Indirect computed tomography lymphography using iodinated nanoparticles to detect cancerous lymph nodes in a cutaneous melanoma model.

RATIONALE AND OBJECTIVES: To evaluate differences in contrast uptake in normal and cancerous lymph nodes on indirect computed tomography (CT) in swine, we conducted lymphographic examinations after subcutaneous injection of a lymphotropic iodinated nanoparticle suspension. METHODS: Perilesional subcutaneous contrast injections (2 ml per lesion) of a 15% wt/vol iodinated nanoparticle suspension were made in immature Sinclair miniature swine (n = 5) with cutaneous melanomas. Average attenuation, iodine concentration, node volume, and total iodine uptake were estimated on the CT scans for each opacified lymph node 24 hr after injection. Nodes were classified as normal or cancerous microscopically, and the percentage of tumor replacement was estimated in cancerous nodes. RESULTS: Average attenuation and iodine concentration were higher in normal nodes, and total iodine uptake was higher in cancerous nodes with greater than 25% replacement (p < .05). Architectural alterations in opacified cancerous nodes included medullary filling defects, expansile cortical lesions, and disruption of corticomedullary junctions. CONCLUSION: Quantitative and qualitative differences in iodinated nanoparticle enhancement characteristics are useful in distinguishing between normal and cancerous lymph nodes on indirect CT lymphography examinations.

Indirect computed tomography lymphography using iodinated nanoparticles: time and dose response in normal canine lymph nodes.

RATIONALE AND OBJECTIVES: We evaluated the effect of time and dose on lymph node iodine uptake after subcutaneous or submucosal administration of iodinated nanoparticles used for computed tomography lymphography. METHODS: We injected 0.1-6 ml of a 15% wt/vol iodinated nanoparticle suspension into the distal extremities subcutaneously (n = 5) or into the buccal submucosa (n = 7) of normal dogs. Precontrast and 4, 12, 24, and 48 hr after contrast administration, CT scans of opacified lymph nodes were obtained. Iodine concentration, node volume, and total iodine uptake were estimated for each node. RESULTS: All estimated parameters increased between 4 and 12 hr postcontrast (p < .05), with no significant increase thereafter. At 24 hr postcontrast, iodine concentration ranged from 0.01 to 16.1 mg/ml (47-568 Hounsfield units). The average iodine concentration and total iodine uptake increased with contrast dose (p < .05) for all lymph node groups evaluated. Node opacification also revealed internal architectural detail. CONCLUSION: Subcutaneous and submucosal injections of iodinated nanoparticles result in a dose-dependent iodine uptake in targeted lymph nodes. In addition, architectural detail within opacified nodes can be visualized.

Indirect computed tomography lymphography of subdiaphragmatic lymph nodes using iodinated nanoparticles in normal dogs.

RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an iodinated particulate contrast agent for indirect computed tomography (CT) lymphography of normal subdiaphragmatic lymph nodes in dogs. METHODS: Four milliliters of a 15% (wt/vol) iodinated nanoparticle suspension was injected into the gastric, colonic, rectal, or cervical submucosa, loose paraprostatic fascia, or metatarsal subcutaneous tissues in 10 healthy beagles. Endoscopic, CT, or ultrasound guidance was used when necessary to facilitate contrast agent delivery. CT and radiographic images were obtained prior to contrast administration and at 4 hr, 24 hr, and 7 days postcontrast injection. Postmortem examinations were then conducted. RESULTS: CT images showed enhancement of regional lymph nodes draining the various injection sites. The mean attenuation of opacified nodes was 678 +/- 463 Hounsfield units 24 hr after injection and remained elevated 7 days later. Lymph node opacification on CT images correlated well with the node location observed on postmortem examinations. CONCLUSION: Subdiaphragmatic lymph nodes can be effectively opacified using an iodinated nanoparticle contrast agent for indirect CT lymphography.

Iodinated nanoparticles for indirect computed tomography lymphography of the craniocervical and thoracic lymph nodes in normal dogs.

RATIONALE AND OBJECTIVES: We evaluated the imaging characteristics of an interstitially or intraperitoneally delivered iodinated particulate contrast agent for computed tomography (CT) lymphography of the craniocervical and thoracic lymph nodes. METHODS: We injected 2-4 ml of 15% wt/vol iodinated nanoparticle suspension subcutaneously, submucosally, or intraperitoneally in eight normal dogs. CT and plain radiographic images were obtained prior to contrast administration and 4 hr, 24 hr, and 7 days after injection. Correlation was made to detailed postmortem assessment. RESULTS: CT images showed enhancement of regional nodes draining injection sites. Mean attenuation of opacified nodes was 313 +/- 297 (mean +/- standard deviation), 536 +/- 453, and 492 +/- 372 Hounsfield units at 4 hr, 24 hr, and 7 days postinjection, respectively. Lymph node opacification on CT images correlated well with node location found at postmortem. CONCLUSION: Craniocervical and thoracic lymph nodes can be effectively opacified from interstitial or intraperitoneal delivery of this iodinated nanoparticulate contrast agent.

