PubMed Health⌕ Search

Biomedical subjects

R D Neumann

Publications and source records attributed to R D Neumann.

At least 55 records · Page 3Linked to original sources
PubMed1995

The cytotoxicity of decays of tritium and iodine-125 incorporated in DNA of mammalian cells. Implications for the low-LET dosimetry of incorporated nuclides.

To quantify the toxicity of low-LET radiation from incorporated radionuclides, we have determined the toxicity of decays of [3H]dThd pulse-incorporated into CHO cells in early S phase, with the cells frozen for decay accumulation at 30, 120 or 360 min after the pulse. D37 values of 1500, 2000 and 2100 decays were found by colony formation assay, corresponding to average nuclear doses of 4.6 and 2.7 Gy at the 30- and 360-min times. As D37 for external irradiation (60Co, 2.2 Gy/min) under these conditions is approximately 18 Gy, these results confirm the inadequacy of the dosimetry used for external irradiation to predict the biological effects of the low-LET radiation from incorporated radionuclides. We also determined the toxicity of 125IdU administered as above, and have confirmed the previously reported finding that D37 falls dramatically from 165 decays at 30 min to 40 decays at 360 min. Using the data for tritium to estimate the effect of the dose of 125I low-LET radiation, we conclude that even at 30 min, most of the toxicity of the 125I decays is due to the high-LET portion of the 125I electron spectrum, not the low-LET portion as reported previously.

Animals↗
PubMed1994

Sequence-specific DNA double-strand breaks induced by triplex forming 125I labeled oligonucleotides.

A triplex-forming oligonucleotide (TFO) complementary to the polypurine-polypyrimidine region of the nef gene of the Human Immunodeficiency Virus (HIV) was labeled with 125I at the C5 position of a single deoxycytosine residue. Labeled TFO was incubated with a plasmid containing a fragment of the nef gene. Decay of 125I was found to cause double-strand breaks (DSB) within the nef gene upon triplex formation in a sequence specific manner. No DSB were detected after incubation at ionic conditions preventing triplex formation or when TFO was labeled with 32P instead of 125I. Mapping DSB sites with single base resolution showed that they are distributed within 10 bp of a maximum located exactly opposite the position of the [125I] IdC in the TFO. We estimate that on average the amount of DSB produced per decay is close to one.

Base Sequence↗
PubMed1994

Two-step targeting of experimental lung metastases with biotinylated antibody and radiolabeled streptavidin.

Two-step monoclonal antibody tumor targeting using an avidin-biotin system has unique characteristics because of the high-affinity binding (10(15) M-1) and the lower molecular weight ligands (avidin, streptavidin, or biotin) used as carriers of radioisotopes, toxins, or drugs. The distribution of radiolabeled streptavidin in a two-step targeting strategy was investigated in lung metastases of line 10 carcinoma in guinea pigs. The microdistribution of administered D3 monoclonal antibody and 125I-labeled streptavidin in metastatic nodules was examined by immunohistochemistry and autoradiography, and the uptake was quantitated. With monoclonal antibody pretargeting, streptavidin was found mainly at the periphery of metastatic nodules 1.5 h after injection; it had penetrated deeper at 4 h and was approaching homogeneity in many of the tumor nodules at 24 h. These results indicate that streptavidin can penetrate into metastatic nodules more rapidly than can the antibody. The concentration of streptavidin in metastatic nodules 4 h after injection was 5.6 times higher for the pretargeted group than for the nonpretargeted group, and the pretargeting index was 4.7. Although the absolute uptake of streptavidin had decreased between 4 and 24 h, the metastasis:blood ratio had increased from 1.2 to 2.4. When compared with the animals injected with 125I-labeled D3 antibody alone, the pretargeted group achieved higher tumor:blood and tumor:lung ratios and a higher localization index at early times after injection of the radiolabeled species.

Animals↗
PubMed1994

Streptavidin distribution in metastatic tumors pretargeted with a biotinylated monoclonal antibody: theoretical and experimental pharmacokinetics.

