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Biomedical subjects

J Deman

Publications and source records attributed to J Deman.

At least 19 recordsLinked to original sources
PubMed1996

Prevention of murine radiogenic thymic lymphomas by tumor necrosis factor or by marrow grafting.

BACKGROUND: Split-dose irradiation (1.75 Gy given weekly for 4 weeks) of C57BL/Ka mice induces the emergence of preleukemic cells (PLCs). These cells develop into leukemic cells after a latency period of 3-6 months. The survival and transformation of PLCs are dependent on radiation-induced alterations of the thymic epithelium and of resident lymphocyte (i.e., thymocyte) subpopulations in the thymus. PLCs can be eliminated, concomitantly with the restoration of the thymus, by grafting bone marrow cells immediately after the last irradiation. Our hypothesis was that any agent able to restore the thymus after leukemogenic irradiation would exert the same effects as a bone marrow graft. Tumor necrosis factor-alpha (TNF-alpha) is one such possible agent, since it has been shown to modulate some functions of the thymic epithelium and thymocyte subpopulations. PURPOSE: The goal of this study was to assess the ability of repeated intraperitoneal injections of TNF-alpha to functionally replace bone marrow transplantation in the restoration of normal intrathymic lymphopoiesis and in the prevention of thymic lymphomas in split-dose-irradiated mice. METHODS: We replaced the bone marrow graft with repeated injections of TNF-alpha (25 000 U/injection) in the split-dose-irradiated (4 x 1.75 Gy) C57BL/Ka mouse model. We analyzed the expression of the cell differentiation markers CD4 and CD8 on thymocytes by flow cytometry. We also studied the thymic environment by isolating thymic nurse cells, the bone marrow prothymocyte activity by analyzing thymic repopulation, and the evolution of PLCs by an in vivo transplantation assay. Local production of TNF-alpha after bone marrow grafting was examined by in situ hybridization. Injections of anti-TNF-alpha antibodies were given to split-dose-irradiated mice to test the effect of neutralizing TNF-alpha in vivo. One-way analysis of variance and Newman-Keuls two-tailed tests were used to test statistical significance. RESULTS: Multiple injections of TNF-alpha into split-dose-irradiated mice did not influence bone marrow prothymocyte activity but restored thymocyte subpopulations and thymic epithelium, induced the disappearance of PLCs, and prevented the development of lymphomas. Moreover, a bone marrow graft significantly stimulated intrathymic production of TNF-alpha messenger RNA (P<.01), and anti-TNF-alpha antibodies partially inhibited the antilymphomatous effects of bone marrow graft in split-dose-irradiated mice (P<.05). CONCLUSION: These data strongly suggest that TNF-alpha is a mediator that is involved in the mechanisms by which bone marrow transplantation functions to prevent thymic lymphomas in split-dose-irradiated mice. IMPLICATIONS: Cytokines might be used in some biological systems, particularly in the hemopoietic system, as a therapeutic agent for the secondary prevention of cancer.

Animals↗
PubMed1996

In vivo expression of interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-6, tumour necrosis factor-alpha and interferon-gamma in the fetal murine thymus.

Cytokines are known to play a role in T-cell lymphopoiesis as potent growth or differentiation factors, but many experiments focusing on their role in the thymus have been conducted only in vitro. We have thus used frozen sections obtained from fetal thymuses of normal C57BL 6 mice to investigate by immunohistochemistry the presence of interleukin-1 beta (I4-1 beta), IL-2. IL-4. IL-6. interferon-7 (IFN-7) and tumour necrosis facor-alpha (TNF-alpha). The results reveal that apart from IL-2, which was not detected, all these cytokines display a time-dependent expression pattern in the normal fetal thymus. First, production of IL-4, IL-6 and TNF-alpha is detected around days 13 14; this is followed by a second wave on days 16 17, with a production of IL-1 beta, IL-4 and IL-6, and finally, just before birth (day 19), by a third wave of IL-1 beta, IL-4, IL-6, IFN-7 and TNF-alpha production. This supports the hypothesis that cytokines play a rote in T-cell lymphopoiesis.

Animals↗
PubMed1995

High tumor necrosis factor alpha (TNF-alpha) production in Trypanosoma cruzi-infected pregnant mice and increased TNF-alpha gene transcription in their offspring.

