Structure and function of bone marrow hemopoiesis: mechanisms of response to ionizing radiation exposure.

It is the purpose of this presentation to review the unique structure and function of bone marrow anchored hematopoiesis in their significance for its response mechanisms to an exposure to ionizing radiation. The ultimate objective of bone marrow hematopoiesis is to maintain in the peripheral blood a constant level of the different blood cell types (erythrocytes, granulocytes, platelets, lymphocytes, etc.). All of them have their particular turnover kinetics (such as granulocytes 120 x 10(9)/d, erythrocytes 200 x 10(9)/d or thrombocytes 150 x 10(9)/d), are semi-autonomous in their steady state regulatory mechanisms and dependent on a life-long supply of mature cells from a stem cell pool with unlimited replicative and pluripotent differentiative potential. The present knowledge of hematopoietic cellular renewal is the result of years of basic experimental and clinical studies using radionuclides in various metabolic forms including (59)Fe, (32)P (DF (32)P), (51)Cr, (131)I, (60)Co, (3)H ((3)HTdR) and (14)C ((14)CTdR). To understand the physiology but in particular the radiation-pathophysiology, it is essential to recognize in detail the infrastructure of the bone marrow as a distinct unit. Indispensable for a life-long cell production is the capsule of the marrow - the bone cortex -, the arterial supply of blood connected to the sinusoidal microvascular architecture with its sinusoids contorti and recti as well as the central (cell collecting) sinusoids. It is further of importance to recognize the significance of nerval regulation of blood flow, characterized by myelinated and unmyelinated nerve fibers. The type of unique lining cells of the sinusoids is the prerequisite for the cell traffic between the hemopoietic parenchyma and the blood. This in turn cannot be achieved without an alternative opening and closing of the sinusoidal segments which - in turn - requires a rigid long capsule to assure an - in toto - constant volume of each bone marrow unit. If a bone marrow unit is exposed to ionizing radiation, a perturbance of the balance between cellular growth pressure and blood flow dynamics can be observed, resulting in a special type of bone marrow hemorrhage and an "excess cell loss" that may result in an non-thrombopenic exhaustion of the stem cell pool. Of great importance is the question as to the mechanisms that allow the bone marrow hemopoiesis to act as one cell renewal system although the bone marrow units are distributed throughout more than 100 bone marrow areas or units in the skeleton. The observation that "the bone marrow" acts and reacts as "one organ" is due to the regulatory mechanisms: the humeral factors (such as erythropoietins, granulopoietins, thrombopoietins etc.), the nerval factors (central nervous regulation) and cellular factors (continuous migration of stem cells through the blood to assure a sufficient stem cell pool size in each bone marrow "sub-unit"). It should be recalled that the bone marrow functions as a physiological chimera and becomes established by the hematogeneic seeding of stem cells to a mesenchymal matrix during embryogenesis. The repopulation of the bone marrow after partial body irradiation, after strongly inhomogeneous radiation exposure or after total body exposure with stem cell transplantation can well be considered as a repetition of the embryogenesis of bone marrow hemopoiesis with the key element of stem cells migrating via the blood to stromal sites of the marrow prepared to accept stem cells to home and start their replication and differentiation if the micro-environmental quality permits. In summary, the radiation biology of bone marrow hemopoiesis requires a thorough understanding of the physiology and pathophysiology of structure, function and regulation not only of the process of cellular renewal but also of the intricate infrastructure.

How to cope with radiation accidents: the medical management.

A concerted action, termed METREPOL, was accepted by the Commission of the European Communities and was started in December 1997. Its purpose was to develop a new approach to the medical management of radiation accident victims with respect to diagnostic procedures and therapeutic options, based on recognition and evaluation of health impairments after acute radiation exposure. The result of this interdisciplinary project is a manual entitled "Medical management of radiation accidents: manual on the acute radiation syndrome". The manual compiles recommendations for assessing the state and outcome of a radiation accident victim in the shortest possible time. Furthermore, it provides guiding support for the medical management of patients accidentally exposed to ionising radiation, based on a new strategic approach for the diagnosis of the acute radiation syndrome: the response category concept. This commentary outlines the background for the development of such a manual and the realisation of the response category concept.

The outcome of local radiation injuries: 14 years of follow-up after the Chernobyl accident.

