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PubMed1989

Sequential topographical portrayal of myocardial blood flow.

Methods to portray myocardial blood flow in a two-dimensional continuum are advantageous in that they allow blood flow history to be overlaid on histological or histochemical descriptions of the consequences of ischemia. We describe here autoradiographic methods that allow such portrayals at three separate times during the evolution of ischemic injury. A computer-based image-analysis system was used to derive such flow maps by taking advantage of the physical characteristics of radioactive isotopes.

Animals↗
PubMed2002

Citrulline is not the major product using the standard "NOS activity" assay on renal cortical homogenates.

A standard approach to assessing nitric oxide synthase (NOS) activity in tissue homogenates is 1) removal of small-molecular-weight substances by size-exclusion chromatography, 2) adding back of substrates/cofactors in precise concentrations with a radioactive isotope of arginine (Arg), and 3) quantification of labeled citrulline (Cit) after separation of Arg and Cit by cation-exchange column chromatography. Using this approach and L-[2,3-3H]Arg, we found that the major product(s) was not Cit in cortical homogenates prepared from rat, mouse, and human kidneys. The product(s) mimicked Cit, insofar as it passed freely through cation-exchange columns and comigrated with Cit on both one-dimensional and two-dimensional straight-phase thin-layer chromatography systems. However, it was clearly resolved from Cit by precolumn derivatization and reverse-phase HPLC. The maximum velocity and Michaelis-Menten constant were approximately 100 pmol x mg protein(-1) x min(-1) and 100 microM, respectively, in renal cortical homogenates from rats. The enzyme activity was the same in the presence or absence of cofactors including Ca2+, calmodulin, tetrahydrobiopterin, and NADPH. It was only modestly inhibited by L-Arg analogs and was mainly in the supernatant after a 100,000 g centrifugation. These enzyme characteristics contrasted markedly with those simultaneously obtained for NOS activity in placental homogenates. Thus results from the conventional NOS activity assay should be viewed cautiously.

Animals↗
PubMed1997

Oxidation of lactate and acetate in rat skeletal muscle: analysis by 13C-nuclear magnetic resonance spectroscopy.

The balance between carbohydrate and fatty acid utilization in skeletal muscle previously has been studied in vivo by using a variety of methods such as arteriovenous concentration differences and radioactive isotope tracer techniques. However, these methodologies provide only indirect estimates of substrate oxidation. We used 13C-nuclear magnetic resonance (NMR) spectroscopy and non-steady-state isotopomer analysis to directly quantify the relative oxidation of two competing exogenous substrates in rat skeletal muscles. We infused [1,2-13C]acetate and [3-13C]lactate intravenously in anesthetized rats during the final 30 min of 35 (n = 10) or 95 (n = 10) min of intense, unilateral, rhythmic hindlimb contractions. 13C-NMR spectroscopy and isotopomer analysis were performed on extracts of gastrocnemius and soleus muscles from both the contracting and contralateral resting hindlimbs. We found that 1) [13C]lactate and [13C]acetate were taken up and oxidized by both resting and contracting skeletal muscles; and 2) high-intensity muscle contractions altered the pattern of substrate utilization such that the relative oxidation of acetate decreased while that of lactate remained unchanged or increased. Based on these findings, we propose that 13C-NMR spectroscopy in combination with isotopomer analysis can be used to study the general dynamics of substrate competition between carbohydrates and fats in rat skeletal muscle.

Acetates↗
PubMed2006

IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples.