We have developed a pharmacokinetic model for the analysis of a protocol that involves injection of a biotinylated monoclonal antibody followed at a later time by radiolabeled streptavidin. Three distinct physiological spaces are described: an avascular tumor nodule, the normal tissue surrounding the tumor, and the plasma. The model incorporates processes such as plasma kinetics, transcapillary transport, interstitial diffusion, binding reactions, and lymphatic clearances. We have modeled cases in which antigen turnover does not occur, in which antigen turnover does occur (24-h time constant), and in which circulating antibody is cleared from the plasma immediately prior to injection of streptavidin. We have calculated the spatial and temporal distributions of a tumor-specific antibody and of streptavidin in the tumor nodule using parameter values that simulate conditions of recent experiments on metastatic nodules in the guinea pig lung. The theoretical distribution of streptavidin in the tumor nodule shows an initial localization at the periphery that progresses to a fairly uniform distribution throughout the nodule, a temporal sequence that is very similar to experimental observation. This finding indicates that, in a tumor pretargeted with biotinylated antibody, streptavidin can encounter significant retardation in its penetration as a consequence of the high affinity interaction between these two species. Tumor:blood and tumor:lung ratios were calculated and compared to experimental results. In addition, the calculated tumor:blood ratios, tumor:lung ratios, and relative exposures were compared to values obtained from a model of one-step antibody delivery. The two-step protocol yielded an approximately 2- to 3-fold enhancement in these pharmacokinetic indices compared with the one-step method.

Animals↗
PubMed1994

Application of high affinity binding concept to radiolabel avidin with Tc-99m labeled biotin and the effect of pI on biodistribution.

In order to label avidin with Tc-99m, we took advantage of the high affinity binding of biotin to avidin; we radiolabeled a biotin derivative with Tc-99m and then bound this Tc-99m labeled biotin derivative to avidin. For our labeling approach, N epsilon-biotinyl-L-lysine (Biocytin) was reacted with the N-hydroxy-succinimide ester of benzoylmercaptoacetyltriglycine (Bz-MAG3). The resulting Bz-MAG3-Biocytin was labeled with Tc-99m using Tc-99m glucarate as a Tc-99m transchelating agent and mixed with avidin at a 1:1 molar ratio resulting in almost a quantitative labeling yield. Tc-99m-MAG3-Biocytin/Avidin was stable in serum at 37 degrees C with 97 and 95% of the total Tc-99m activity still bound to avidin at 2 and 24 h, respectively. The biodistribution of Tc-99m-MAG3-Biocytin/Avidin in normal Balb/c mice showed a high liver and kidney uptake with 56.6 and 28.9%, respectively at 10 min. We attempted to lower the liver and the kidney activities by reducing the isoelectric point (pI) of avidin by conjugating succinic acid moieties at lysine residues of avidin (pI 10). The kidney uptake decreased to 19.0, 3.1 and 1.7% when the pI of avidin was reduced to 7.0-9.3, 5.5-6.2 and 4.0-4.8, respectively. The lowering of the pI, however, did not change the liver activity appreciably.

Animals↗
PubMed1994

Effect of metabolism on retention of indium-111-labeled monoclonal antibody in liver and blood.

UNLABELLED: The effect of a chelator structure on the metabolic fate of the 111In-labeled monoclonal antibody (Mab) T101 was investigated in normal Balb/c mice to assess the importance of this chemical parameter in the reduction of the background radioactivity in blood and liver. METHODS: Mab T101 was conjugated with either 2-(p-isothiocyanatobenzyl)-6-methyl-diethylaminetriaminepentaac etic acid (DTPA) (1B4M), 2-(p-isothiocyanatobenzyl) cyclohexyl-DTPA (CHX-B) or cyclic DTPA dianhydride (cDTPA) and then radiolabeled with 111In. Normal mice were injected intravenously with these 111In-labeled T101 conjugates and sacrificed in groups of five up to 5 days postinjection for comparative biodistribution studies and analyses of liver, blood and urine samples for radioindium products. RESULTS: The biodistribution of 111In-1B4M-T101 and 111In-CHX-B-T101 were similar to each other but significantly different from that of 111In-cDTPA-T101, particularly in the blood and liver. Size-exclusion high-performance liquid chromatography indicated that the concentration of the intact 111In-immunoglobulin (Ig)G in liver decreased with similar rates for the three conjugates. Meanwhile, the concentration of a small DTPA-like metabolite in liver increased to a different peak value (4.6% ID/g for the cDTPA conjugate and 1.6% ID/g for the 1B4M and CHX-B conjugates) approximately at 24 hr and maintained a steady-state concentration up to 5 days. CONCLUSION: The thiourea linkage between T101 and the 111In-labeled chelates and a higher complex stability and higher lipophilicity of 111In-1B4M and 111In-CHX-B appear to be responsible for lower liver and higher blood radioactivity for the 1B4M and CHX-B conjugates.

