The Role of Hyperinsulinemia, the Sympathetic Nervous System and Nitric Oxide in Cardiovascular Function During the Development of Obesity-Induced Hypertension.

The interaction of hyperinsulinemia, the sympathetic nervous system (SNS) and nitric oxide (NO) was examined in lean and obese unilaterally lumbar sympathectomized dogs. Six lean and six obese dogs were studied while on a treadmill, during hyperinsulinemic euglycemic clamp (HIEC) procedures with and without concurrent nitric oxide synthase (NOS) inhibition with nitro-L-arginine (LNA). Changes in plasma insulin, femoral vascular resistance (FVR), heart rate (HR) and mean arterial pressure (MAP) were measured prior to and during a 7-week overfeeding period, and response to LNA administration was examined in the lean and obese state. Body weight increased from 19.9 $\pm$ 0.70 to 29.7 $\pm$ 0.77kg and % body fat from 23.0% to 48.8% during overfeeding(OF). Heart rate, MAP and plasma insulin also increased during overfeeding. Femoral vascular resistance initially increased (p $\u3c$ 0.01 in both the intact and denervated limbs), but returned to baseline levels by OF-week 3 in the denervated limb, and by week 6 in the intact limb. No significant correlation was evident between insulin levels and other cardiovascular parameters. Hyperinsulinemic euglycemia alone did not affect MAP in either weight group. However, when hyperinsulinemia was initiated following NOS inhibition, MAP in the lean animals tended to decrease, whereas that of the obese dogs increased slightly. HR response to hyperinsulinemia (alone or concurrent with NOS inhibition) was not different between weight groups. The FVR response to hyperinsulinemia alone or with NOS inhibition was not different between the weight groups. However, heart rate and vascular response to LNA was reduced in the obese dog. In summary, sympathetic activity may influence the vascular response to weight gain. Also, hyperinsulinemia does not affect MAP, HR or FVR in lean or obese dogs, while walking slowly on a treadmill. However, when NOS is concurrently inhibited, lean and obese dogs show a tendency toward differential MAP and HR responses to hyperinsulinemia. Thus, the insulin and nitric oxide interaction may differ in lean and obese dogs, and may mediate development of hypertension in the obese population. Finally, the obese have a reduced cardiovascular response to NOS inhibition compared to the lean

Imaging Long-Term Fate of Intramyocardially Implanted Mesenchymal Stem Cells in a Porcine Myocardial Infarction Model

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC–associated [18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI

Novel Antiseptic Urinary Catheters for Prevention of Urinary Tract Infections: Correlation of In Vivo and In Vitro Test Results▿

Urinary catheters are widely used for hospitalized patients and are often associated with high rates of urinary tract infection. We evaluated in vitro the antiadherence activity of a novel antiseptic Gendine-coated urinary catheter against several multidrug-resistant bacteria. Gendine-coated urinary catheters were compared to silver hydrogel-coated Foley catheters and uncoated catheters. Bacterial biofilm formation was assessed by quantitative culture and scanning electron microscopy. These data were further correlated to an in vivo rabbit model. We challenged 31 rabbits daily for 4 days by inoculating the urethral meatus with 1.0 × 109 CFU streptomycin-resistant Escherichia coli per day. In vitro, Gendine-coated urinary catheters reduced the CFU of all organisms tested for biofilm adherence compared with uncoated and silver hydrogel-coated catheters (P < 0.004). Scanning electron microscopy analysis showed that a thick biofilm overlaid the control catheter and the silver hydrogel-coated catheters but not the Gendine-coated urinary catheter. Similar results were found with the rabbit model. Bacteriuria was present in 60% of rabbits with uncoated catheters and 71% of those with silver hydrogel-coated catheters (P < 0.01) but not in those with Gendine-coated urinary catheters. No rabbits with Gendine-coated urinary catheters had invasive bladder infections. Histopathologic assessment revealed no differences in toxicity or staining. Gendine-coated urinary catheters were more efficacious in preventing catheter-associated colonization and urinary tract infections than were silver hydrogel-coated Foley catheters and uncoated catheters

Pharmacokinetics, Metabolism, Biodistribution, Radiation Dosimetry, and Toxicology of F-18-Fluoroacetate (F-18-FACE) in Non-human Primates

Introduction: To facilitate the clinical translation of 18F-fluoroacetate ( 18F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of 18F-FACE were determined in non-human primates. Methods: 18F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with 18F-FACE (165.4±28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0-30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of 18F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of 18F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of 18F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. Results: The blood clearance of 18F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of 18F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that 18F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9 of total radioactivity in blood at 180 min after the 18F-FACE injection. The uptake of free 18F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90-7.81 mSv from the administration of 185-370 MBq of 18F-FACE. Conclusions: The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of 18F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of 18F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011