Dual energy CT for the assessment of reperfused chronic infarction - a feasibility study in a porcine model.

BACKGROUND: Detection of myocardial infarction has been the focus of considerable research over the past few decades. Recently developed dual source computed tomography (DSCT) scanners with dual energy mode have been used to detect myocardial infarction, but the studies on this topic are few. PURPOSE: To evaluate the feasibility and performance of dual energy CT (DECT) during arterial phase in coronary CT angiography for the detection of chronic infarction compared with late enhancement MRI (LE-MRI) and histopathology in a porcine model of reperfused myocardial infarction. MATERIAL AND METHODS: Myocardial infarctions were induced by 30 min occlusion of the proximal left anterior descending coronary artery in eight minipigs. DECT, post-contrast LE-MRI and histopathology were performed 60 days after infarct induction. The CT scan was performed in dual energy mode using a dedicated protocol. Myocardial iodine distribution was superimposed as color maps on grey scale multiplanar reformats of the heart. Two radiologists in consensus interpreted all imaging studies for presence of gadolinium uptake at LE-MRI reduced iodine content at DECT and hypoenhanced areas in the initial 100 kV coronary CT angiography images that were acquired during the DECT-acquisition. Results were compared with histopathology. RESULTS: Based on evaluable segments, DECT showed a sensitivity and specificity of 0.72 and 0.88; LE-MRI showed a sensitivity and specificity of 0.78 and 0.92; and the 100 kV data-set of the DECT scan showed a sensitivity and specificity of 0.60 and 0.93, respectively, for the detection of histological proved ischemia. CONCLUSION: DECT during arterial phase coronary CT angiography, which is ordinarily used for coronary artery evaluation, is feasible for the detection of a chronic reperfused myocardial infarction.

Growth hormone supplementation increased latency to tumourigenesis in Atm-deficient mice.

Growth hormone (GH) is important for cell growth and differentiation, has multiple effects on lymphoid tissue and may promote blast cell proliferation and cancer development. We studied the effect of GH on longevity and tumour formation in Atm-deficient mice, an established model of the human cancer prone syndrome ataxia telangiectasia (AT). AT is a devastating recessive disorder that is characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability and cancer susceptibility. Since AT patients also show endocrinological abnormalities the question has been raised as to whether GH therapy could be beneficial and/or increase the cancer risk in AT. We found that treatment with GH significantly increased longevity of Atm-deficient mice. In addition, GH ameliorated locomotoric behaviour and improved T-cell immunity. Thus, our data demonstrated that GH treatment is not necessarily accompanied by increased cancer development in diseases with chromosomal instability and cancer susceptibility and might be beneficial for AT patients.

Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis.

Spontaneous and experimental metastasis can be effectively inhibited by the widely used anticoagulant heparin in different tumor models. At the cellular level, many of the antimetastatic effects of heparin in vivo are due to its action on P-selectin-mediated binding. Whereas previous attention has focused on P-selectin-dependent tumor-cell-platelet interactions in blood-borne metastasis, we sought to address the potential contribution of endothelial P-selectin expression to adhesive events between the microvasculature and melanoma cells in vivo. Transplantation of bone marrow from P-selectin-deficient into wild-type mice conveyed inhibition of ex-perimental melanoma metastasis. However, the extent to which bone marrow-conferred lack of platelet P-selectin expression attenuated melanoma lung metastasis was significantly less than that seen in P-selectin-deficient mice, suggesting that endothelial P-selectin expression may additionally contribute to formation of hematogenous metastases. This assumption was supported by our intravital microscopy studies, in which a significant proportion of melanoma cells were capable of directly interacting with postcapillary venules of the murine ear in a P-selectin-dependent manner. Heparin not only inhibits P-selectin-mediated melanoma cell rolling but also attenuates melanoma metastasis formation in vivo, further supporting the concept that endothelial P-selectin expression may represent an additional target of heparin action in experimental melanoma lung metastasis.

Activated, not resting, platelets increase leukocyte rolling in murine skin utilizing a distinct set of adhesion molecules.

Selectin-mediated tethering and rolling initiates the multi-step process of leukocyte extravasation which is crucial for the formation of an inflammatory infiltrate. We studied the impact of platelets on this process in the skin. Using intravital microscopy, we analyzed platelet interactions with cutaneous post-capillary venules of mouse ears and observed an increase in platelet rolling if platelets were activated (41.6+/-20.2% vs. 13.1+/-8.5% rolling of resting platelets). Experiments with P-selectin deficient mice and antibodies blocking either P-selectin, GPIIb/IIIa or GPIb showed that rolling depends on platelet PSGL-1 and GPIIb/IIIa on one hand, and endothelial P-selectin on the other. Next, formation of platelet-leukocyte aggregates was demonstrated by simultaneous observation of platelets and leukocytes in vivo utilizing a newly developed two-color technique. Aggregates increased overall leukocyte rolling (leukocytes alone: 27.4+/-11.2%, leukocytes with resting platelets: 25.3+/-10.2%, leukocytes with activated platelets 38.1+/-11.8%). To investigate if activated platelets may contribute to the pathogenesis of chronic cutaneous inflammation, platelet P-selectin expression was studied in 8 patients with psoriasis. A correlation between platelet P-selectin expression and disease severity was established. In summary, we show that activated, not resting, platelets increase leukocyte rolling in murine skin. This increased rolling is due to the aggregate formation of platelets with leukocytes. We also provide evidence for a potential role of this mechanism in the pathogenesis of chronic inflammatory skin diseases.

