Myocardial Edema Imaging by Cardiovascular Magnetic Resonance: Current Status and Future Potential

Cardiovascular magnetic resonance (CMR) imaging is widely established, free of radioactive material or ionizing radiation, and the accepted noninvasive gold standard for numerous noninvasive cardiac markers. Using a technique called T2-weighted imaging, CMR can be used to assess myocardial edema as a reliable marker for acute, potentially reversible myocardial injury. Contrast agents are not required as the myocardial free water content affects the magnetic properties of the tissue, thus providing inherent image contrast. In this review, we illustrate the utility of T2-weighted techniques in the assessment of myocardial edema in a range of clinical scenarios. The detection of myocardial edema is clinically relevant in many acute settings and may be further helpful to better understand the pathophysiology of many non-acute clinical diseases. Currently, T2-weighted CMR represents the only imaging modality that can accurately depict and quantify the presence of myocardial edema in a noninvasive fashion. Thus, T2-weighted imaging should be included in a comprehensive CMR imaging protocol, especially if an acute injury is suspected.     

Comparison of a parasite lactate dehydrogenase-based immunochromatographic antigen detection assay (OptiMAL) with microscopy for the detection of malaria parasites in human blood samples

Microscopic examination of blood smears remains the gold standard for malaria diagnosis, but is labor-intensive and requires skilled operators. Rapid dipstick technology provides a potential alternative. A study was conducted in The Gambia to compare the performance of OptiMAL, an immunochromatographic antigen detection assay for the diagnosis of malaria using parasite lactate dehydrogenase, against standard microscopy in patients with suspected malaria. For initial diagnosis of Plasmodium falciparum, irrespective of stage, this assay had a sensitivity of 91.3%, a specificity of 92%, a positive predictive value of 87.2%, and a negative predictive value of 94.7%. The sensitivity of the test decreased markedly at parasitemias < 0.01%. This assay can be used for the diagnosis of malaria in areas where microscopy is not available and for urgent malaria diagnosis at night and at weekends, when routine laboratories are closed and when relatively inexperienced microscopists may be on duty.     

Cyclooxygenase-2 activation mediates the proangiogenic effect of nitric oxide in colorectal cancer.

PURPOSE: Up-regulation of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) enzymes has been reported in colorectal cancer. We aimed at evaluating the possible interaction between the nitric oxide and COX-2 pathways, and its effect on promoting tumor angiogenesis. EXPERIMENTAL DESIGN: Expression of iNOS, COX-2, vascular endothelial growth factor (VEGF), and CD31 was analyzed in tumor samples and corresponding normal mucosa obtained from 46 surgical specimens. We also evaluated iNOS activity, prostaglandin E(2) (PGE(2)), cyclic GMP and cyclic AMP production in the same specimens. Nitrite/nitrate levels, and PGE(2) and VEGF production were assessed in HCT116 and HT29 colon cancer cell lines after induction and selective inhibition of the two enzyme pathways. RESULTS: A significant correlation was found between iNOS and COX-2 immunohistochemical expression. PGE(2) production significantly correlated with iNOS activity and cGMP levels. A significant correlation was also found among PGE(2) production, microvessel density, and VEGF expression. Coinduction of both iNOS and COX-2 activities occurred after lipopolysaccharide (LPS) and epidermal growth factor (EGF) treatment in HCT116 and HT29 cells. Inhibition of iNOS by 1400W significantly reduced both LPS- and EGF-induced PGE(2) production. Treatment with LPS, EGF, and arachidonic acid significantly increased VEGF production in the iNOS-negative/COX-2-positive HT29 cells. This effect was completely reversed by treatment with the selective COX-2 inhibitor celecoxib. CONCLUSIONS: Our data showed a prominent role of nitric oxide in stimulating COX-2 activity in colorectal cancer. This interaction is likely to produce a cooperative effect in promoting angiogenesis through PGE(2)-mediated increase in VEGF production.     

Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala

We investigated the effects of agents acting at histamine receptors on both, spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the effects of histamine on cognition might be explained by the modulation of cholinergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modulates the spontaneous release of ACh. The addition of 100 mm KCl to the perfusion medium strongly stimulated ACh release, whereas, 0.5 microm tetrodotoxin (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H3 antagonists (ciproxifan, clobenpropit and thioperamide), directly administered to the BLA, decreased ACh spontaneous release, an effect fully antagonized by the simultaneous perfusion of the BLA with cimetidine, an H2 antagonist. Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H1 antagonists failed to alter ACh spontaneous release. Rats receiving intra-BLA, bilateral injections of the H3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear conditioning, showed memory consolidation impairment of contextual fear conditioning. Post-training, bilateral injections of 50 microg scopolamine also had an adverse effect on memory retention. These observations provide the first evidence that histamine receptors are involved in the modulation of cholinergic tone in the amygdala and in the consolidation of fear conditioning.     

