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T M Fliedner

Publications and source records attributed to T M Fliedner.

At least 55 records · Page 3Linked to original sources
PubMed1996

Older workers in the construction industry: results of a routine health examination and a five year follow up.

OBJECTIVE: To describe the health status of older construction workers and the occurrence of early retirement due to disability or of mortality within a five year follow up. METHODS: Firstly, a cross sectional study was performed among 4958 employees in the German construction industry, aged 40-64 years, who underwent standardised routine occupational health examinations in 1986-8. The study population included plumbers, carpenters, painters/varnishers, plasterers, unskilled workers, and white collar workers (control group). Job specific prevalence and age adjusted relative prevalence were calculated for hearing loss, abnormal findings at lung auscultation, reduced forced expiratory volume, increased diastolic blood pressure, abnormalities in the electrocardiogram, increased body mass index, hypercholesterolaemia, increased liver enzymes, abnormal findings in an examination of the musculoskeletal system, and abnormalities of the skin. Secondly, follow up for disability and all cause mortality was ascertained between 1992 and 1994 (mean follow up period = 4.5 y). Job specific crude rates were calculated for the occurrence of early retirement due to disability and for all cause mortality. With Cox's proportional hazards model, job specific relative risks, adjusted for age, nationality, and smoking were obtained. RESULTS: Compared with the white collar workers, a higher prevalence of hearing deficiencies, signs of obstructive lung diseases, increased body mass index, and musculoskeletal abnormalities were found among the construction workers at the baseline exam. During the follow up period, 141 men died and 341 men left the labour market due to disability. Compared with white collar workers, the construction workers showed a 3.5 to 8.4-fold increased rate of disability (P < 0.05 for all occupational groups) and a 1.2 to 2.1-fold increased all cause mortality (NS). CONCLUSIONS: This study shows the need and possibilities for further health promotion in workers employed in the construction industry, targeting both work related conditions and personal lifestyle factors. Rehabilitation measures should be enforced to limit the rate of disability among construction workers.

Adult↗
PubMed1996

Is blood a better source of allogeneic hematopoietic stem cells for use after radiation accidents?

Peripheral blood and cord blood are increasingly used as sources of hematopoietic stem cells. They offer several advantages over bone marrow-derived stem cell grafts and are expected to replace bone marrow transplantation for treatment of malignant hematological disorders and solid tumors. Since the benefit of bone marrow transplantation for treatment of victims of radiation accidents has been seriously questioned, it is reasonable to examine if these alternative stem cell sources may change future strategies. Cord blood is attractive since it is an immediately available and fully characterized allogeneic stem cell source. However, experience with transplants in children suggests that recovery times are too long to benefit a victim of a radiation accident. Because of their potential to rapidly restore hematopoiesis, peripheral blood stem cells may currently be the best stem cell source for a patient who is expected to die from the consequences of prolonged pancytopenia (and not from damage of nonhematopoietic tissue). However, before getting accepted as the optimal stem cell source, the risk of acute and chronic GVHD must be confirmed to be low and unrelated donors must be shown to accept the potential risk of treatment with mobilizing agents. Future strategies should aim at developing methods of transiently rather than permanently engrafting allogeneic stem cells, since essentially all patients exposed to high doses of irradiation are expected to recover autologous marrow function.

Blood Cells↗
PubMed1996

The evolution of clinical peripheral blood stem cell transplantation.

Our growing physiological understanding of hematopoietic progenitor cells has led to the clinical use of circulating progenitor cells, including stem cells, for either reconstitution of hematopoietic function, up to the transduction of functional genes into a self-renewing cell system. In the following, an attempt has been made to recollect the major steps in the evolution of clinical blood stem transplantation, from the morphological description of small lymphocytes circulating in the blood up to somatic gene therapy covering a time period of 87 years.

Animals↗
PubMed1995

Blood stem cell transplantation: from preclinical to clinical models.