The class III receptor tyrosine kinase FLT3 is expressed on the blasts of >90% of patients with B-lineage acute lymphoblastic leukemias (ALL). In addition, it is expressed at extremely high levels in ALL patients with mixed lineage leukemia rearrangements or hyperdiploidy and is sometimes mutated in these same patients. In this report, we investigate the effects of treating ALL cell lines and primary samples with human anti-FLT3 monoclonal antibodies (mAb) capable of preventing binding of FLT3 ligand. In vitro studies, examining the ability of two anti-FLT3 mAbs (IMC-EB10 and IMC-NC7) to affect FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. FLT3 phosphorylation was consistently inhibited by IMC-NC7 treatment, but in some cell lines, IMC-EB10 actually stimulated FLT3 activation, possibly as a result of antibody-mediated receptor dimerization. Through antibody-dependent, cell-mediated cytotoxicity, such an antibody could still prove efficacious against leukemia cells in vivo. In fact, IMC-EB10 treatment significantly prolonged survival and/or reduced engraftment of several ALL cell lines and primary ALL samples in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This occurred even when IMC-EB10 treatment resulted in FLT3 activation in vitro. Moreover, fluorescence-activated cell sorting and PCR analysis of IMC-EB10-treated NOD/SCID mice surviving 150 days post-leukemic cell injection revealed that FLT3 immunotherapy reduced leukemic engraftment below the level of detection in these assays (<0.001%). Furthermore, in vivo IMC-EB10 treatment did not select for resistant cells, because cells surviving IMC-EB10 treatment remain sensitive to IMC-EB10 cytotoxicity upon retransplantation. In vivo studies involving either partial depletion or activation of natural killer (NK) cells show that most of the cytotoxic effect of IMC-EB10 is mediated through NK cells. Therefore, such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3.

Animals↗
PubMed1985

Collagen and glycosaminoglycan synthesis of injured gastrocnemius muscle in rat.

The synthesis of collagen and glycosaminoglycans in a partially ruptured gastrocnemius muscle were studied in 30 rats by giving a single 3H-labelled proline and 14C-labelled glucosamine injection intraperitoneally 2-21 days after a standard transverse contusion injury induced to the left calf of the animals. Both injured and contralateral uninjured gastrocnemius muscles were cut into four analogous 5-mm thick transverse pieces using the center of injury as a site for the middle incision in the injured muscle. The muscle slices were homogenized, dialyzed and then burned in a sample oxidizer which automatically divides the two radioisotopes into two different sample flasks. The radioactivities were measured using a liquid scintillation spectrometer. The content of glycosaminoglycans within the site of injury increased to a maximum 5 days after trauma, and decreased in amount thereafter. The uptake of 3H-proline indicating the synthesis of collagen was very low 5 days after trauma but increased to a maximum between the 10th and 14th day; more intensively in the proximal border of the injury than in the distal one. The uptake decreased again in amount 21 days after trauma. Burning of an in vivo radioactively labelled sample in a sample oxidizer provides a simple method in determination of the two radioactive isotopes as indicators of two main components of granulation and scar tissue.

Animals↗
PubMed1977

Failure of lactose and glucose to influence in vivo intestinal calcium transport in normal rats.

The influence of luminal lactose and glucose on intestinal calcium transport was examined in vivo in normal post-weaned young rats. In situ segments of duodenum, midgut and ileum were perfused through the lumen for 1 h with an isotonic solution of 3.4 mM calcium containing radioactive isotopic 45Ca as tracer and additionally either 10 mM lactose or 10 mM glucose, or, for the control group, no saccharide. Net absorption was measured by disappearance of luminal calcium; lumen-to-plasma flux was determined from the disappearance of tracer 45Ca. This concentration of luminal lactose or glucose had no direct effect on calcium transport under these steady state conditions.

Animals↗
PubMed1986

Geranylgeranylacetone, a novel anti-ulcer drug, stimulates mucus synthesis and secretion in rat gastric cultured cells.

Aim of this study was to investigate the effect of geranylgeranylacetone (GGA) on mucus synthesis and secretion in rat gastric cultured cells, and their relationship to prostaglandin (PG) synthesis. Rate of mucus synthesis was estimated by incorporation of 3H-glucosamine into the cultured cells. Release of 3H-glucosamine from the cells, which were preincubated in the medium containing the radioactive isotope, into the culture media was measured for the evaluation of mucus secretion. PG production by the cultured cells was measured by radioimmunoassay. GGA increased glycoprotein synthesis in a dose-dependent manner (p less than 0.01). Secretion of mucus from cultured cells was also significantly enhanced by GGA. GGA did not significantly increase PG (E2 and I2) production. These results indicate that GGA has the ability to stimulate mucus production by the gastric epithelial cells, and this action may play an important role in protective effect of GGA. It is, however, unlikely that this effect of GGA is mediated by endogenous PGs.