Dual-energy computed tomography for the detection of late enhancement in reperfused chronic infarction: a comparison to magnetic resonance imaging and histopathology in a porcine model.

OBJECTIVES: To evaluate the performance of late enhancement dual-energy CT (LE-DECT) for the detection of infarcted myocardium as compared with 1.5-T late enhancement magnetic resonance imaging (LE-MRI) in a porcine model of reperfused chronic myocardial infarction (MI), using histopathology as standard of reference. MATERIALS AND METHODS: In 8 healthy minipigs, MI was induced by 30-minute balloon occlusion of the left anterior descending coronary artery. Sixty-one ± 4 days after left anterior descending coronary artery occlusion, LE-DECT was performed 5, 10, and 15 minutes subsequent to contrast material injection. Therefore, a dual-source CT scanner (Somatom Definition, Siemens Healthcare, Forchheim, Germany) was used in dual-energy mode with the following protocol: tube potential/current 140 kV/95 mAs on tube A and 100 kV/165 mAs on tube B, collimation 2 × 32 × 0.6 mm, 1.5 mL/kg contrast material injected at 3 to 4 mL/s. Myocardial iodine distribution was calculated from the dual-energy data and superimposed on the gray scale multiplanar reformats of the heart in short-axis view. Fifty ± 12 minutes after LE-DECT imaging, 1.5-T LE-MRI (Magnetom Avanto, Siemens Healthcare, Forchheim, Germany) was performed 10 minutes successive to injection of contrast material using phase-sensitive inversion recovery sequences. For all pigs investigated, 2,3,5-triphenyltetrazolium chloride staining and histopathology of stained-tissue samples were acquired. Two experienced radiologists assessed all imaging studies in a random manner and were blinded to the results of the other techniques for the presence of late enhancement (LE). The American Heart Association 17-segment model was used to compare the results of LE-DECT, 100 kV grayscale LE images, LE-MRI, and histopathology. Size of MI was calculated for histopathological findings, LE-MRI, LE-DECT, and 100 kV grayscale LE images 10 minutes after contrast agent injection. Agreement between infarct size assessed with imaging modalities and histopathology was evaluated with Bland-Altman analysis. RESULTS: Of the 136 myocardial segments in 8 minipigs, histopathology found MI in 27 segments. Diagnostic per-segment sensitivities and specificities for 100 kV grayscale LE images, LE-DECT images, and MR images obtained 10 minutes after contrast agent injection for both the readers were 0.62, 0.77, 0.79 and 0.97, 0.92, 0.94, respectively. Although sensitivities were higher for LE-DECT and LE-MRI than for 100 kV grayscale images, no statistically significant difference for the diagnostic accuracies of 100 kV grayscale LE images, LE-DECT images, and MR images (0.9, 0.89, 0.9) existed 10 minutes successive to contrast agent injection (all P > 0.05). Infarct size for LE-MRI, LE-DECT, and 100 kV grayscale LE images correlated well with histopathological findings (r = 0.97, 0.96, and 0.94; all P < 0.01). CONCLUSIONS: This feasibility study shows a high accuracy and a good correlation of LE-DECT and LE-MRI to histopathology for the detection of LE in a porcine model of reperfused chronic MI.

Lowering of tumor interstitial fluid pressure reduces tumor cell proliferation in a xenograft tumor model.

High tumor interstitial fluid pressure (TIFP) is a characteristic of most solid tumors. TIFP may hamper adequate uptake of macromolecular therapeutics in tumor tissue. In addition, TIFP generates mechanical forces affecting the tumor cortex, which might influence the growth parameters of tumor cells. This seems likely as, in other tissues (namely, blood vessels or the skin), mechanical stretch is known to trigger proliferation. Therefore, we hypothesize that TIFP-induced stretch modulates proliferation-associated parameters. Solid epithelial tumors (A431 and A549) were grown in Naval Medical Research Institute nude mice, generating a TIFP of about 10 mm Hg (A431) or 5 mm Hg (A549). Tumor drainage of the central cystic area led to a rapid decline of TIFP, together with visible relaxation of the tumor cortex. It was found by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis that TIFP lowering yields a decreased phosphorylation of proliferation-associated p44/42 mitogen-activated protein kinase and tumor relaxation. In confirmation, immunohistochemical staining showed a decrease of tumor-associated proliferation marker Ki-67 after TIFP lowering. These data suggest that the mechanical stretch induced by TIFP is a positive modulator of tumor proliferation.