This introductory statement to the International Symposium "Ten Years of Blood Stem Cell Transplantation in Heidelberg" provides the opportunity to review the experimental work that was necessary to set the stage for the first successful clinical studies to use blood-derived stem cells to treat hemopoietic and other malignancies. The Ulm University research group used the preclinical canine model to systematically and extensively explore the possibilities and limitations of the therapeutic use of blood-derived hemopoietic stem and progenitor cells. It became clear that blood stem cells are physiological elements of the circulating blood, that their concentration can be drastically increased by chemical and biological means, that they do not lose their function during appropriate cryopreservation, and that they can be "purified" and used successfully to restore hemopoiesis after myeloablative conditioning both in the autologous and allogeneic situation. If compared to fetal liver-derived stem cells, there is excellent experimental evidence that fetal liver-derived stem cells may have even more potential in their ability to restore hemopoiesis, and it is evident that much more experimental work is needed.

Animals↗
PubMed1995

Response of hemopoiesis in dogs to continuous low dose rate total body irradiation.

Among the cytotoxic agents which particularly cause damage to cell renewal systems, ionizing radiation is one of the most effective ones since it leads to inactivation of all types of proliferating cells including resting stem cells. It is the aim of this paper to present the effects of continuous low dose rate total body irradiation (TBI) on hemopoiesis in dogs. The animals were exposed to gamma-rays from a 60-Co source, receiving a daily radiation dose of 0.0188 Gy for indefinite times. Sequential hematological studies performed included determinations of peripheral blood cell counts and of total cell numbers in standardized bone marrow samples, assessments of progenitor cells GM-CFC in the blood and bone marrow, and of colony-stimulating activity (CSA) in the serum. The lymphocytes, the thrombocytes and neutrophilic granulocytes uniformly showed early decreases within the first 200 to 500 days corresponding to cumulative radiation doses in the range up to 3.8 to 9 Gy, but remained stable at subnormal levels in the period up to 1,700 days of exposure. The GM-CFC numbers in bone marrow samples from the rib clearly showed a strong decrease within the first 150 days of exposure preceding the changes in the blood granulocyte concentration. A transient partial recovery of the GM-CFC was observed at later times between 700 and 1,200 days of exposure, followed by another decrease to extremely low values at cumulative doses in the range of 32 Gy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Biologic indicators of exposure: are markers associated with oncogenesis useful as biologic markers of effect?

Radiation-induced molecular and cellular alterations play an important role in the transformation of a normal cell into a cancer cell. However, the basic molecular and cellular alterations upon exposure to ionizing irradiation are still poorly understood. Identification of such alterations would be of importance for the assessment of exposure dose, as well as for the assessment of an exposed individual's risk of developing cancer. Extensive studies of the mechanisms of oncogenesis have led to the identification of altered genes, such as proto-oncogenes and tumor suppressor genes as well as other genes intimately involved in cellular proliferation and differentiation, that are more or less frequently associated with a variety of human malignancies. It can be assumed that at least some of these mechanisms are associated with radiation-induced oncogenesis. The longevity of stem cells, particularly those of the hemopoietic system, makes them the prime target cell population to accumulate genetic alterations due to exposure to a variety of agents. Improvements in purification strategies for hemopoietic stem cells, as well as the availability of sensitive techniques such as the polymerase chain reaction (PCR) and flow cytometry analysis, should allow in-depth studies at the molecular and cellular level after exposure to physical and chemical agents.

Animals↗
PubMed1995

Analysis of gene expression in small numbers of purified hemopoietic progenitor cells by RT-PCR.