The Chernobyl nuclear power plant accident on April 26, 1986 was the largest in the history of the peaceful use of nuclear energy. Of the 237 individuals initially suspected to have been significantly exposed to radiation during or in the immediate aftermath of the accident, the diagnosis of acute radiation sickness (ARS) could be confirmed in 134 cases on the basis of clinical symptoms. Of these, 54 patients suffered from cutaneous radiation syndrome (CRS) to varying degrees. Among the 28 patients who died from the immediate consequences of accidental radiation exposure, acute hemopoietic syndrome due to bone marrow failure was the primary cause of death only in a minority. In 16 of these 28 deaths, the primary cause was attributed to CRS. This report describes the characteristic cutaneous sequelae as well as associated clinical symptoms and diseases of 15 survivors of the Chernobyl accident with severe localized exposure who were systematically followed up by our groups between 1991 and 2000. All patients presented with CRS of varying severity, showing xerosis, cutaneous telangiectasias and subungual splinter hemorrhages, hemangiomas and lymphangiomas, epidermal atrophy, disseminated keratoses, extensive dermal and subcutaneous fibrosis with partial ulcerations, and pigmentary changes including radiation lentigo. Surprisingly, no cutaneous malignancies have been detected so far in those areas that received large radiation exposures and that developed keratoses; however, two patients first presented in 1999 with basal cell carcinomas on the nape of the neck and the right lower eyelid, areas that received lower exposures. During the follow-up period, two patients were lost due to death from myelodysplastic syndrome in 1995 and acute myelogenous leukemia in 1998, respectively. Other radiation-induced diseases such as dry eye syndrome (3/15), radiation cataract (5/15), xerostomia (4/15) and increased FSH levels (7/15) indicating impaired fertility were also documented. This study, which analyzes 14 years in the clinical course of a cohort of patients with a unique exposure pattern, corroborates the requirement for long-term, if not life-long, follow-up not only in atomic bomb survivors, but also after predominantly local radiation exposure.

SEARCH: a system for evaluation and archiving of radiation accidents based on case histories.

Overexposure of humans to ionizing radiation has occurred worldwide in the past and will surely occur again in the future. In order to allow an effective radiation accident management, it is consequently necessary to be prepared for such emergency situations and to improve means and ways to help people suffering from radiation-induced health impairments. Such approaches should rely on knowledge and experience gained from previous radiation incidents. A prerequisite for any scientific evaluation and comparison of information related to radiation accidents is to collect data in a standardized way. Therefore, the SEARCH database (System for Evaluation and Archiving of Radiation accidents based on Case Histories) has been developed in our department and implemented as an Oracle 8.0 database containing to date more than 800 case histories. The use of this registry is so far limited to active contributors and requires each contributor to sign a cooperation agreement. More information is available under http://www.faw.uniulm.de/radmed/.

The radiation accident in Georgia: clinical appearance and diagnosis of cutaneous radiation syndrome.

BACKGROUND: Eleven male Georgian soldiers were accidentally exposed to radiation by cesium 137 during their training in a military exercise camp in Lilo, Georgia between November 1996 and May 1997. OBJECTIVE: The characteristic sequelae of accidental cutaneous irradiation and available diagnostic methods are described. METHODS: Magnetic resonance imaging (MRI) of radiation ulcers was performed in all patients; thermography was performed in 2. In 7 patients ulcers and white macules were examined with high-frequency 20 MHz sonography; histologic results were obtained from all patients. RESULTS: Predominant lesions were radiation ulcers in 11 patients and white hairless macules in 7. MRI showed ulcers down to the muscles and an increase of signal intensity in the musculature in 9 cases. The corresponding muscle histology demonstrated vasculitis in 7 patients and necrosis in 2. In 2 patients, MRI signal intensity of the musculature was normal. In 3 patients, 20 MHz sonography showed dermal defects; 1 patient had cutaneous fibrosis. Thermography demonstrated hypothermic zones with extended inflammatory zones adjacent to the radiation ulcers in both patients examined. CONCLUSION: High-frequency 20 MHz sonography, MRI, and thermography are useful noninvasive methods for diagnosis of the extent of cutaneous radiation syndrome and for therapy planning.

Biomarkers of genetic damage and inflammation in blood and bronchoalveolar lavage fluid among former German uranium miners: a pilot study.

