Sources of hepatic triglyceride accumulation during high-fat feeding in the healthy rat

Hepatic triglyceride (HTG) accumulation from peripheral dietary sources and from endogenous de novo lipogenesis (DNL) was quantified in adult Sprague-Dawley rats by combining in vivo localized 1H MRS measurement of total hepatic lipid with a novel ex vivo 2H NMR analysis of HTG 2H enrichment from 2H-enriched body water. The methodology for DNL determination needs further validation against standard methodologies. To examine the effect of a high-fat diet on HTG concentrations and sources, animals (n = 5) were given high-fat chow for 35 days. HTG accumulation, measured by in vivo 1H MRS, increased significantly after 1 week (3.85 ± 0.60% vs 2.13 ± 0.34% for animals fed on a standard chow diet, P < 0.05) and was maintained until week 5 (3.30 ± 0.60% vs 1.12 ± 0.30%, P < 0.05). Animals fed on a high-fat diet were glucose intolerant (13.3 ± 1.3 vs 9.4 ± 0.8 mM in animals fed on a standard chow diet, for 60 min glycemia after glucose challenge, P < 0.05). In control animals, DNL accounted for 10.9 ± 1.0% of HTG, whereas in animals given the high-fat diet, the DNL contribution was significantly reduced to 1.0 ± 0.2% (P < 0.01 relative to controls). In a separate study to determine the response of HTG to weaning from a high-fat diet, animals with raised HTG (3.33 ± 0.51%) after 7days of a high-fat diet reverted to basal HTG concentrations (0.76 ± 0.06%) after an additional 7 days of weaning on a standard chow diet. These studies show that, in healthy rats, HTG concentrations are acutely influenced by dietary lipid concentrations. Although the DNL contribution to HTG content is suppressed by a high-fat diet in adult Sprague-Dawley rats, this effect is insufficient to prevent overall increases in HTG concentrations. Copyright © 2008 John Wiley & Sons, Ltd

τ-regioselective addition of (-)-Nα -tert-butoxycarbonyl-L-histidine methyl ester to diethyl fumarate

Addition of (-)-Nα-tert-butoxycarbonyl-L-histidine methyl ester to diethyl fumarate regioselectively yielded diethyl 2-[4-(2-methoxycarbonyl-2-tert-butoxycarbonylaminoethyl) imidazol-1-yl] succinate as a 1:1 mixture of diastereomers. These compounds were identified by NMR using (Eu(fod)3 as a stereospecific shift reagent, but were impossible to separate and characterise independently. Neutral hydrolysis of the mixture yielded the corresponding deprotected diastereomeric N τ-(2-ethoxycarbonyl-1-carboxy)ethyl-L-histidine.This work was supported by Community of Madrid (Grupo Estratégico 2000-2003), NIH, grant R01CA77575, and SAF 2001-2245.Peer Reviewe

The subcellular metabolism of water and its implications for magnetic resonance image contrast

Peer reviewe

Oxygenation imaging by nuclear magnetic resonance methods

Oxygen monitoring is a topic of exhaustive research due to its central role in many biological processes, from energy metabolism to gene regulation. The ability to monitor in vivo the physiological distribution and the dynamics of oxygen from subcellular to macroscopic levels is a prerequisite to better understand the mechanisms associated with both normal and disease states (cancer, neurodegeneration, stroke, etc.). This chapter focuses on magnetic resonance imaging (MRI) based techniques to assess oxygenation in vivo. The first methodology uses injected fluorinated agents to provide quantitative pO2 measurements with high precision and suitable spatial and temporal resolution for many applications. The second method exploits changes in endogenous contrasts, i.e., deoxyhemoglobin and oxygen molecules through measurements of T2* and T1, in response to an intervention to qualitatively evaluate hypoxia and its potential modulation.Method development and application supported in part by CPRIT RP140399, RP120670-03, P30 CA142543, and P41 EB015908.Peer reviewe

Gd(III)-EPTPAC16, a new self-assembling potential liver MRI contrast agent: in vitro characterization and in vivo animal imaging studies