Primitive hemopoietic stem cells represent the most probable targets for genetic alterations due to exposure to ionizing irradiation or chemical carcinogens. We have applied a two-step protocol for the purification of CD34+HLA-DR-/low hemopoietic progenitor cells from cord blood (CB). CD34+ cells were isolated by monoclonal antibody (mAb) against CD34 (My10) and immunomagnetic beads. Beads were cleaved off the CD34+ cells by enzymatic treatment with chymopapain. Due to chymopapain-resistance of epitopes recognized by the used mAbs purity control of CD34+ cells and separation into CD34+HLA-DR-/low and CD34+HLA-DR+ subsets could be performed by using flow cytometry. Two miniaturized procedures were applied to isolate poly(A)+ mRNA for the reverse transcription polymerase chain reaction (RT-PCR) from small numbers of CD34+HLA-DR-/low cells. In five experiments, the mean purity of immunomagnetically isolated CD34+ cells was 93.8% +/- 3.9. Flow cytometry sorting of CD34+ cells resulted in pure CD34+HLA-DR-/low populations (purity > 98.8%; range 98.8% to 99.9%; viability > 96%) with an average yield of 2600 +/- 800 cells/5 x 10(7) low density CB cells. By RT-PCR using both poly(A)+ mRNA isolation procedures, sequences corresponding to CD34 and beta 2-microglobulin were amplified from as few as 20 cells. Furthermore, a sequence-independent RT-PCR (SIP-RT-PCR) was applied to amplify the cDNA derived from five erythroblasts isolated from a burst-forming unit-erythroid (BFU-E). Upon hybridization, full-length c-fos message was detected in the SIP-RT-PCR amplified material. Our data demonstrate that gene expression can be detected at the transcriptional level in small numbers of hemopoietic progenitor cells. In addition, the SIP-RT-PCR may allow the amplification of unique mRNA species when subtractive hybridization procedures are performed. The presented data should be useful to analyze gene expression in rare subsets of radiation-exposed immature hemopoietic stem/progenitor cells.

Antigens, CD34↗
PubMed1995

The role of stable chromosome aberrations as biological indicators of radiation effect: studies in patients after total body irradiation and bone marrow transplantation.

The so-called unstable aberrations measured primarily as dicentrics and ring chromosomes are very useful as indicators of human radiation exposure. The role of stable chromosomal aberrations as indicators of radiation effects is not yet known. Stable chromosome aberrations persist longer in radiation-exposed individuals because cells with monocentric aberrations (= stable) have a higher probability of survival after cell division than multicentric or acentric aberrations (= unstable). Aberrations were investigated in 89 patients with chronic myelogenous leukemia undergoing total body irradiation (TBI) for bone marrow transplantation (BMT). Serial follow-up investigations were performed in 31 patients by analyzing lymphocytes of the peripheral blood. Patients had TBI of 10 to 12 Gy as conditioning therapy for BMT. Stable anomalies were investigated by Giemsa-banding and karyotyping in addition to standard analysis. A very high number of cells with stable aberrations was found up to five years after TBI. Investigations of the blood showed that a considerable number of cells with stable aberrations derive from radiation-damaged and clonally expanded hemopoietic precursor cells. We conclude that stable aberrations are useful as indicators of radiation effects in human beings. Clonal stable aberrations represent cellular radiation effects conserved at the stem cell level. Stable aberrations should be analyzed not only by the use of fluorescence in situ hybridization with chromosome painting probes, but also by karyotyping. The latter is necessary to detect stem cell effects by proving the clonal expansion of chromosomal aberrations, and should be performed with the assistance of an automatic chromosome analysis system.

Blood Cells↗
PubMed1995

DNA-damage detection in man after radiation exposure--the comet assay--its possible application for human biomonitoring.

The exposure of human beings to ionizing radiation is still of great concern to occupational and environmental medicine. The goal of this workshop is to identify a panel of biological markers that could be used in humans after exposure to ionizing radiation. The comet assay or single cell gel (SCG) assay is a new method that allows efficient determination of single-strand breaks (SSB) and double-strand breaks (DSB), as well as alkali-labile sites in the DNA of single cells. In order to demonstrate the practicability of the comet assay for the detection of DNA damage caused by low doses of ionizing radiation, we exposed human peripheral blood cells to radiation in vitro. The extent of DNA damage in blood cells irradiated with x-rays (0.05-1 Gy) was significantly increased above the control values even at 0.05 Gy and shows a clear dose-relationship. To investigate the repair kinetics for x-ray-induced DNA damage following acute and chronic (fractionated) irradiation, we exposed peripheral blood to 1 Gy and examined the tail moment at different time intervals. The effect of one acute dose is repaired within two h, whereas the effect of fractionated irradiation gives a totally different result. The tail moment of the initial damage increased indicating an accumulation of the damage, and the repair activity clearly decreased. Until now, there was no data available concerning DNA damage in vivo. For this reason, we explored patients subjected to radioiodine therapy as well as a Chernobyl liquidator.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Haemopoietic cell renewal in radiation fields.