Former East German uranium miners who are known to have been exposed to radon are estimated to be at high risk for lung carcinogenesis. Among these miners over 200 occupationally caused lung cancer cases are expected to occur each year, resulting in a total of 7,000-24,000 excess lung cancer cases in the coming years. It is still unknown whether there is a correlation between biomarkers and the exposure of the uranium miners to ionizing radiation that might enable us to trace those miners with high lung cancer risk. The primary aim of this pilot study was to test the possibility of performing a biomarker study in this unique cohort of former uranium miners in spite of several limitations that had to be taken into consideration when comparing them with healthy controls, such as old age, age-dependent diseases and potential confounding artefacts from dissimilar smoking patterns. The second aim was to test a range of biomarkers for DNA damage and inflammation in leukocytes and bronchoalveolar fluid for their ability to detect biological effects. In this cohort of miners we found an increased frequency of chromosomal aberrations in blood lymphocytes and an increased prevalence of both fibronectin and tumour necrosis factor alpha in the bronchoalveolar fluid.

Stable chromosomal aberrations in haemopoietic stem cells in the blood of radiation accident victims.

PURPOSE: The detection of long-term persistent chromosome aberrations in circulating haemopoietic stem cells after accidental radiation exposure. MATERIAL AND METHODS: Peripheral blood samples from highly exposed persons were collected 7-25 years after the radiation accidents in Moscow (1971), Kazan (1975) and Chernobyl (1996). Haemopoietic blood stem cells were analysed when investigating individual colonies derived from haemopoietic progenitor cells: burst-forming units-erythroid (BFU-E), granulocyte-macrophage-colony-forming cells (GM-CFC) and multipotent granulocyte-erythrocyte-macrophage- megakaryocyte-colony-forming cells (GEMM-CFC). Colony formation was obtained in methylcellulose cultures. Chromosome preparations in single colonies were performed using a microtechnique. RESULTS: Nine patients were investigated at 1 to 4 follow-up time points after radiation exposure. Three hundred and thirty-four single colonies were analyzed resulting in 1375 mitoses. It was found that colonies showed chromosome aberrations (ChA) up to 25 years after radiation exposure by classical cytogenetics and by fluorescence in situ hybridization (FISH). Stable aberrations were detected in 21% of colonies. They were clonal in 19% of colonies, i.e. the same abnormality was found in all cells derived from a single colony. In 2% of colonies ChA were stable but non-clonal; unstable ChA were not observed. CONCLUSIONS: The results indicate that blood-derived haemopoietic stem cells may serve as a biological indicator to detect radiation-induced ChA. Since they are considered to be in dynamic and functional exchange with stem cells in the medullary sites of blood cell formation such as bone marrow, the use of blood stem cells as a marker of radiation effects should be explored to assess the repair status of the stem cell pool as such.

Internet-based physician's workbench as user interface for a central medical case repository.

Two World Health Organization Radiation Medical Emergency Preparedness and Assistance Network centers have constructed a standardized central repository of acute radiation syndrome case histories. The case histories are stored on a database server. Radiation protection centers can remotely access the database by user-friendly client software over the Internet. Physicians can use the medical information system to retrieve similar case histories for decision support, to improve their medical knowledge by inspecting real case histories, and for research on the acute radiation syndrome. The system architecture is presented and it is shown in detail how the information system can be employed to deliver medical decision support. Dialogue-response times over narrow-bandwidth Internet connections are better than when using conventional World-Wide-Web technology. However, the latter does not require the installation of client software other than a browser. A Java applet as client could combine the advantages of the two approaches.

Project RATEMA--one year's experience.

The RATEMA project is an international cooperation between the University of Ulm in Germany and the Urals Research Centre for Radiation Medicine in Chelyabinsk, Russia. For one year we conducted weekly conferences between the two sites, based on a satellite link with a 384 kbit/s connection. During the videoconferences the physicians on both sides--experts in radiation medicine--discussed the health status of Russian patients who had been chronically exposed to ionizing radiation in the South Urals region. The German partners presented patients with comparable haematological and oncological diseases. The project has shown the advantages and difficulties of working in an international and interdisciplinary environment. The experience gained has been very valuable for planning new projects with similar tasks. The results and the contents of the RATEMA database are the basis for education and research for physicians involved in the management of radiation victims.

Laser pyrolysis products-genotoxic, clastogenic and mutagenic effects of the particulate aerosol fractions.

