Detecting In Vivo Free Radicals in Various Disease Models

In vivo free radical imaging in pre-clinical models of disease is now possible. Free radicals have traditionally been characterized by ESR or EPR spin trapping spectroscopy. The disadvantage of the ESR/EPR approach is that spin adducts are short-lived due to biological reductive and/or oxidative processes. Immuno-spin trapping (IST) involves the use of an antibody that recognizes macromolecular DMPO-spin adducts (anti-DMPO antibody), regardless of the oxidative/reductive state of trapped radical adducts. The IST approach has been extended to an in vivo application that combines IST with molecular magnetic resonance imaging (mMRI). This combined IST-mMRI approach involves the use of a spin trapping agent, DMPO, to trap free radicals in disease models, and administration of a mMRI probe, an anti-DMPO probe, that combines an antibody against DMPO-radical adducts and a MRI contrast agent, resulting in targeted free radical adduct detection. The combined IST-mMRI approach has been used in several rodent disease models, including diabetes, ALS, gliomas, and septic encephalopathy. The advantage of this approach is that heterogeneous levels of trapped free radicals can be detected directly in vivo and in situ to pin-point where free radicals are formed in different tissues. The approach can also be used to assess therapeutic agents that are either free radical scavengers or generate free radicals. The focus of this review will be on the different applications that have been studied, advantages and limitations, and future directions

In Vitro Phase-Contrast Magnetic Resonance Investigation on Development of Human Carotid Sinus in Young Age

Figure 1 . Three dimensional reconstruction process of morphologically averaged human carotid artery bifurcations using the measurements of arterial dimensions from two orthogonal (AP and LAT) projections

Erratum to: Magnetothermoacoustics from magnetic nanoparticles by short bursting or frequency chirped alternating magnetic field: A theoretical feasibility analysis

We correct one typographical error that has occurred in four equations in Med Phys, 2013. 40(6): p. 063301.Electrical and Computer Engineerin

LINE-1 Hypomethylation in a Choline-Deficiency-Induced Liver Cancer in Rats: Dependence on Feeding Period

Chronic feeding of methyl-donor (methionine, choline, folic acid, and vitamin B12) deficient diet induces hepatocellular carcinoma formation in rats. Previous studies have shown that promoter CpG islands in various cancer-related genes are aberrantly methylated in this model. Moreover, the global genome in methyl-donor-deficient diet fed rats contains a lesser amount of 5-methylcytosine than control livers. It is speculated that more than 90% of all 5-methylcytosines lie within the CpG islands of the transposons, including the long/short interspersed nucleotide elements (LINE and SINE). It is considered that the 5-methylcytosines in LINE-1 limit the ability of retrotransposons to be activated and transcribed; therefore, the extent of hypomethylation of LINE-1 could be a surrogate marker for aberrant methylation in other tumor-related genes as well as genome instability. Additionally, LINE-1 methylation status has been shown to be a good indicator of genome-wide methylation. In this study, we determined cytosine methylation status in the LINE-1 repetitive sequences of rats fed a choline-deficient (CD) diet for various durations and compared these with rats fed a choline-sufficient (CS) diet. The methylation status of LINE-1 was assessed by the combined bisulfite restriction analysis (COBRA) method, where the amount of bisulfite-modified and RsaI-cleaved DNA was quantified using gel electrophoresis. Progressive hypomethylation was observed in LINE-1 of CD livers as a function of feeding time; that is, the amount of cytosine in total cytosine (methylated and unmethylated) increased from 11.1% (1 week) to 19.3% (56 weeks), whereas in the control CS livers, it increased from 9.2% to 12.9%. Hypomethylation in tumor tissues was slightly higher (6%) than the nontumorous surrounding tissue. The present result also indicates that age is a factor influencing the extent of cytosine methylation

Temporary opening of the blood-brain barrier with the nitrone compound OKN-007

The blood-brain barrier (BBB) is usually impermeable to several drugs, which hampers treatment of various brain-related diseases/disorders. There have been several approaches to open the BBB, including intracarotid infusion of hyperosmotic concentrations of arabinose, mannitol, oleic or linoleic acids, or alkylglycerols, intravenous infusion of bradykinin B2, administration of a fragment of the ZO toxin from vibrio cholera, targeting specific components of the tight junctions (e.g. claudin-5) with siRNA or novel peptidomimetic drugs, or the use of ultrasound with microbubbles. We propose the use of a low molecular weight (MW), nitrone-type compound, OKN-007, which can temporarily open up the BBB for 1-2 hours. Gadolinium (Gd)-based compounds assessed ranged in MW from 546 (Gd-DTPA) to 465 kDa (beta-galactosidase Gd DOTA). We also included an albumin-based CA (albumin-Gd-DTPA-biotin) for assessment, as well as an antibody (Ab) against a neuron-specific biomarker conjugated to Gd-DOTA (anti-EphB2-Gd-DOTA). For the anti-EphB2 (goat Ab)-Gd-DOTA assessment, we utilized an anti goat Ab conjugated with horse radish peroxidase (HRP) for confirmation of the presence of the anti-EphB2-Gd-DOTA probe. In addition, a Cy5 labeled anti-EphB2 Ab was co-administered with the anti-EphB2-Gd-DOTA probe, and assessed ex vivo. This study demonstrates that OKN-007 may be able to temporarily open up the BBB to augment the delivery of various compounds ranging in MW from as small as similar to 550 to as large as similar to 470 kDa. This compound is an investigational new drugfor glioblastoma (GBM) therapy in clinical trials. The translational capability for human use to augment the delivery of non-BBB-permeable drugs is extremely high