Space flight activities are inevitably associated with a chronic exposure of astronauts to a complex mixture of ionising radiation. Although no acute radiation consequences are to be expected as a rule, the possibility of Solar Particle Events (SPE) associated with relatively high doses of radiation (1 or more Gray) cannot be excluded. It is the responsibility of physicians in charge of the health of astronauts to evaluate before, during and after space flight activities the functional status of haemopoietic cell renewal. Chronic low level exposure of dogs indicate that daily gamma-exposure doses below about 2 cGy are tolerated for several years as far as blood cell concentrations are concerned. However, the stem cell pool may be severely affected. The maintenance of sufficient blood cell counts is possible only through increased cell production to compensate for the radiation inflicted excess cell loss. This behaviour of haemopoietic cell renewal during chronic low level exposure can be simulated by bioengineering models of granulocytopoiesis. It is possible to define a "turbulence region" for cell loss rates, below which an prolonged adaptation to increased radiation fields can be expected to be tolerated. On the basis of these experimental results, it is recommended to develop new biological indicators to monitor haemopoietic cell renewal at the level of the stem cell pool using blood stem cells in addition to the determination of cytokine concentrations in the serum (and other novel approaches). To prepare for unexpected haemopoietic effects during prolonged space missions, research should be increased to modify the radiation sensitivity of haemopoietic stem cells (for instance by the application of certain regulatory molecules). In addition, a "blood stem cell bank" might be established for the autologous storage of stem cells and for use in space activities keeping them in a radiation protected container.

Aerospace Medicine↗
PubMed1994

Cytotoxic immigration of granulocytes into megakaryocytes as a late consequence of irradiation.

The immigration of neutrophilic granulocytes into megakaryocytes was studied in the bone marrow of normal and X-irradiated beagles under various exposure conditions. Two groups of dogs received homogeneous total-body irradiation. One group received a dose of 1.6 Gy and the other received a dose of 2.4 Gy (midline tissue). A third group was irradiated from the left side of the body only. This exposure resulted in an inhomogeneous total-body irradiation (entrance dose 3.8 Gy, exit dose 0.9 Gy). A fourth group of animals received partial-body irradiation with a dose of 11.7 Gy delivered to the anterior two-thirds of the body, thereby subjecting about 70% of the hemopoietic marrow to irradiation. Dogs of a fifth group remained unexposed to irradiation and served as controls. The marrow was analyzed in sections of the ribs approximately 1 year after irradiation. The total number of megakaryocytes in one section was evaluated. The number of megakaryocytes showing granulocytes in their cytoplasm was determined and expressed as a percentage. This phenomenon can be explained as cytotoxic immigration of granulocytes into megakaryocytes. It was observed in approximately 1-2% of the megakaryocytes in the marrow of normal dogs. One year after irradiation the value increased to 10-26%. It was observed that neutrophilic granulocytes penetrated only into the large mature megakaryocytes in which the nuclei were mostly pyknotic. This phenomenon may be considered as a late effect of irradiation.

Animals↗
PubMed1993

Radioprotective effect of N-acetylcysteine on granulocyte/macrophage colony-forming cells of human bone marrow.

N-Acetylcysteine, known as a radical scavenger, was examined for its influence on the radiotolerance of progenitor cells of granulocytopoiesis. Added before and after irradiation in a dose of 2 mg/ml to suspension cultures of non-adherent low-density human bone marrow cells N-acetylcysteine (AcCys) clearly improved the survival. The D0 value of the survival curve for granulocyte/macrophage colony-forming cells increased by a factor of 1.56 as compared to non-treated control suspensions. The improvement of radiation tolerance is probably not only based on the radical scavenger properties (radioprotective component) of AcCys, but also on the support of repair processes.

Acetylcysteine↗
PubMed1992

Haematological effects of rhGM-CSF in dogs exposed to total-body irradiation with a dose of 2.4 Gy.

