Serial magnetic resonance imaging based assessment of the early effects of an ACE inhibitor on postinfarction left ventricular remodeling in rats

In vivo assessment of treatment efficacy on postinfarct left ventricular (LV) remodeling is crucial for experimental studies. We examined the technical feasibility of serial magnetic resonance imaging (MRI) for monitoring early postinfarct remodeling in rats. MRI studies were performed with a 7-Tesla unit, 1, 3, 8, 15, and 30 days after myocardial infarction (MI) or sham operation, to measure LV mass, volume, and the ejection fraction (EF). Three groups of animals were analyzed: sham-operated rats (n = 6), MI rats receiving lisinopril (n = 11), and MI rats receiving placebo (n = 8). LV dilation occurred on day 3 in both MI groups. LV end-systolic and end-diastolic volumes were significantly lower in lisinopril-treated rats than in placebo-treated rats at days 15 and 30. EF was lower in both MI groups than in the sham group at all time points, and did not differ between the MI groups during follow-up. Less LV hypertrophy was observed in rats receiving lisinopril than in rats receiving placebo at days 15 and 30. We found acceptable within- and between-observer agreement and an excellent correlation between MRI and ex vivo LV mass (r = 0.96; p < 0.001). We demonstrated the ability of MRI to detect the early beneficial impact of angiotensin-converting enzyme (ACE) inhibitors on LV remodeling. Accurate and noninvasive, MRI is the tool of choice to document response to treatment targeting postinfarction LV remodeling in rats

Laboratory experiments on multipolar vortices in a rotating fluid

The instability properties of isolated monopolar vortices have been investigated experimentally and the corresponding multipolar quasisteady states have been compared with semianalytical vorticity-distributed solutions to the Euler equations in two dimensions. A novel experimental technique was introduced to generate unstable monopolar vortices whose nonlinear evolution resulted in the formation of multipolar vortices. Dye-visualization and particle imaging techniques revealed the existence of tripolar, quadrupolar, and pentapolar vortices. Also evidence was found of the onset of hexapolar and heptapolar vortices. The observed multipolar vortices were found to be unstable and generally broke up into multipolar vortices of lesser complexity. The characteristic flow properties of the quadrupolar vortex were in close agreement with the semianalytical model solutions. Higher-order multipolar vortices were observed to be susceptible to strong inertial oscillations. © 2010 American Institute of Physic

New starch-based radiotracer for lung perfusion scintigraphy

PURPOSE: In order to avoid the microbiological risks linked to human serum albumin macroaggregates (MAA) used for lung perfusion scintigraphy, we developed a new starch-based Tc-99m potential radiopharmaceutical. METHODS: Microparticles were prepared from oxidised starch coupled to natural polyamine for Tc-99m complexation. Suspensions were formulated as ready-to-use kits for easy one-step labelling procedures. RESULTS: Particle-size analysis, electron microscopy, and confocal microscopy were performed for microparticle characterisation, and gave a typical size distribution ranging from 7 to 63 microm, with a homogenous population of spherical or oval-shaped microparticles. Radiochemical purity exceeded 95%, and was stable for at least 8 h. When challenged with histidine and human plasma, labelling was also stable. Dynamic scintigraphic acquisitions and biodistribution studies conducted on healthy Wistar rats showed a tracer accumulation with more than 80% of the ID in the lungs after 15 min. CONCLUSIONS: With clinically significant characteristics such as a lung half-life of 3 h, a lung-to-vascular ratio of 900, and a lung-to-liver ratio of 90, starch-based microparticles exhibit all the qualities for an effective new lung perfusion agent

Experimental models of disseminated scedosporiosis with cerebral involvement

Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients. Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects. Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps. To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula were administered via the penile vein and a clinical scale (0-9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test. Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining. Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i.v. or oral routes, respectively. Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole. Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling

Volumetric assessment of myocardial viability in rats using 3D double contrast enhanced T1 and T2-weighted MRI

OBJECTIVE: Volumetric evaluation of the myocardial viability post-infarction in rats using 3D in vivo MR imaging at 7 T using injection of an extracellular paramagnetic contrast agent and intravascular superparamagnetic iron oxide nanoparticles in the same imaging session. MATERIALS AND METHODS: Five hours after induction of permanent myocardial infarction in rats (n=6), 3D in vivo T1- and T2-weighted MR Imaging was performed prior to and after Gd-DOTA injection (0.2 mmol/kg) and prior to and after nanoparticle injection (5 mg Fe/kg) to assess infarct size and myocardial viability. RESULTS: 3D MR Imaging using a successive contrast agent injection showed a difference of infarct size after Gd-DOTA injection on T1-weighted images compared to the one measured on T2-weighted images after Gd-DOTA and nanoparticle injection. CONCLUSION: The use of 3D T1- and T2-weighted MR Imaging using a double contrast agents protocol made possible the accurate characterization of myocardial infarction volume and allowed the detection of myocardial viability post-infarction in rats

In vitro and in vivo evaluation of superparamagnetic iron oxide nanoparticles coated by bisphosphonates: the effects of electrical charge and molecule length.