Animals↗
PubMed1983

Bromodeoxyuridine in tumors and chromosomes detected with a monoclonal antibody.

Using a monoclonal antibody to bromodeoxyuridine (BUdR) and immunohistochemistry, we measured the incorporation of this thymidine analogue into the DNA of human normal and malignant cells exposed in vivo. BUdR given as a constant intravenous infusion for 12 or 24 h daily for up to 13 d resulted in a steady-state plasma level of 10(-6) M during the infusion. We demonstrated extensive incorporation of BUdR into both normal skin, normal bone marrow, and malignant melanoma cells. In addition, this infusion of BUdR was adequate to identify sister chromatid exchanges from human marrow chromosomes exposed in vivo. Using this constant infusion, significant but reversible (acute) toxicity was observed with myelosuppression and skin photosensitivity. These techniques, which are considerably less cumbersome and time-consuming than the use of radioactive isotopes of thymidine, can be used for further human studies of cell kinetics and chromosomal replication in both normal and malignant cells.

Animals↗
PubMed1998

First report of Hürthle cell carcinoma revealed by octreotide scanning.

Octreotide is an 8-chain amino acid analog of somatostatin. Somatostatin and its receptors occur naturally in multiple sites within the body and serve a suppressive role in endocrine hormone release. When octreotide, which has a considerably longer half-life than somatostatin, is combined with a radioactive isotope, receptor-based imaging can be performed to visualize tumors with high concentrations of somatostatin receptors. Tumors of neural crest origin -- pituitary adenomas, islet cell tumors, medullary thyroid carcinomas, pheochromocytomas, carcinoids, and paragangliomas -- all express high levels of somatostatin receptors. We present the first reported positive octreotide scan of a Hürthle cell carcinoma of the thyroid and, more important, discuss the role of octreotide scanning in otolaryngology, which has not yet been reviewed by our literature.

Adenocarcinoma↗
PubMedDate not supplied

Preliminary study of sentinel node identification with 99mTc colloid and blue dye in patients with endometrial cancer.

AIMS AND BACKGROUND: Intraoperative lymphatic mapping and sentinel node (SLN) biopsy have generated a tremendous amount of interest and are already established as part of the standard practice in the surgical management of breast cancer and melanoma. To reduce extensive radical procedures and decrease the morbidity in the treatment of gynecologic malignancies, much effort is being made to use less aggressive interventions. The purpose of our study was to determine the feasibility of SLN mapping in a group of patients with endometrial cancer at early stages. METHOD AND STUDY DESIGN: Between September 2000 and May 2001 11 patients with endometrial cancer FIGO stage Ib (n = 10) and IIa (n = 1) underwent laparoscopic SNL detection during laparoscopy-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy and bilateral systematic pelvic lymphadenectomy. Radioactive isotope injection was performed 24 hours before surgery and blue dye injection was performed just before surgery in the cervix at 3,6, 9 and 12 hours. A 350 mm laparoscopic gamma scintyprobe MR 100 type 11, 99mTc settled (Pol Hi Tech), was used intraoperatively for SLN detection. RESULTS: Seventeen (17) SLNs were detected with lymphoscintigraphy (six bilateral and five unilateral). At laparoscopic surgery we found the same locations belonging at internal iliac lymph nodes (the so-called Lebeuf-Godard area, lateral to the inferior vesical artery, ventral to the origin of the uterine artery and medial or caudal to the external iliac vein). Fourteen (14) SLNs were negative on histological analysis and three were positive for micrometastases (mean SLN sections = 60). All other pelvic lymph nodes were negative at histological analysis. The same SLN locations detected with the gamma scintyprobe were observed at laparoscopy after patent blue dye injection. CONCLUSIONS: Our preliminary data suggest that combined 99mTc-labeled colloid and vital blue-dye techniques are feasible for SLA detection in endometrial cancer; they represent a very promising tool to transform the management of early-stage endometrial cancer. The clinical validity of this combined technique should be evaluated prospectively.