Prediction of coronary events in a low incidence population. Assessing accuracy of the CUORE Cohort Study prediction equation

BACKGROUND: The aims of this paper are to derive a 10-year coronary risk predictive equation for adult Italian men, and to assess its accuracy in comparison with the Framingham Heart Study (FHS) and PROCAM study equations. METHODS: The CUORE study is a prospective fixed-cohort study. Eleven cohorts, from the north and the centre-south of Italy, had been investigated at baseline between 1982 and 1996, adopting MONICA methods to measure risk factors. Among this sample of 6865 men, aged 35-69 years and free of coronary heart disease (CHD) at baseline, 312 first fatal and non-fatal major coronary events occurred in 9.1 years median follow-up. Calibration, as the difference between 10-year predicted and actual risk, and discrimination, as the ability of the risk functions to separate high-risk from low-risk subjects, have been assessed to compare accuracy of the FHS, the PROCAM, and the CUORE study equations. RESULTS: The best CUORE equation includes age, total cholesterol, systolic blood pressure, cigarette smoking, HDL-cholesterol, diabetes mellitus, hypertension drug treatment, and family history of CHD (area under the ROC curve = 0.75). The uncalibrated estimates of the 10-year risk in this CUORE follow-up data were 0.093 and 0.109 higher (P < 0.05) from the Framingham and PROCAM risk scores, respectively, than the Kaplan-Meier estimate for CUORE, indicating risk overestimates for both equations. Standard recalibration techniques improved accuracy of the FHS equation only. PROCAM overestimates were prominent in the higher risk deciles. With an alternative method for recalibration better risk estimates were obtained, but a cohort study was needed to obtain a properly calibrated risk equation. CONCLUSIONS: The CUORE Project predictive equation showed better accuracy of the FHS and PROCAM equations, overcoming frequently reported risk overestimates. The CUORE equation may be adopted to identify men with high coronary risk in Italy.     

Physicochemical and biopharmaceutical characterization of endo-2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1H-benz[e]isoindol-1-one (CR3124) a novel potent 5-HT3 receptor antagonist

The physicochemical and biopharmaceutical properties, such as pK(a), crystal habit, water solubility, logD, molecular structure and dynamics, and membrane permeability of CR3124 (endo-2-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-1H-benz[e]isoindol-1-one, a novel potent 5-HT(3) receptor antagonist) have been studied in order to obtain preformulation information. The study showed that CR3124 is a very rigid molecule in which conformational freedom due to the presence of a rotatable bond is restricted by the interaction between an activated hydrogen and the amide oxygen and the conformation of the tropane piperidine ring is regulated by the environment in such a manner as to optimize the intermolecular interactions with the solvent. This chameleon behavior appears to be capable of explaining the biopharmaceutical properties showed by CR3124, such as low wettability, relatively good solubility, and very high membrane permeability.     

In vitro cultivation of Cryptosporidium parvum and screening for anticryptosporidial drugs.

Sporozoites of Cryptosporidium parvum which were excysted in vitro from oocysts isolated from calves or patients with acquired immune deficiency syndrome underwent development in monolayers of the mouse fibroblast cell line L929. Asexual multiplication occurred, with the maximum numbers of parasites usually being observed between 24 and 48 h after infection. Gametocytes were also found, but their numbers were relatively small compared with those of the asexual stages. A study was made of the effect on parasite development of 20 antimicrobial agents, most of which were anticoccidial or antimalarial agents. The majority of the drugs had a limited inhibitory effect on parasite development, but usually only at high concentrations. The two most active drugs were monensin and halofuginone, which reduced parasite multiplication by more than 90% at high concentrations. In the case of monensin, however, inhibition of parasite development at higher concentrations was due, at least in part, to a toxic effect of the drug on the host cells.     

Biliary complications after living donor adult liver transplantation.

The highest rate of complications characterizing the adult living donor liver transplantation (ALDLT) are due to biliary problems with a reported negative incidence of 22-64%. We performed 23 ALDLT grafting segments V-VIII without the middle hepatic vein from March 2001 to September 2005. Biliary anatomy was investigated using intraoperative cholangiography alone in the first five cases and magnetic resonance cholangiography in the remaining 18 cases. In 13 cases we found a single right biliary duct (56.5%) and in 10 we found multiple biliary ducts (43.7%). We performed single biliary anastomosis in 17 cases (73.91%) and double anastomosis in the remaining six (26%) cases. With a mean follow up of 644 days (8-1598 days), patient and graft survivals are 86.95% and 78.26%, respectively. The following biliary complications were observed: biliary leak from the cutting surface: three, anastomotic leak: two, late anastomotic strictures: five, early kinking of the choledochus: one. These 11 biliary complications (47.82%) occurred in eight patients (34.78%). Three of these patients developed two consecutive and different biliary complications. Biliary complications affected our series of ALDLT with a high percentage, but none of the grafts transplanted was lost because of biliary problems. Multiple biliary reconstructions are strongly related with a high risk of complication.     

Molecular analysis of cell-free circulating DNA for the diagnosis of somatic mutations associated with resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

In non-small-cell lung cancer, the molecular diagnosis of somatic mutations is instrumental for the choice of the most appropriate treatment. However, despite an initial response, resistance to tyrosine kinase inhibitors occurs and thereafter tumors progress. For this reason, next generation inhibitors able to overcome acquired resistances are currently in development. Therefore, the identification of the molecular determinants of resistance is needed to adapt treatment accordingly. The analysis of circulating cell-free tumor DNA represents a powerful tool to monitor the somatic changes induced by treatment. This review focuses on the most recent advantages in the diagnosis of acquired resistance in circulating cell-free tumor DNA and underlines the strategies ready to be translated in the clinical practice.