Laser therapy has gained wide acceptance and application in many medical disciplines. Nevertheless, during surgical procedures, the thermal destruction of tissue creates a smoke plume. Recent research data indicate that pyrolysates liberated during vaporisation of tissue induce DNA damage. However, assessing potential health hazards during medical laser treatment requires comprehensive insight into the cytotoxic, genotoxic, clastogenic and mutagenic capacity of laser pyrolysis products (LPP). Therefore, the aim of this study was to evaluate the cytotoxic, genotoxic, clastogenic and mutagenic potential of substances resulting from laser irradiation. Four different types of porcine tissues were irradiated with a surgical CO2 laser, the aerosols were sampled under defined conditions and subjected to the SCE test, micronucleus test and the HPRT test. The results showed that the pyrolysis products are strong inducers of cytotoxic effects. The pyrolysis products induced positive effects in the SCE test, micronucleus test and the HPRT test. The ability and extent to induce genotoxic and mutagenic effects turned out to be dependent on the type of tissue that had been irradiated. In general, the effects were most pronounced with liver pyrolysate. In all test systems, a clear dose relationship could be established. In conclusion, we were able to prove that the particulate fraction of laser pyrolysis aerosols originating from biological tissues undoubtedly have to be classified as cytotoxic, genotoxic, clastogenic and mutagenic. Therefore, they could be potential health hazards for humans.

Relapse in chronic myeloid leukemia after bone marrow transplantation: biomathematical modeling as a new approach to understanding pathogenesis.

A biomathematical model was developed to simulate relapse development in patients with chronic myeloid leukemia (CML) following bone marrow transplantation (BMT). The purpose of this study was to better understand the pathophysiology of the time evolution of CML relapse and to provide means whereby the outcomes of patients with CML relapse can be projected and treatment modified accordingly. The model consists of three parallel series of catenated compartments representing granulopoiesis in normal (donor) cells from the marrow, in CML cells from the marrow, and in CML cells from extramedullary sites. It was assumed that CML stem cells were resistant to feedback control and that CML-derived neutrophils, as well as normal neutrophils, exercised feedback regulation of normal stem cells. The known longer generation times for CML neutrophil precursors compared with normal neutrophil precursors were used, and it was assumed that 10(7) pluripotential stem cells were infused with BMT. The model was evaluated for its ability to simulate the reappearance of CML (Philadelphia chromosome positive) metaphases in the marrow and the recovery pattern in the blood neutrophil count in six patients who had relapsed following BMT (allogeneic in three patients, allogeneic with T-cell depletion in two patients, and syngeneic in one patient). The variables tested included the site of origin of the CML stem cells responsible for relapse (marrow alone versus marrow and extramedullary sites), the minimum number of CML stem cells responsible for relapse, and the time delay between BMT and the onset of relapse. Model profiles based on the observed values were obtained in each case. The simulations pointed to the fact that relapse began from a small number of CML cells in medullary and extramedullary sites. The time delay between BMT and the onset of relapse varied from 15 to 240 days. We suggest that this biomathematical model should be further investigated as a possible means of predicting outcome and guiding the treatment for patients with CML relapsing after BMT.

Light on population health status.

A new approach to illustrating and analysing health status is presented which allows comparisons of various aspects of health in a population at different times and in different populations during given periods. Both quantitative and qualitative elements can be represented, the impact of interventions can be monitored, and the extent to which objectives are achieved can be assessed. The practical application of the approach is demonstrated with reference to the health profiles to Tunisia in 1966 and 1994.

PIP: In response to a World Health Organization's Global Advisory Committee on Health Research initiative, a "visual health information profile" was developed that provides a quantitative description of and an assessment of multidimensional aspects of health in a population. The profile uses a hierarchy of indicators, with first-level domains covering: 1) disease conditions and health impairments, 2) the health care system, 3) sociocultural characteristics, 4) environmental determinants, and 5) food and nutrition. Indicators at all levels can be disaggregated. A decile reference method can be used to display indicators by country and to rank performance for specific years, thus allowing country and time comparisons. The circular visual health information profile has radial sectors representing health domains (with sectors representing the indicators in each domain). Scaling is arranged so that situations needing urgent attention are displayed on the periphery. With fixed reference points, comparisons can be made over time. A prototype of this profile is available via the World Wide Web at http://faw.uni-ulm.de/planet/health-profile/circle.html. The profile was evaluated by superimposing indicators for Tunisia for 1994 over those for 1966. Because of the immediate impact of the visual display of information, the profile, which can be applied to indicators at various levels, can contribute to the improvement of public health.