Animals↗
PubMed1994

Ultrastructure and mineral composition of urinary calculi from horses.

Urinary calculi from 17 horses with urolithiasis were examined to study their mineral content and ultrastructure. Among the analytic methods used were X-ray diffractometry, scanning electron microscopy, and electron microprobe analysis. The calculi initially were observed by use of a stereoscopic dissecting microscope and generally were found to have nodular surfaces surrounding a banded or granular-to-chalky interior. Observation by scanning electron microscopy revealed an intricate pattern of irregularly concentric, fine bands and spherules. These had a round, finely banded, globular texture formed by precipitation of ultrafine-grained radiating crystals. The original pore spaces (ie, between spherules, between bands and spherules, or between crystal generations) could be observed as primary porosity. Precipitation and dissolution of these urinary calculi were observed to be spontaneous processes, which can occur simultaneously within an individual calculus. Another prominent feature of the ultrastructure was secondary porosity (spontaneous dissolution) which, in its incipient stages, appeared to be site-selective (ie, some bands appeared to be more susceptible to development of pinpoint porosity). Textures indicative of dissolution were observed not only on the calculus surface, but within the calculus interior as well. Areas that had more advanced stages of dissolution, resulting in increased secondary porosity, also were observed. All 17 samples of the study were found to be composed of calcium carbonate in the form of the mineral calcite, although minor quantities of 2 other polymorphs of calcium carbonate, minerals vaterite and aragonite, also were encountered. Vaterite was observed in 5 of the samples, whereas aragonite was found in 1 sample. Strontium and sulfur were observed as trace elements in 3 of the calculi, whereas magnesium was present in all calculi. Magnesium was observed to substitute for calcium within the calcite crystal lattice in larger quantities than those of strontium or sulfur. Magnesium K alpha X-ray dot maps generated by use of an electron microprobe analyzer indicated that the distribution pattern of magnesium appeared to closely follow layer-by-layer growth of the calculus. Magnesium distribution also appeared to be related to porosity development. In samples where preferential dissolution was observed, the more porous areas had higher magnesium content. Quantitative chemical analyses, using the electron microprobe analyzer, confirmed these observations. Association of the magnesium distribution pattern to the primary growth texture of the calculus indicated that magnesium content of the calculus varied during the formation process. This also indicated that changes in urine chemical analytes may be reflected in composition of the calculi formed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The role of gallium-67 tumour scintigraphy in patients with small, non-cleaved cell lymphoma.

Two hundred and thirty-four scintigraphic studies were performed in 34 patients (27 men, 7 women, age 17.3 +/- 7.7 years) with small, non-cleaved cell lymphoma who had follow-up for 3-96 months (mean 21.6 +/- 21.7 months). Whole-body scintigraphy was performed 48-72 h following i.v. injection of 370 MBq gallium-67 citrate. "Gold standards" for truth determinations were surgery, autopsy, histology, axial x-ray computed tomography, magnetic resonance imaging, ultrasonography and clinical follow-up. Overall, 181 of 234 studies were true negative. Eighty proven sites of disease had true positive 67Ga uptake (in 21 patients/37 studies). Nineteen sites (in 12 patients/15 studies) were false positive. In addition, 31 benign lesions were detected and interpreted correctly in terms of non-malignancy. Ten lymphoma sites (in 6 patients/10 studies) were missed by scintigraphy. Overall, sensitivity of gallium scintigraphy was 89% when calculated by sites and 79% when calculated by studies. Corresponding specificities were 91% and 92%, respectively. Positive predictive values were 81% (sites) and 71% (studies), and negative predictive values 95% (sites and studies). Thus, gallium scintigraphy proved to be a sensitive and specific method for staging and follow-up in patients with small, non-cleaved cell lymphoma.

Adolescent↗
PubMed1993

A simple method for affinity purification of radiolabeled monoclonal antibodies.

A simple method is described for affinity purification of radiolabeled antibodies using glutaraldehyde-fixed tumor target cells. The cell-bound antibody fraction is removed from the cells by an acid wash and then immediately subjected to buffer-exchange chromatography. The method was applied to the D3 murine monoclonal antibody which binds to a 290 kDa antigen on the surface of Line 10 guinea pig carcinoma cells. No alteration in the molecular size profile was detected after acid washing. Purification resulted in a significant increase in immunoreactivity by an average of 14 +/- 47% (SD; range 4-30%).