Early myocardial dysfunction in streptozotocin-induced diabetic mice: a study using in vivo magnetic resonance imaging (MRI)

BACKGROUND: Diabetes is associated with a cardiomyopathy that is independent of coronary artery disease or hypertension. In the present study we used in vivo magnetic resonance imaging (MRI) and echocardiographic techniques to examine and characterize early changes in myocardial function in a mouse model of type 1 diabetes. METHODS: Diabetes was induced in 8-week old C57BL/6 mice with two intraperitoneal injections of streptozotocin. The blood glucose levels were maintained at 19–25 mmol/l using intermittent low dosages of long acting insulin glargine. MRI and echocardiography were performed at 4 weeks of diabetes (age of 12 weeks) in diabetic mice and age-matched controls. RESULTS: After 4 weeks of hyperglycemia one marker of mitochondrial function, NADH oxidase activity, was decreased to 50% of control animals. MRI studies of diabetic mice at 4 weeks demonstrated significant deficits in myocardial morphology and functionality including: a decreased left ventricular (LV) wall thickness, an increased LV end-systolic diameter and volume, a diminished LV ejection fraction and cardiac output, a decreased LV circumferential shortening, and decreased LV peak ejection and filling rates. M-mode echocardiographic and Doppler flow studies of diabetic mice at 4 weeks showed a decreased wall thickening and increased E/A ratio, supporting both systolic and diastolic dysfunction. CONCLUSION: Our study demonstrates that MRI interrogation can identify the onset of diabetic cardiomyopathy in mice with its impaired functional capacity and altered morphology. The MRI technique will lend itself to repetitive study of early changes in cardiac function in small animal models of diabetic cardiomyopathy

Biaxial mechanical data of porcine atrioventricular valve leaflets

This dataset contains the anisotropic tissue responses of porcine atrioventricular valve leaflets to force-controlled biaxial mechanical testing. The set includes the first Piola-Kirchhoff Stress and the specimen stretches (λ) in both circumferential and radial tissue directions (C and R, respectively) for the mitral valve anterior and posterior leaflets (MVAL and MVPL), and the tricuspid valve anterior, posterior, and septal leaflets (TVAL, TVPL, and TVSL) from six porcine hearts at five separate force-controlled biaxial loading protocols. This dataset is associated with a companion journal article, which can be consulted for further information about the methodology, results, and discussion of this biaxial mechanical testing (Jett et al., https://doi.org/10.1016/j.jmbbm.2018.07.024)Support from the American Heart Association Scientist Development Grant (SDG) Award (16SDG27760143) is gratefully acknowledged. CHL was in part supported by the institutional start-up funds from the School of Aerospace and Mechanical Engineering (AME) and the research funding through the Faculty Investment Program from the Research Council at the University of Oklahoma (OU). SJ, RK, and DL were supported by the Mentored Research Fellowship from the Office of Undergraduate Research at OU. KK was supported by the Undergraduate Research Opportunities Program from the Honors College at OU. Open Access charges for this publication provided by University of Oklahoma Libraries Open Access Fund.Ye

Mechanics of the tricuspid valve: from clinical diagnosis/treatment, in vivo and in vitro investigations, to patient-specific biomechanical modeling

Proper tricuspid valve (TV) function is essential to unidirectional blood flow through the right side of the heart. Alterations to the tricuspid valvular components, such as the TV annulus, may lead to functional tricuspid regurgitation (FTR), where the valve is unable to prevent undesired backflow of blood from the right ventricle into the right atrium during systole. Various treatment options are currently available for FTR; however, research for the tricuspid heart valve, functional tricuspid regurgitation, and the relevant treatment methodologies are limited due to the pervasive expectation among cardiac surgeons and cardiologists that FTR will naturally regress after repair of left-sided heart valve lesions. Recent studies have focused on (i) understanding the function of the TV and the initiation or progression of FTR using both in-vivo and in-vitro methods, (ii) quantifying the biomechanical properties of the tricuspid valve apparatus as well as its surrounding heart tissue, and (iii) performing computational modeling of the TV to provide new insight into its biomechanical and physiological function. This review paper focuses on these advances and summarizes recent research relevant to the TV within the scope of FTR. Moreover, this review also provides future perspectives and extensions critical to enhancing the current understanding of the functioning and remodeling tricuspid valve in both the healthy and pathophysiological states