Glutathione as a determinant of cellular response to doxorubicin.

We have studied in detail the relationship between glutathione (GSH) depletion and sensitivity of HEp3 human carcinoma cells to doxorubicin [Adriamycin (ADR)]. Exponentially growing HEp3 cells were incubated with L-buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, for different periods so that a range of GSH depletion could be obtained. These GSH-depleted cells were then treated with a combination of BSO and ADR (1 microgram/ml) for various durations. Under these conditions, the cytotoxicity of ADR was significantly enhanced by GSH depletion. The extent of ADR dose enhancement was found to be inversely proportional to cellular GSH level at the time of ADR treatment. Furthermore, it was shown that the dose-enhancement factors (DEF) also correlated with the duration of combined BSO and ADR treatment. For example, at a GSH level of 45% of untreated control, 18.5 +/- 3 fmol/cell or 4.8 +/- 0.3 X 10(-3) fmol/mum3 (+/- SD), DEF of 8.0, 6.4, and 5.0 were obtained for treatment periods of 3 hours, 2 hours, and 1 hour, respectively. Further study showed that the GSH kinetics differed significantly for the different treatment times, which indicates that GSH kinetics may be an important factor in determining the intrinsic sensitivity of HEp3 cells to ADR. Furthermore, the kinetics of GSH response to ADR varied significantly between cell lines. In the study of the effect of such differences, the GSH kinetics of 3 human ovarian tumor cell lines with different intrinsic sensitivities to ADR were investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of antibody response by excess dietary zinc exposure during certain stages of ontogeny.

A study was made of the effects of excess dietary zinc on the antibody response to sheep red blood cells (SRBC) in mice. C57BL/6J mice were divided into 10 different dietary groups and exposed to diets containing zinc in normal (50 ppm) or excess (2000 ppm) concentrations during gestation/lactation/postweaning development in the sequences (1) 50/50/50; (2) 50/50/2000; (3) 2000/50/50; (4) 2000/2000/50; (5) 2000/50/2000; (6) 50/2000/50; (7) 50/2000/2000; (8) 2000/2000/2000; (9) 50/50/50 (pair-fed); and (10) chow/chow/chow. Mice in group 8 had severe signs of copper deficiency at 8 weeks of age, such as reduced plasma copper, lowered plasma hematocrit, and achromotrichia. Mice receiving 2000 ppm zinc during gestation had fewer offspring per litter (measured at 2 weeks of age) and more nonviable births than mice given 50 ppm zinc during gestation. The growth curve of mice exposed to excess zinc in the 50/50/2000 group was identical to that of the control (50/50/50) group. Growth curves for all other groups were reduced by varying amounts. The plaque-forming cell response to SRBC was reduced only in the groups receiving 50/2000/2000 and 2000/2000/2000 ppm zinc (P less than 0.05); this reduced response was not associated with atrophy of the lymphoid organs. Splenic cell surface markers and mitogenic responsiveness were similar in the 50/50/50 and 2000/2000/2000 groups. These results suggest that the immune response is more susceptible to dietary manipulation during development than after the immune response has been developed.

Lymphoid alterations and impaired T lymphocyte reactivity in experimental renal hypertension.

Alterations in the number and reactivity of thymic and splenic lymphocytes were studied during the development of experimental renal hypertension in Sprague-Dawley rats. The mitotic responses of thymocytes and splenic T and B lymphocytes were tested by the T cell mitogen concanavalin A and the B cell mitogen dextran sulfate 3, 8, 12, and 36 days after the initiation of hypertension. At 3 days, hypertensive rats showed a fourfold increase in plasma corticosteroid levels, marked thymic atrophy, and a 50% reduction in the total number of thymocytes. The mitotic reactivity of the cells remaining in the organ was depressed 60% when compared to sham-operated controls. At 8 days a similar reduction in thymus size was accompanied by similarly decreased lymphocyte populations. Twelve days after initiation of hypertension structural recovery of the gland, lymphoid proliferation, and slightly increased thymocyte populations were observed. Differences with sham-operated controls were, however, still remarkable. Hypertensive rats sacrificed at 36 days showed thymus hypertrophy, and the thymocyte populations were larger than those of sham-operated animals. Despite the fluctuations in the number of thymocytes registered during the development of renal hypertension, the impaired mitotic reactivity of these cells to concanavalin A was sustained throughout the 36 days of the experiment. A similar reduction in the total number of cells and a similar depression in T lymphocyte reactivity was observed in the spleen between 8 and 36 days of hypertension. In contrast, after an initial depressed response, splenic B lymphocytes showed a slight but sustained increase in reactivity throughout the entire experimental period. These results indicate that with evolving renal hypertension there is a reduction in the number of lymphocytes as well as a depression in the ability of the remaining T lymphocytes to react with concanavalin A. Since T lymphocytes are important regulators of immunological homeostasis, this reduction in T cell reactivity may suggest the existence of an immunological imbalance accompanying the development of experimental renal hypertension.