Adult↗
PubMedDate not supplied

Radioimmunotherapy for acute leukemia.

BACKGROUND: The use of monoclonal antibodies to deliver radioactive isotopes directly to tumor cells has become a promising strategy to enhance the antitumor effects of native monoclonal antibodies. In this article, we summarize the role of radioimmunotherapy in the treatment of leukemia. METHODS: The authors reviewed the published clinical trials of radioimmunotherapy in acute leukemia. RESULTS: Radioimmunoconjugates that emit beta-particles, such as 131I-anti-CD33, 90Y-anti-CD33, 131I-anti-CD45, and 188Re-anti-CD66c, deliver significant doses of radiation to the bone marrow and may be particularly effective when used as part of a conditioning regimen for hematopoietic stem cell transplantation. Radioimmunoconjugates that emit short-ranged alpha-particles, such as 213Bi-anti-CD33, are better suited for the treatment of low-volume or residual disease. CONCLUSIONS: Radiolabeled antibodies can be administered safely to patients with advanced leukemias and have significant antileukemic activity. Radiolabeled antibodies can potentially intensify the antileukemic effects of conditioning regimens when used in conjunction with hematopoietic stem cell transplantation. Whether or not radiolabeled antibodies improve the outcome of patients with leukemia remains to be demonstrated by randomized studies.

Acute Disease↗
PubMed1986

Detection of viral DNA and RNA by in situ hybridization.

Using cloned restriction endonuclease fragments of Herpes simplex virus (HSV), human papillomavirus (HPV), and cytomegalovirus (CMV) DNA as probes, viral DNA and RNA sequences have been detected in human tissues. The probes were labeled either with a radioactive isotope, for subsequent detection by autoradiography, or with biotin. This latter technique has been successfully used to visualize HPV DNA in tissues that have been fixed in formalin and embedded in paraffin, and is therefore of value in retrospective studies of histological specimens. HPV DNA was detected under non-stringent conditions (Tm = -42 degrees C) with heterologous probes in plantar and common warts, laryngeal papillomas, and anogenital condylomas. The specific type of HPV was established using stringent hybridization conditions (Tm = - 17 degrees C). Results from these and from malignant tissues show the distribution and localization of HSV and HPV RNA and DNA sequences in malignancies of squamous cell origin in the anogenital region. Both HSV and HPV DNA sequences have occasionally been detected in the same tumor, providing a further impetus to test the hypothesis that an initiator-promoter relationship might involve these common human viruses in the development of some tumors.

Base Sequence↗
PubMedDate not supplied

New agents and future directions in biotherapy.

Many new biotherapy agents to treat cancer are being studied as single agents and in combination with conventional cancer therapy, such as chemotherapy. These agents include the monoclonal antibodies, rituximab, trastuzumab, alemtuzumab, and IMC-C225. Radioimmunotherapy, a type of biotherapy that combines a radioactive isotope with a monoclonal antibody, also is being studied and has shown promise in the treatment of lymphoma. A tyrosine kinase inhibitor, STI 571, has been approved recently by the U.S. Food and Drug Administration. Several vaccines as cancer treatment are currently under investigation. Other biotherapy agents being investigated include angiogenesis inhibitors, such as endostatin, antivascular endothelial cell growth factor, and thalidomide, an agent that inhibits the formation of blood vessels that supply tumors.

Antibodies, Monoclonal↗
PubMed1977

Bioassay for prolactin: densitometric analysis on polyacrylamide gels of milk protein production by mammary explants in vitro.

