time-activity curve is obtained from a region of interest (ROI) of the left ventricle (LV), the size of which is in theory not critical.

Toward a checklist for exchange and interpretation of data from a toxicology study.

Data from toxicology and toxicogenomics studies are valuable, and can be combined for meta-analysis using public data repositories such as Chemical Effects in Biological Systems Knowledgebase, ArrayExpress, and Gene Expression Omnibus. In order to fully utilize the data for secondary analysis, it is necessary to have a description of the study and good annotation of the accompanying data. This study annotation permits sophisticated cross-study comparison and analysis, and allows data from comparable subjects to be identified and fully understood.

Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression.

Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species such as rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncratic reactions account for over half of toxicity-related drug failures in the marketplace, and improving the preclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceutical industry. The formation of reactive metabolites is common among most drugs associated with idiosyncratic drug reactions and may cause deleterious effects through covalent binding and/or oxidative stress.

Hepatic expression of heme oxygenase-1 and antioxidant response element-mediated genes following administration of ethinyl estradiol to rats.

Heme oxygenase-1 (HO-1) is one of several enzymes induced by hepatotoxicants, and is thought to have an important protective role against cellular stress during liver inflammation and injury. The objective of the present study was to evaluate the role of HO-1 in estradiol-induced liver injury. A single dose of ethinyl estradiol (500 mg/kg, po) resulted in mild liver injury.

Predictive toxicogenomics approaches reveal underlying molecular mechanisms of nongenotoxic carcinogenicity.

Toxicogenomics technology defines toxicity gene expression signatures for early predictions and hypotheses generation for mechanistic studies, which are important approaches for evaluating toxicity of drug candidate compounds. A large gene expression database built using cDNA microarrays and liver samples treated with over one hundred paradigm compounds was mined to determine gene expression signatures for nongenotoxic carcinogens (NGTCs). Data were obtained from male rats treated for 24 h.

Application of genomics in preclinical drug safety evaluation.

Understanding the response of biological systems to xenobiotics is fundamental to the evaluation of drug safety. Toxicologists have traditionally gathered pathological, morphological, chemical and biochemical information from in vivo studies of preclinical species in order to assess drug safety and to determine how new drugs can be safely administered to the human patient population. In recent years the emerging "-omics" technologies have been developed and integrated into preclinical studies in order to better assess drug safety by gaining information on the cellular and molecular events underlying adverse drug reactions.

Effect of observer variability on glomerular filtration rate measurement by renal scintigraphy in dogs.

Observer variation in kidney depth measurement for correction of soft-tissue attenuation and kidney region of interest (ROI) drawing was evaluated using 60 clinical dogs with a wide range of glomerular filtration rate (GFR) for their effect on the calculated percentage uptake of 99mTc-diethylenetriamine pentaacetic acid (DTPA) and individual kidney GFR by scintigraphy. Kidney depth was measured separately on the lateral image using two color tables: a threshold and a continuous red-green-blue. Within-observer variability of the semi-automatic ROI drawing of the estimated total GFR was up to 10% for the right kidney (RK) and 9% for the left kidney (LK).

Effects of meloxicam on renal function in dogs with hypotension during anaesthesia.

Objective: To evaluate the effects of meloxicam on renal function in dogs anaesthetized and rendered hypotensive with acepromazine-thiopental-isoflurane.

Animals: Eight healthy beagles, four males and four females, 25.6 +/- 19.

The evolution of gene expression studies in drug safety assessment.

Since the identification in the 1950s of deoxyribonucleic acid as the building block of life, the impact of molecular biology has been far-reaching. Understanding the processes of how DNA is replicated, transcribed into RNA and then translated into protein products has not only provided a fundamental knowledge of life but has also spawned a plethora of applications. Molecular biology has been high profile and widespread in research into the biology of disease and in drug discovery.

Drug-induced oxidative stress in rat liver from a toxicogenomics perspective.

Macrophage activators (MA), peroxisome proliferators (PP), and oxidative stressors/reactive metabolites (OS/RM) all produce oxidative stress and hepatotoxicity in rats. However, these three classes of hepatotoxicants give three distinct gene transcriptional profiles on cDNA microarrays, an indication that rat hepatocytes respond/adapt quite differently to these three classes of oxidative stressors. The differential gene responses largely reflect differential activation of transcription factors: MA activate Stat-3 and NFkB, PP activate PPARa, and OS/RM activate Nrf2.