It was the specific aim of this study to test the stimulatory effects of recombinant human GM-CSF (rhGM-CSF) on haemopoietic regeneration in dogs which had received total-body irradiation (TBI) with a dose of 2.4 Gy. In normal dogs rhGM-CSF given subcutaneously at 10 microgram/kg per day or 30 microgram/kg per day for 21 days caused strong but transient increases in the peripheral blood neutrophils. The monocyte counts also showed a transient rise during treatment in a dose-dependent fashion, whereas the lymphocyte counts increased only at the higher dose of rhGM-CSF and the platelet counts were transiently depressed during the course of the treatment. In the irradiated animals treatment with rhGM-CSF decreased the severity and shortened the duration of neutropenia but had no significant influence on monocyte or lymphocyte recovery. The granulocyte values showed a characteristic pattern of fluctuations with the first peak occurring at the same time (day 10 to day 13) when the abortive rise was observed in the untreated dogs. In contrast the GM-CFC in the peripheral blood remained depressed during the whole treatment course, similar to the untreated irradiated controls. These results indicate that treatment with GM-CSF can be an effective biological monotherapy for radiation-induced bone marrow failure, but that for higher radiation doses the number of GM-CSF responsive target cells will become a critical determinant of therapeutic efficacy.

Animals↗
PubMed1992

Cancer after bone marrow transplantation. IBMTR and EBMT/EULEP Study Group on Late Effects.

Cancer may be serious late effect of marrow transplantation. Radiation, chemotherapy, immunosuppression and the original disease for which transplantation was performed may predispose to the development of cancer. 116 of 9732 patients reported to the IBMTR (International Bone Marrow Transplant Registry) have developed a new malignancy. Late effects were evaluated by the EBMT-EULEP (European Bone Marrow Transplant-European Late Effect Project) Late Effect Study Group in 147 patients surviving 6 years and 79 patients surviving more than 10 years. New malignancies developed in 11 of these patients. Lymphomas and leukemia comprised 73 cases reported to the IBMTR and one case reported to the EBMT-EULEP study. Tumors of the skin, oropharynx, vulva vagina and cervix prevailed in 41 patients with solid tumors. The distribution of malignancies is similar to that observed in organ transplant patients not given radiation or chemotherapy and suggests immunosuppression as a major contributory factor. In dogs the incidence of malignancies was studied after either chemotherapy or total body radiation in various regimens and marrow transplantation. Both chemotherapy and radiation shortened tumor-free survival in comparison to untreated dogs. Higher doses, larger fractions and shorter treatment schedules enhanced earlier tumor development. Soft tissue sarcomas and thyroid carcinoma were most frequent in treated, mammary carcinoma in untreated dogs. In treated dogs deaths from cancer were observed starting at the age of 5 years as compared to untreated dogs at the age of 9 years. The data from animal experiments indicate that the incidence of solid tumors in marrow transplant patients may still rise in the coming decades.

Animals↗
PubMed1991

Autologous blood stem cell (ABSCT) versus purged bone marrow transplantation (pABMT) in standard risk AML: influence of source and cell composition of the autograft on hemopoietic reconstitution and disease-free survival.

Complete and sustained hemopoietic function following myeloablative therapy can be successfully achieved by autologous transfusion of blood derived hemopoietic stem cells. It was the purpose of this study to compare autologous blood stem cell transplantation (ABSCT) in 20 patients with autologous transplantation of a mafosfamide purged marrow (pABMT) in 23 patients; all were transplanted in first complete remission (CR) of acute myelogenous leukemia (AML) using the same pretransplant regimen (14.4 Gy total body irradiation and 200 mg/kg cyclophosphamide). The autografts, mostly differing in source of hemopoietic stem cells, cell composition and CFU-GM number, were evaluated for their ability to reconstitute hemopoiesis and induce long-term disease-free survival (DFS). Prior to harvest, hemopoietic stem cells were mobilized by inducing transient myelosuppression (ara-C 100 mg/m2 every 12 h s.c. days 1-5 and daunorubicin 45 mg/m2, days 3 and 4) followed by an overshooting of peripheral stem cell concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