The recently reported amphiphilic chelate, [Gd(EPTPAC16)(H2O)]2-, forms supramolecular aggregates in aqueous solution by self-assembly of the monomers with a relaxometrically determined critical micellar concentration (CMC) of 0.34 mM. The effect of sonication on the aggregate size was characterized by dynamic light scattering and relaxometry, indicating the presence of premicellar aggregates and an overall decrease in aggregate size and polydispersity upon sonication, slightly below the CMC. {[153Sm](EPTPAC16)(H2O)}2- radiotracer was evaluated in vivo from gamma scintigraphy and biodistribution in Wistar rats. It was found to depend strongly on the sample concentration, below or above the CMC, and its sonication, in a way that correlates with the effect of the same factors on the size of the aggregates formed in solution. Below CMC, the very large aggregates of the [153Sm]3+-labeled chelate were persistently and mainly taken up by the lungs, and also by the macrophage-rich liver and spleen. Sonication of this solution led to loss of the lung uptake. Above CMC, the metal chelate was mainly taken up by the liver, with very little uptake by the spleen and lungs. In vivo, dynamic contrast-enhanced (DCE)-MRI evaluation of the micellar [Gd(EPTPAC16)(H2O)]2- compound in Wistar rats showed a persistent hepatic positive-contrast effect in T1-weighted images, qualitatively similar to the clinically established GdIII-based hepatobiliary-selective agents. No enhancement effect was observed in the lungs because of the scarcity of mobile protons in this organ, despite the scintigraphic evidence of significant lung retention of the [153Sm]3+-labeled chelate at concentrations below the CMC. Copyright © 2007 John Wiley & Sons, Ltd

Amide conjugates of the DO3A-N-(alpha-amino)propionate ligand: leads for stable, high relaxivity Contrast Agents for MRI?

International audienceA novel synthetic methodology for preparing amide conjugates of the DO3A-N-(α-amino)propionate chelator is described, using the synthesis of the DO3A-N-(α-benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N-(α-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+) . The Gd[DO3A-N-(α-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A-N-(α-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents

Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies

The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [153Sm]3+ or Gd3+ complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled [153Sm]-DOTAGal2 by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50% by the presence of its high-affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmacokinetic studies on Wistar rats using the [153Sm]3+-labeled glycoconjugates show a high uptake in the receptor-rich organ liver of the radiolabeled compounds containing terminal galactosyl groups, but very little uptake for those compounds with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd3+ chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. This probably results from the quick wash-out from the liver of these highly hydrophilic complexes, before they can be sufficiently concentrated within the hepatocytes via receptor-mediated endocytosis. Copyright © 2006 John Wiley & Sons, Ltd

Riscos en incendis de vehicles de nova generació

Les actuacions de bombers en operatius d'extinció d'incendis, habitualment es fan per inèrcies històriques. Ara, si diem: “Per a l'extinció d'un incendi de un vehicle heu d'estacionar l’autobomba a una certa distància, pendent amunt i a contravent, refrigerar a distància el vehicle amb con d'atac, i evitar els extrems del vehicle”, segurament més d'un pensarà o expressarà en veu alta “Això deu ser una broma, oi? Si hem estat apagant cotxes cada dia a la nostra manera… quin és el problema?". Bé, doncs n’hi ha uns quants, de problemes. Podem considerar un incendi en un vehicle com una bomba de temps amb un ble que s'encén abans de l'arribada de la dotació de bombers. Les actuacions inicials en aquests incendis han de centrar-se en la desactivació d'aquesta metxa. Els incendis en vehicles presenten una múltiple varietat perills reals. Els canvis en el disseny i la construcció d'automòbils exigeixen un canvi en la manera com els serveis de bombers s’enfronten als incendis de vehicles. Els nous materials i components incorporats a la indústria automobilística s'han traduït en un millor rendiment, una major economia de combustible, una millor resistència al xoc i en una reducció de les emissions de gasos. Malauradament, alguns d'aquests mateixos materials i components fan que l’extinció d’un automòbil modern sigui més difícil i perillosa que en vehicles més vells. En l’actualitat, un incendi d’un vehicle comporta més fums, més toxicitat, més temperatura, elements sotmesos a pressió, risc de projecció d’elements i la possibilitat d’energies alternatives... en definitiva, molts més riscos. Per donar una resposta adequada a aquest augment del risc, organitzativament cal augmentar les mesures preventives de seguretat, i operativament cal una estratègia d’extinció més cautelosa, tàctiques menys agressives i un major nivell de protecció personal