Mammary explants from mice in midpregnancy cultured in a synthetic medium containing insulin and hydrocortisone respond to the addition of prolactin by the synthesis of milk proteins. The secretory response in alveolar lumina has served as a histologic endpoint in a sensitive bioassay for prolactin developed by Kleinberg and Frantz (J Clin Invest 50: 1557, 1971). This report demonstrates that the quantitative densitometric analysis of stained milk proteins (caseins) made in response to prolactin is a useful modification of that bioassay. Electrophoretic analysis of the proteins extracted from the explants permits a quantitative estimate of casein content. The amount of casein present after 5 days of incubation was found to be a measure of the prolactin concentration in the medium. No radioactive isotopes are used. The use of electrophoretic analysis has practical advantages over the histologic scoring used earlier, and has approximately the same range of sensitivity.

Animals↗
PubMed1989

Increased plasma 3,5,3'-triiodothyronine sulfate in rats with inhibited type I iodothyronine deiodinase activity, as measured by radioimmunoassay.

In contrast to the glucuronide conjugate, T3 sulfate (T3S) undergoes rapid deiodinative degradation in the liver and accumulates in rats and rat hepatocyte cultures if type I iodothyronine deiodinase activity is inhibited. We here report the RIA of plasma T3S in rats treated with the antithyroid drugs propylthiouracil (PTU) or methimazole (MMI), of which only PTU inhibits type I deiodinase. Male Wistar rats were treated acutely by ip injection with 1 mg PTU or MMI/100 g BW and subsequently for 4 days by twice daily injections with these drugs together with 0.5 microgram T4 or 0.25 microgram T3/100 g BW. Blood was obtained 4 h after the last injection, and plasma T4, rT3, T3, and T3S were determined by RIA and compared with pretreatment values. Serum concentrations (mean +/- SEM; nanomoles per liter) in untreated rats were: T4, 51 +/- 1; T3, 1.37 +/- 0.03; T3S, 0.09 +/- 0.01; and rT3, 0.03 +/- 0.002. Serum T3 was decreased, and T3S and rT3 were increased by acute PTU treatment [T3, 1.16 +/- 0.05 (P less than 0.01); T3S, 0.33 +/- 0.04 (P less than 0.001); rT3, 0.27 +/- 0.02 (P less than 0.001)], but unaffected by acute MMI treatment (T3, 1.37 +/- 0.05; T3S, 0.09 +/- 0.01; rT3, 0.02 +/- 0.003). In T4-treated rats, serum T3 was decreased and T4, T3S, and rT3 were increased by PTU vs. MMI [T4, 86 +/- 5 vs. 58 +/- 4 (P less than 0.001); T3, 0.51 +/- 0.07 vs. 0.88 +/- 0.06 (P less than 0.001); T3S, 0.38 +/- 0.03 vs. 0.12 +/- 0.01 (P less than 0.001); rT3, 0.86 +/- 0.19 vs. 0.08 +/- 0.01 (P less than 0.005)]. In T3-substituted rats T3S was increased by PTU vs. MMI (1.09 +/- 0.13 vs. 0.25 +/- 0.03; P less than 0.001). The T3S/T3 ratio in the PTU-treated T3 -replaced rats (0.60 +/- 0.09) was in agreement with that determined by HPLC of serum radioactivity in animals that in addition to this treatment also received about 10 microCi [125I]T3 with the last two injections (0.92 +/- 0.13). In conclusion, this investigation demonstrates the feasibility of the measurement of serum T3S by RIA. Our findings confirm previous observations with radioactive isotopes, suggesting that sulfation is an important pathway for the metabolism of T3 in rats. Analogous to rT3, the accumulation of T3S in PTU-treated rats indicates that this conjugate is metabolized predominantly by type I deiodination.

Animals↗
PubMed1983

Theoretical analysis of a method for determining the pattern of macromolecular synthesis during the cell cycle.