Since tumor necrosis factor alpha (TNF-alpha) is known to be involved in the feto-maternal relationship, this cytokine was studied in Trypanosoma cruzi-infected pregnant BALB/c mice and their fetuses and offspring. Pregnant chronically infected mice displayed significantly higher levels of circulating TNF-alpha than animals either only infected or only pregnant. TNF-alpha was undetectable in sera of uninfected and nonpregnant mice as well as in breast milk obtained from infected and uninfected animals. Fetuses from infected mice exhibited significantly more cells containing TNF-alpha mRNA in their thymus than fetuses from uninfected mothers. When infected 2 months after birth, offspring born to infected and uninfected mothers displayed similar amounts of circulating TNF-alpha during chronic infection, whereas this cytokine was only weakly detectable during the acute phase of the disease. An intravenous injection of lipopolysaccharide during acute infection strongly increased the production of TNF-alpha in offspring born to infected mothers to levels higher than those in progeny from uninfected mice. These results suggest that TNF-alpha is an important cytokine in the feto-maternal relationship during T. cruzi infection and that fetuses and offspring of infected mothers are primed to produce elevated levels of TNF-alpha.

Animals↗
PubMed1995

Spontaneous and induced apoptosis after whole body radiation exposure: experimental approaches. Observations in radio-induced thymic lymphomagenesis.

Radio-induced thymic lymphomagenesis is associated with alterations in the balance between thymocyte subsets and cytokinetic perturbations. The objectives of this work were to investigate whether these alterations are associated with alterations in the basic levels of thymocyte apoptosis. For this purpose, we tested DNA fragmentation by gel electrophoresis, analyzed DNA content by propidium iodide staining of ethanol fixed cells and looked for DNA strand breaks on tissue sections by in situ end labeling. We described an increase of the levels of apoptosis in cultured thymocytes during the preleukemic period, while the basic levels of apoptosis observed in situ are similar in normal and in preleukemic thymuses. We propose that after leukemogenic irradiations, there is an increase of cells wherein the cell suicide program is activated but that environmental thymic factors rescue them from apoptosis. Preleukemic cells could belong to this abnormally surviving population of cells "programmed to die," wherein additional genomic abnormalities would lead to fully neoplastic transformation.

Animals↗
PubMed1994

Analysis by in situ hybridization of cytokine mRNA expression in the murine developing thymus.

We have used in situ hybridization to investigate the expression of IL-1, IL-2, IL-4, IL-6 and IFN-gamma genes by thymic cells during fetal development in mice. Two waves of mRNAs were detected in thymic cells for IL-1 at days 16 and 19 of gestation, for IL-2 at days 14 and 18, and for IL-4 at days 14 and 16. Three peaks for IL-6 were observed at days 13, 17 and around birth. Finally, only one peak of cells positive for IFN-gamma was detected. Whereas cells positive for IL-1 were generally grouped and more often localized in the external area of the thymus, the other positive cells were isolated and evenly distributed in the thymus. Our results illustrated the presence of cytokine transcripts in the developing thymus following a developmentally controlled sequence and support the hypothesis that cytokines could play a role in T cell development.

Animals↗
PubMed1992

Analysis by in situ hybridization of cells expressing mRNA for tumor-necrosis factor in the developing thymus of mice.

We have used in situ hybridization to investigate the expression of TNF-alpha genes by thymic cells during fetal development in mice. In 14-day-old fetal thymuses, very scarce cells produce TNF-alpha mRNA. A second phase of cytokine gene expression starts on day 16. The density of positive cells progressively increases up to day 20. Thymuses at 15 days of gestation and after birth do not express detectable cytokine mRNA. In an attempt to identify the nature of the TNF-alpha mRNA-producing cells, acid phosphatase activity, which is characteristic of the macrophage lineage, was studied in the same thymuses. Acid phosphatase-positive cells only appear on day 15. Their frequency increases up to birth. However, no correlation can be established between acid phosphatase--and TNF alpha mRNA--positive cells. The results indicate that a small subset of thymic cells is responsible for TNF-alpha mRNA production during ontogeny: These cells are not yet identified. The possible role of TNF-alpha in thymic ontogeny is discussed.

Acid Phosphatase↗
PubMed1988

Cyclotron production of carrier-free 66Ga as a positron emitting label of albumin colloids for clinical use.

A method for producing carrier free 66Ga (T1/2:9.4 h; beta +) by 4He bombardment of natural copper targets is presented. 66Ga is formed by means of the 63Cu (4He, n) 66Ga reaction. Production yields are given in the 17.5 to 8 MeV 4He energy range. Chemical purification of 66Ga from the copper target is described. The only radionuclidic impurity found in the final product was 67Ga. Albumin colloids from commercially available kits designed for use with 99mTc could easily be labeled with 66Ga and employed for studies of the lymphatic system by positron emission tomography.

