We examined the efficacy and side effects of a newly developed contrast agent for intravenous myocardial contrast echocardiography, QW3600 Injection (EchoGen; Sonus Pharmaceuticals, Bothell, Wash.). Doses of 0.1, 0.2, 0.5, and 0.8 ml/kg of this agent were administered intravenously to 8 open-chested dogs. The left ventricular (LV) myocardium was uniformly well opacified for the 0.5 and 0.8 ml/kg doses, for which the peak intensity was an average of 40 gray levels above the baseline intensity. The myocardial opacification persisted even after the contrast echo intensity in the LV cavity had decreased. After ligation of the coronary artery, the area at risk was clearly delineated by the same doses. The agent emulsion and dissolved bubbles were examined microscopically in vitro and in vivo to elucidate the mechanism of prolonged opacification. A microscopic investigation of the mesenteric vessels of a rat indicated that bubbles had formed, growing as large as 30 to 50 microm [corrected] in diameter. The hemodynamic parameters did not change at low doses (0.1 and 0.2 ml/kg), but the systemic pressure fell and the arterial blood oxygen saturation decreased at high doses (0.5 and 0.8 ml/kg). EchoGen provides prolonged contrast for myocardial contrast echocardiography via peripheral venous administration, although the hemodynamic parameters deteriorate at high doses.

Animals↗

PubMedDate not supplied

Disruption of the blood-brain barrier caused by nonionic contrast medium used for abdominal angiography: CT demonstration.

We describe a case of disruption of the blood-brain barrier (BBB) by nonionic, low osmolality contrast medium after abdominal angiography. One plausible explanation of this event is that acute hypertension during angiography may have increased the BBB permeability, allowing the contrast medium to leak across it.

Aged↗

PubMedDate not supplied

Acute parietal and chief cell changes induced by a lethal dose of lipopolysaccharide in mouse stomach before thrombus formation.

The common lipopolysaccharide (LPS)-induced gastric lesions, such as erosions or ulcers, have been investigated in depth. Little is known, however, about the acute gastric lesions following a high dose of LPS. In a time-course study, ICR female mice were given a high subcutaneous dose of LPS (50 mg/kg). Mice were sacrificed at 4, 6, 12, and 24 hours after dosing and were assessed histopathologically for acute gastric lesions. The major gastric changes were seen in the fundic region and included vacuolar degeneration of parietal cells and apoptosis of chief cells. The vacuole in parietal cells was apparent as early as 4 hours postinjection (PI), and apoptosis of chief cells was apparent at 12 hours PI. Thrombus formation, in contrast, was not seen until 24 hours PI. No erosion, ulcer, or hemorrhage was seen in any gastric region in any of the treated animals at 24 hours PI. These results indicate that a subcutaneous high dose of LPS in mice causes vacuolar degeneration of parietal cells and apoptosis of chief cells before thrombus formation or subsequent ulcerative lesions.

Acute Disease↗

PubMedDate not supplied

Treatment of ras-induced cancers by the F-actin-bundling drug MKT-077.

A rhodacyanine dye called MKT-077 has shown a highly selective toxicity toward several distinct human malignant cell lines, including bladder carcinoma EJ, and has been subjected to clinical trials for cancer therapy. In the pancreatic carcinoma cell line CRL-1420, but not in normal African green monkey kidney cell line CV-1, it is selectively accumulated in mitochondria. However, both the specific oncogenes responsible for its selective toxicity toward cancer cells, and its target proteins in these cancer cells, still remain to be determined. This study was conducted using normal and ras-transformed NIH 3T3 fibroblasts to determine whether oncogenic ras mutants such as v-Ha-ras are responsible for the selective toxicity of MKT-077 and also to identify its targets, using its derivative called "compound 1" as a specific ligand. We have found that v-Ha-ras is responsible for the selective toxicity of MKT-077 in both in vitro and in vivo. Furthermore, we have identified and affinity purified at least two distinct proteins of 45 kD (p45) and 75 kD (p75), which bind MKT-077 in v-Ha-ras-transformed cells but not in parental normal cells. Microsequencing analysis has revealed that the p45 is a mixture of beta- and gamma-actin, whereas the p75 is HSC70, a constitutive member of the Hsp70 heat shock adenosine triphosphatase family, which inactivates the tumor suppressor p53. MKT-077 binds actin directly, bundles actin filaments by cross-linking, and blocks membrane ruffling. Like a few F-actin-bundling proteins such as HS1, alpha-actinin, and vinculin as well as F-actin cappers such as tensin and chaetoglobosin K (CK), the F-actin-bundling drug MKT-077 suppresses ras transformation by blocking membrane ruffling. These findings suggest that other selective F-actin-bundling/capping compounds are also potentially useful for the chemotherapy of ras-associated cancers.

3T3 Cells↗