Physicochemical coating properties are often considered to be determining factors for in vivo characteristics of superparamagnetic iron oxide nanoparticles, used as contrast agent in Magnetic Resonance Imaging (MRI). To investigate the electrical charge (modified by zero, one or two ammonium groups) and the molecule length (3, 5 or 7 methylene chains) effects of bisphosphonate-type coatings, we assessed the complement activation, in vivo plasma and tissue relaxation time alterations of intravenously injected small iron oxide nanoparticles (<25 nm) on male healthy Wistar rats. The presence of ammonium groups induces a weak activation of the complement whatever the size and the concentration of particles, whereas hydroxyethylenebisphosphonate (HEBP)-coated particles are poor complement activators only at the lowest concentration. In vivo, HEBP-coated nanoparticles have the greatest prolonged relaxation time effects, despite their higher negative electrical charge, contrary to two ammonium bearing coatings. No significant differences were observed between mono-ammonium molecular coatings

High throughput screening for identification of mycolactone targets : Relations between M. ulcerans and nervous system

Buruli ulcer is an infectious disease transmitted by arthropod vectors harboring Mycobacterium ulcerans, a mycobacterium which belong to the same family of bacteria causing tuberculosis and leprosy. The infection causes painless swelling and severe skin lesions. One key feature of M. ulcerans bacterium is its ability to secrete a necrotic toxin, the mycolactone within small lipophilic vesicles, which are critical for the bacterial induced cytotoxicity. The biological knowledge as well as the preventive and therapeutic means for this invalidating disease is still very limited.   Our first approach was to investigate whether the mycolactone toxin could be involved in the neutralization of pain by acting directly on the peripheral nervous system without causing destruction of nervous fibers. By use of live time fluorescence microscopy and appropriate markers, we showed that the addition of toxin at sub-toxic dose provokes modification of ionic currents of neuron cells. Based on this ability of the toxin, a molecular high throughput methodology was developed for the screening of a genome wide siRNA library and small molecules inhibitors to enable the search of the cellular targets for the toxin. The cell-based assay relies on automated confocal microscopy on macrophages coupled with dedicated image analysis. These two screening allowed us to identify a putative toxin target, and a toxin inhibitor. A binding assay confirmed that the putative target is a receptor of the toxin. Together these results allowed us to build a potential signaling pathway activated by the mycolactone and implicated in ionic channel activities.   The second approach was to confirm this model in the mouse model of M. ulcerans infection and its role in the hypoesthesia of the lesions. Toxin inhibitor, daily administered to mice, which were experimentally infected by M. ulcerans, conducted to the absence of the hypoesthesia of the lesions. Furthermore, a histological study of neuronal fibers did not show a destruction of neuronal cells. Moreover, in vitro studies have showed that M. ulcerans are able to colonize neuronal cells. Then, these results suggested that the hypoesthesia of the M. ulcerans lesions could be caused by a non-destructive process of nervous cells.

Assessment of myocardial viability in rats: Evaluation of a new method using superparamagnetic iron oxide nanoparticles and Gd-DOTA at high magnetic field

The aim of this study was to detect salvageable peri-infarction myocardium by MRI in rats after infarction, using with a double contrast agent (CA) protocol at 7 Tesla. Intravascular superparamagnetic iron oxide (SPIO) nanoparticles and an extracellular paramagnetic CA (Gd-DOTA) were used to characterize the peri-infarction zone, which may recover function after reperfusion occurs. Infarcted areas measured from T1-weighted (T1-w) images post Gd-DOTA administration were overestimated compared to histological TTC staining (52% +/- 3% of LV surface area vs. 40% +/- 3%, P=0.03) or to T2-w images post SPIO administration (41% +/- 4%, P=0.04), whereas areas measured from T2-w images post SPIO administration were not significantly different from those measured histologically (P=0.7). Viable and nonviable myocardium portions of ischemically injured myocardium were enhanced after diffusive Gd-DOTA injection. The subsequent injection of vascular SPIO nanoparticles enables the discrimination of viable peri-infarction regions by specifically altering the signal of the still-vascularized myocardium