Animals↗
PubMed1987

Clinical comparison of 11C-ACPC (aminocyclopentane carboxylic acid) and 13N-ammonia as tumour tracers.

Positron emission tomography is a potential method for exploring the biochemical behaviour of tumours. In 28 patients with known neoplastic lesions a comparison was made between two agents which are known to be accumulated in malignant tumours, viz. 13N-ammonia and 11C-aminocyclopentane carboxylic acid (ACPC). Absolute concentration of both agents in various tumoural tissues and normal organs was calculated. As a rule a parallelism was found between the two tracers as to their accumulation in a given tumour, although the concentration was often higher for ACPC. In normal tissues the ACPC accumulation was either lower or at most equal to NH3 levels. As tumour tracer ACPC is superior to NH3 because of its higher absolute accumulation in many neoplastic lesions and its lower uptake in various non-tumorous tissues. ACPC concentration in tumours seems to be largely independent of blood flow.

Abdominal Neoplasms↗
PubMed1985

Kinetics of 13N-ammonia incorporation in human tumours.

After intravenous injection of 13N-labelled ammonia time-activity curves were obtained in a series of malignant neoplasms in man from serial cross-sectional scans through the tumour, using positron emission tomography. Low noise images with virtually no artefacts were obtained using a maximum likelihood reconstruction technique. Tracer concentration was expressed as a fraction of the injected dose ml-1 of tumour tissue. In a first group (eight observations) maximum activity [0.9 to 5.2 (mean: 3.3) X 10(-5) of administered dose ml-1 of tumour tissue] was attained approximately 1 to 3 min post injection. This peak was followed by a clearance phase with a half-time varying between 28.3 and 112 (mean: 73.1) min. In a second group (of six cases) after an initial rapid rise of the activity, no clearance was detectable during the time of observation, tracer concentration remaining in plateau or even continuing to rise slightly. Maximum activity in this group ranged from 1.1 to 5.3 (mean: 2.6) X 10(-5) of the administered dose ml-1 of tissue. So far no relation has been established between the height and/or shape of the 13NH3 time-activity curve and a particular tumour type.

Adult↗
PubMed1982

Visualization of muscles involved in unilateral tremor using 13N-ammonia and positron emission tomography.

Using positron emission computerized tomography (PCT), a high uptake of IV injected 13N-ammonia was observed in the muscles of the right forearm and leg of a patient with a rightsided static tremor. In some muscles the concentration of 13NH3 was 8.5 times higher than in the symmetrical normal limb. Confrontation of the clinical, neurological, and electromyographic findings with the results of the PCT proved that the muscles with the high uptake corresponded to the muscles responsible for the tremulous movements. There is strong evidence that the high uptake of 13NH3 was related to the increased blood flow produced by the continuous rhythmic exercise of the muscles involved in the tremor. To our knowledge a similar observation has not been described before. It is suggested that the combined use of suitable positron emitters and PCT might provide a valuable tool for the noninvasive study of perfusion of individual skeletal muscles.

Aged↗
PubMed1982

Uptake of 13N-ammonia by human tumours as studied by positron emission tomography.

Tumour uptake of 13N-labelled ammonia was studied by means of positron emission computerised axial tomography in 46 patients with various extensive neoplastic conditions. Eleven of the patients have been followed sequentially before, during and after radio- and/or chemotherapeutic treatment. Substantial accumulation of 13NH3 (up to five times the amount found in comparable normal tissues) was noted in some cases of breast cancer and their metastases, as well as in soft tissue sarcomas, in malignant neck nodes secondary to head and neck tumours, in lung tumours and their metastases, in melanomas, in malignant lymphomas, in metastasis prostatic carcinoma and in the case of ovarian carcinoma examined. Little or no extra uptake of 13NH3 was found ion necrotic or non-malignant tumours or in primary brain tumours, or in some primary breast cancer which otherwise appeared well vascularized and actively growing. In those patients who were followed sequentially, 13NH3 uptake could be seen to decrease with tumour regression. However, during the course of a radiotherapeutic treatment a transitory increase of 13NH3 uptake could be observed. If the therapy had not been successful, 13NH3 uptake was found to persist after treatment. Uptake of 13NH3 in tumours is to be regarded as the result of a complex interaction of both circulatory and metabolic influences. Studies using more specific tracers of flow and tissue metabolism will probably help to unravel the contributory physiological components.

Aged↗