The dual-labelling centrifugal-elutriation method has been extensively used to study patterns of macromolecular synthesis and accumulation in the yeast cell cycle. Cells are long-term labelled with a radioactive precursor for about 1.5 cycles (a measure of macromolecular mass), then pulse-labelled with a precursor containing a different radioactive isotope for the final 0.1 cycle (a measure of rate of synthesis). Harvested cells are fractionated into cell cycle stages by centrifugal elutriation, and changes in pulse : long-term labelling during the cycle determined. This pattern of change is compared with theoretical changes in rate : mass calculated for various patterns of synthesis. Using this method, it has been suggested that rates of synthesis and accumulation of several types of RNA and protein all increase exponentially through the cycle. In contrast, experiments using synchronous cultures or zonal centrifugation for cell cycle analysis have suggested other synthetic patterns, including periodic doubling in rate in each cycle. In this paper we analyse whether the dual-labelling, centrifugal-elutriation method is capable of discriminating between exponential and periodic rate-doubling patterns. Three possible sources of imprecision in the method and its application are examined. (1) Theoretical rate : mass curves have been simulated for macromolecules with a wider range of properties than previously considered. It is shown that for some important classes, such as messenger RNAs, with turnover rates in the range measured experimentally, and proteins, differences between rate : mass curves for exponential and periodic rate-doubling models are considerably smaller than previously suggested. (2) Long-term labelling is shown to be an accurate measure of macromolecular mass, but pulse-labelling can be inadequate as a measure of rate of synthesis. The error is greater with RNAs with faster turnover, and again reduces the ability of the method to discriminate exponential and periodic rate-doubling models of synthesis. The error is greater with RNAs with faster turnover, and again reduces the ability of the method to discriminate exponential and periodic rate-doubling models of synthesis. (3) Imperfections in cell cycle fractionation by centrifugal elutriation are examined, and by computer simulation it is shown that these also reduce the ability of the method to distinguish between the two models of synthesis. The three sources of imprecision are cumulative. It is concluded from simulation analyses that the differences between exponential and periodic rate-doubling patterns analysed by the method would be so small as to be almost impossible to establish against the background of error in experimental measurement. We therefore suggest that in practice, the dual-labelling centrifugal-elutriation method is unable to discriminate between the exponentially increasing and periodic rate-doubling models. The mathematical treatment developed in this paper should be applicable to analysis of other methods and cell cycle events.

Cell Cycle↗
PubMed1975

Evaluation of the significance of scintillation angiocardiography for determination of the left ventricular volume.

A method for the determination of the left ventricular volume by scintillation angiocardiography following a peripheral venous injection of a radioactive isotope was described. Salient points in its methodology were as follows: 1. This volume study was composed of non-gated scintillation angiocardiography and cumulative gated scintiphotography. 2. The non-gated scintillation data were stored into video recording system. 3. The gated scintiphotography was performed during a play-back of non-gated scintillation data, opening the gate at desired points of time during a cardiac cycle. 4. The left ventricular scintillation image was photographied in life-size on x-ray film by superimposing, 10-20 times, the gated image of the several consecutive heart beats during the "left ventricular phase" of the dilution of intravenously injected radionuclide. For validation of this method, the stroke volume obtained with this method was compared with that obtained by precordial radionuclide dilution curve recordable during the non-gated scintillation angiocardiography, and also with that obtained by non-simultaneous radiocardiography. It was concluded that the present method may be sufficiently accurate for clinical use.

Adolescent↗
PubMed1982

Plasma volume determination by use of enzyme dilution in the dog.

The use of enzymes for plasma volume determination in the dog was investigated. Plasma volume was determined from dilution of intravenously injected enzymes and compared with results obtained by high molecular weight fluorescein-labelled dextran. Aspartate aminotransferase and alanine aminotransferase from liver tissue gave good results, but the activities of creatine kinase and lactate dehydrogenase from heart tissue were inhibited in plasma, resulting in an overestimation of plasma volume. Enzymes offer a useful alternative to methods presently used since no radioactive isotopes are needed. In laboratory animals the enzyme preparations are readily obtainable and there is minimal risk of immunological complications arising after repeated determinations.

Alanine Transaminase↗