The role of blood stem cells in hematopoietic cell renewal.

It has been the purpose of this keynote address to review available evidence for the notion that the stem and progenitor cells circulating in the peripheral blood play a decisive role in the homeostasis of blood cell formation distributed throughout dozens of bone marrow units in the skeleton. Furthermore, if this notion is correct, one could speculate that the quantity and quality of stem and progenitor cells in the blood should reflect the functional state of the hematopoietic stem cell system throughout the skeletal bone marrow and provide a new tool for the evaluation of alteration in blood cell production. On this basis, the following questions are considered: A) What do we know about the quality and quantity of blood stem cells in steady-state conditions? B) In what way do blood stem cells respond to perturbations of the "steady-state" of blood cell formation? C) Which role do blood stem cells play during hemopoietic development assuming that the establishment of bone marrow hemopoiesis requires the "seeding" of blood stem cells into an appropriate cellular environment? D) What is the role of blood stem cells in hemopoietic regeneration after partial body irradiation with a small volume of marrow (and hence stem cells) protected? and E) What are the mechanisms and/or kinetics of hemopoietic recovery if stem cells introduced into the circulation were collected from exogenous (autologous or allogeneic) sources? In this review presentation, experimental work of our group and of other members of the scientific community is summarized. It becomes obvious that blood stem and progenitor cells play a key role in hematopoietic homeostasis. Furthermore, their physiology and pathophysiology deserve rigorous experimental studies in order to develop a novel tool in the diagnosis and prognosis of neoplastic and non-neoplastic disorders of blood cell formation.

Telematics in research planning processes: an example from global health.

It is increasingly recognized that the appropriate application of information and communication technology can substantially improve communication and cooperative work processes in terms of quantity, quality and cost-effectiveness. Within large organizations, strategic decision making is one of the key cooperative processes which have to be faced. In this paper the authors discuss one example of this class of cooperative processes: research planning within the World Health Organization (WHO). The paper presents conceptual details of a process designed to assist in creating global networks of scientists, planners and field workers interested in cooperating to promote health development activities of WHO. The implementation of this process was realized in an Internet-based system to support global research planning. In particular, this application shows that the utilization of information and communication technology can not only quantitatively change existing processes, but can create new ones--and on a qualitatively improved level.

Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and all-cause mortality.

BACKGROUND: Gamma-glutamyl transferase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) are widely used as markers of hepatobiliary disorders in occupational health surveillance. Little is known, however, about the prevalence and occupational and non-occupational determinants of elevated levels of these enzymes in specific occupational groups or about the prognostic value of elevated levels with respect to long-term outcomes such as all-cause mortality and vocational disability. METHODS: A cohort study was conducted among 8,043 male construction workers aged 25-64 years who had undergone occupational health examinations in 6 centers in southern Germany from 1986 to 1988 and had been followed until 1994. The prevalence of elevated levels of GGT, ALT, and AST, depending on the sociodemographic and medical characteristics determined at the baseline examination and the risk of vocational disability and all-cause mortality in relation to elevated liver enzyme activity at baseline were assessed. Covariates considered in multivariate analysis included age, nationality, occupation, body mass index (BMI), smoking, and alcohol consumption. RESULTS: The baseline prevalence of elevated activity levels of GGT (>28 U/1 at 25 degrees C), ALT (>22 U/1), and AST (>18 U/1) was 32%, 22%, and 12%, respectively. Factors most strongly related to elevated serum activity levels for all three enzymes were self-reported alcohol consumption, diabetes, and hypertension. BMI was strongly associated with elevations in GGT and ALT but not in AST. Elevated levels of AST and GGT were strongly related to early retirement and all-cause mortality. Men with AST levels exceeding 18 U/1 had a 2-fold risk of early retirement and a 3 times higher risk of all-cause mortality as compared with men with lower AST levels. No significant association was observed between ALT and either of the long-term outcomes. CONCLUSIONS: Our findings suggest that screening for elevated GGT and AST levels, which are a common finding among construction workers, may be a powerful tool for the identification of individuals at increased risk of early retirement and preterm mortality and may be helpful in targeting of prevention efforts.