Animals↗
PubMed1993

A malignant melanoma imaging agent: synthesis, characterization, in vitro binding and biodistribution of iodine-125-(2-piperidinylaminoethyl)4-iodobenzamide.

In order to develop improved radiopharmaceuticals for imaging malignant melanoma, we have synthesized and characterized 125I-and 131I-labeled (2-piperidinylaminoethyl)4-iodobenzamide (PAB). In vitro binding profiles of IPAB and N-(2-diethylaminoethyl)4-iodobenzamide (IDAB, a structurally related analog of IPAB) for a variety of neurotransmitter receptors suggested that both IPAB and IDAB possessed a high sigma-1 affinity and a low affinity for sigma-2 sites. In vitro homologous competition binding studies of [125I]PAB with human malignant melanoma cell A2058 showed that the tracer was bound to the cells with a high affinity (Ki = 6.0 nM) and that the binding was saturable. Biodistribution studies in nude mice implanted with human malignant melanoma xenografts showed good tumor uptake (3.87% ID/g at 1 hr, 2.91% ID/g at 6 hr and 1.02% ID/g at 24 hr) of [125I]PAB. High tumor-to-nontarget organ ratios were obtained at 24 hr postinjection. Tumor-to-blood, liver, muscle, lung, intestines, heart and brain ratios at 24 hr were 17.80, 3.88, 94.58, 14.29, 10.87, 37.07 and 90.01, respectively. Tumor imaging with [131I]PAB in a nude mice model xenografted with human malignant melanoma at 24 hr clearly delineated the tumor with very little activity in any other organ. These results demonstrate that sigma-1 receptors could be used as external markers for malignant melanoma.

Animals↗
PubMed1993

[Role of magnetic resonance in the study of benign and malignant pheochromocytomas. Quantitative analysis of the intensity of the resonance signal].

In order to assess the clinical role of Magnetic Resonance (MR) imaging in patients with benign or malignant pheochromocytomas, the MR signal intensity ratios of benign and malignant tumors were evaluated. Eighteen patients (9 men and 9 women, mean age: 37 +/- 8 years) with benign (n = 10) or malignant (n = 8) pheochromocytomas were studied. A total of 27 lesions (12 benign and 15 malignant) were analyzed. In all patients, histology confirmed the disease. MR studies were performed using a 1.5-T superconducting magnet system. Sequences were used to obtain T1-weighted (TR/TE 300/12 ms) and T2-weighted (TR/TE 2000/80 ms) images. On both T1- and T2-weighted MR images, the mean absolute signal intensity values of tumor lesions, of liver, muscle and fat tissues, and of image background were measured to obtain the corresponding signal intensity ratios for each lesion. Our results exhibited no statistically significant differences in both T1 and T2 MR signal intensity ratios between benign and malignant lesions. In conclusion, our results suggest that MR imaging cannot differentiate benign from malignant lesions in patients with pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1993

Iodine-131-metaiodobenzylguanidine scintigraphy in preoperative and postoperative evaluation of paragangliomas: comparison with CT and MRI.

Iodine-131-metaiodobenzylguanidine (MIBG) scintigraphy, transmission computed tomography and magnetic resonance imaging were used to evaluate 36 patients with clinically suspected functioning paragangliomas. The patients were divided into two groups. In Group 1 (n = 21), studied before surgery, patients mainly had benign adrenal disease. In Group 2 (n = 15), studied after surgery, patients frequently had malignant or extra-adrenal tumors. In Group 1, transmission computed tomography and magnetic resonance imaging were more sensitive (100% for both) than MIBG scintigraphy (82%), which, however, was the most specific (100%). In Group 2, MIBG scintigraphy and magnetic resonance imaging were more sensitive (83% for both) than transmission computed tomography (75%), but MIBG was again the most specific (100%). Thus, all three were complementary modalities for localizing paragangliomas both preoperatively and postoperatively. MIBG imaging is indicated for both groups but it is especially recommended for postsurgical patients with recurrence because the disease is often malignant or extra-adrenal.

3-Iodobenzylguanidine↗
PubMed1993

Ultrastructural histology correlates with results of thallium-201/technetium-99m parathyroid subtraction scintigraphy.

Specimens from 15 scintigraphically true-positive adenomas (golden standard: histology), 15 false-negative adenomas, 15 true-positive hyperplasias, 15 false-negative hyperplasias, 15 true-negative normal glands from patients with hyperparathyroidism, and 15 normal glands from patients without hyperparathyroidism, all selected randomly, were studied. After fixation, sectioning and H and E staining, in all 90 tissues the number of oxyphil, chief, and clear cells was counted in five randomly selected squares (103 x 103 microns). In 30 tissues, the number of mitochondria per cell was counted in five randomly selected cells from each lesion in transmission electron photomicrographs. Total cell counts in each group and number of chief cells showed no correlation with lesion detectability by scintigraphy. However, true-positive lesions had a significantly higher number of oxyphil cells than false-negative or normal glands. Twenty-one of 30 true-positive lesions had a oxyphil-to-clear cell ratio > 1; in contrast to only two of 30 false-negative lesions and 0 of 30 normal glands (p < 0.0005). The number of mitochondria per cell was higher in oxyphil cells in true-positive lesions (adenomas: 155 +/- 58, hyperplasias: 55 +/- 18) than in chief or clear cells in false-negative or normal lesions (30 +/- 15, p < 0.001). Our data suggest that the detectability of abnormal parathyroid glands by 201TI/99mTc subtraction scintigraphy is in part dependent upon the presence of mitochondria-rich oxyphil cells.

Adenoma↗
PubMed1992

Radiolabeled products in rat liver and serum after administration of antibody-amide-DTPA-indium-111.

Anti-human serum albumin antibody (Ab) was used as a model antibody. Ab was conjugated with DTPA using cyclic DTPA dianhydride reaction and radiolabeled with 111In. The labeled Ab was purified by affinity chromatography. Size exclusion HPLC of this product showed 62% of 111In bound to monomeric Ab and 38% of the activity bound to antibody oligomers with molecular weights ranging from 300,000 to 450,000. The labeled antibody preparation was injected into the tail vein of rats. The radioactive substances in serum and the supernatant from liver homogenates were analyzed for molecular weight and immunoreactivity. Size exclusion HPLC of the serum samples indicated that the monomeric and dimeric Abs disappeared from the serum at a similar rate over a 48 h period. In addition, a new radioactive substance with an estimated molecular weight of 35,000 appeared in the serum. The immunoreactive fraction of the circulating 111In substances decreased slowly, somewhat proportional to the appearance of the metabolite. On the other hand, the immunoreactivity of the 111In substances in the supernatant from the liver homogenate decreased rapidly and no appreciable immunoreactivity was observed after 48 h. The labeled antibody was catabolized very rapidly in the liver and the major activity in the supernatant was associated with a small molecular weight metabolite which had a HPLC retention time identical to that of DTPA-111In. The second metabolite had an estimated molecular weight of 35,000. No radioactivity was associated with transferrin.

Animals↗
PubMed1992

Pulmonary and oxygen transport effects of intravenously administered endotoxin in normal humans.

Little data are available describing the initial changes in pulmonary function and oxygen transport during human endotoxemia. We studied 26 normal humans after intravenously administered endotoxin (4 ng/kg). To evaluate alterations in gas exchange, hemodynamic monitoring was performed in nine subjects given endotoxin and six subjects given saline only. Compared with the control subjects, no changes in gas exchange occurred at 3 h, but after volume loading (mean, 2.2 L saline infused from 3 to 5 h) the PaO2 fell (86.1 +/- 2.3 mm Hg, p = 0.042), and the AaPO2 widened (18.5 +/- 1.7 mm Hg, p = 0.005). Oxygen consumption and delivery both increased significantly at 3 h (219 +/- 17 and 1,030 +/- 43 ml/min.min2) and 5 h (203 +/- 7 and 949 +/- 48 ml/min.min2) (p less than or equal to 0.035), whereas oxygen extraction fell at 3 h (p = 0.041). Seventeen subjects underwent bronchoalveolar lavage 14 +/- 4 days before and at 1.5 to 3 h (n = 8) or 5 h after (n = 9) the administration of endotoxin. No increase in the total number of cells or percent or absolute number of neutrophils was found at either time point. The rate of clearance of inhaled 99mTc-diethylenetriamine pentacetate aerosol, a measure of alveolar epithelial permeability, increased in subjects scanned before 3 h (n = 8; p less than 0.05), whereas no significant changes occurred in subjects scanned 5 h after endotoxin (n = 5) or in control subjects (n = 6). Early inflammatory responses after intravenous administration of endotoxin to normal humans results in alterations in gas exchange and lung permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