Public health response and medical management of internal contamination in past radiological or nuclear incidents: A narrative review.

Following a radiological or nuclear emergency, workers, responders and the public may be internally contaminated with radionuclides. Screening, monitoring and assessing any internal contamination and providing necessary medical treatment, especially when a large number of individuals are involved, is challenging. Experience gained and lessons learned from the management of previous incidents would help to identify gaps in knowledge and capabilities on preparedness for and response to radiation emergencies. In this paper, eight large-scale and five workplace radiological and nuclear incidents are reviewed cross 14 technical areas, under the broader topics of emergency preparedness, emergency response and recovery processes. The review findings suggest that 1) new strategies, algorithms and technologies are explored for rapid screening of large populations; 2) exposure assessment and dose estimation in emergency response and dose reconstruction in recovery process are supported by complementary sources of information, including 'citizen science'; 3) surge capacity for monitoring and dose assessment is coordinated through national and international laboratory networks; 4) evidence-based guidelines for medical management and follow-up of internal contamination are urgently needed; 5) mechanisms for international and regional access to medical countermeasures are investigated and implemented; 6) long-term health and medical follow up programs are designed and justified; and 7) capabilities and capacity developed for emergency response are sustained through adequate resource allocation, routine non-emergency use of technical skills in regular exercises, training, and continuous improvement.

Modeling principles of protective thyroid blocking.

PURPOSE: In the case of a nuclear incident, the release of radioiodine must be expected. Radioiodine accumulates in the thyroid and by irradiation enhances the risk of cancer. Large doses of stable (non-radioactive) iodine may inhibit radioiodine accumulation and protect the thyroid ('thyroid blocking'). Protection is based on a competition at the active carrier site in the cellular membrane and an additional temporary inhibition of the organification of iodide (Wolff-Chaikoff effect). Alternatively, other agents like e.g. perchlorate that compete with iodide for the uptake into the thyrocytes may also confer thyroidal protection against radioiodine exposure.Biokinetic models for radioiodine mostly describe exchanges between compartments by first order kinetics. This leads to correct predictions only for low (radio)iodide concentrations. These models are not suited to describe the kinetics of iodine if administered at the dosages recommended for thyroid blocking and moreover does not permit to simulate either the protective competition mechanism at the membrane or the Wolff-Chaikoff effect. Models adapted for this purpose must be used. Such models may use a mathematical relation between the serum iodide concentration and a relative uptake suppression or a dependent rate constant determining total thyroidal radioiodine accumulation. Alternatively, the thyroidal uptake rate constant may be modeled as a function of the total iodine content of the gland relative to a saturation amount. Newer models integrate a carrier-mechanism described by Michalis-Menten kinetics in the membrane and in analogy to enzyme kinetics apply the rate law for monomolecular irreversible enzyme reactions with competing substrates to model the competition mechanism. An additional total iodide uptake block, independent on competition but limited in time, is used to simulate the Wolff-Chaikoff effect. CONCLUSION: The selection of the best model depends on the issue to be studied. Most models cannot quantify the relative contributions of the competition mechanism at the membrane and the Wolff-Chaikoff effect. This makes it impossible or exceedingly difficult to simulate prolonged radioiodine exposure and the effect of repetitive administrations of stable iodine. The newer thyroid blocking models with a separate modeling of competition and Wolff-Chaikoff effect allow better quantitative mechanistic insights and offer the possibility to simulate complex radioiodine exposure scenarios and various protective dosage schemes of stable iodine relatively easily. Moreover, they permit to study the protective effects of other competitors at the membrane carrier site, like e.g. perchlorate, and to draw conclusions on their protective efficacy in comparison to stable iodine.

Ascorbic acid-2 glucoside mitigates intestinal damage during pelvic radiotherapy in a rat bladder tumor model.

PURPOSE: Ascorbic acid is a strong antioxidant and has potent radioprotective effects on radiation injuries. Ascorbic acid 2-glucoside (AA2G) is a stabilized derivative of ascorbic acid and rapidly hydrolyzed into ascorbic acid and glucose. Since there is the possibility that AA2G treatment interferes with the antitumor activity of radiotherapy, we investigated the effect of AA2G treatment during radiotherapy on acute radiation enteritis and antitumor activity of radiotherapy in rats. MATERIALS AND METHODS: AY-27 rat bladder tumor cells were used to induce bladder tumors in rats. Two weeks after inoculation rats received fractionated pelvic radiotherapy in eight fractions for 4 weeks totaling 40 Gy. During radiotherapy, one group of rats received per os AA2G (ascorbic acid: 250 mg/kg/day) and its bolus engulfment (ascorbic acid: 250 mg/kg) 8 h before each X-irradiation fraction. Seven days after the last X-irradiation, we studied histology, DNA double strand break (DSB) damage (by 53BP1 foci staining), and the M1/M2 macrophage response by immunohistochemistry of paraffin-fixed bladder and intestinal tissues. RESULTS: AA2G treatment reduced the intestinal damage (shortening of villi) but did not reduce antitumor effectiveness of radiotherapy against bladder tumors. Like the controls, AA2G-treated rats showed no residual tumor lesions in the bladder after X-irradiation. Both AA2G-treated and control groups showed similar persistent DSB damage (53BP1 foci) both in bladders and ilea seven days after radiotherapy. Radiotherapy tended to reduce CD163+ M2 macrophages, which are considered as an anti-inflammatory subtype favoring tissue repair, in the bladders. X-irradiation also reduced the occurrence of M2 macrophages in the ilea. AA2G treatment significantly increased CD163+/CD68+ macrophage ratio in the ilea of rats after pelvic irradiation in comparison to the sham irradiated control rats. AA2G treatment increased, albeit not significantly, the CD163+/CD68+ macrophage ratio in the irradiated bladders relative to the control irradiated rats. On the other hand, bladders and ilea of the irradiated rats with and without AA2G treatment showed similar frequencies of CD68+ macrophages. CONCLUSIONS: AA2G treatment mitigated radiation-induced intestinal damage without reducing antitumor activity after fractionated pelvic radiotherapy against bladder tumors in rats. The beneficial effect of AA2G treatment seems to promote a restoration of the M2 answer as well as tissue remodeling and wound healing. Similar residual DNA damage in bladders and ilea seven days post-irradiation is consistent with tumor control in both groups.

mRNA and small RNA gene expression changes in peripheral blood to detect internal Ra-223 exposure.

PURPOSE: Excretion analysis is the established method for detection of incorporated alpha-emitting radionuclides, but it is laborious and time consuming. We sought a simplified method in which changes in gene expression might be measured in human peripheral blood to detect incorporated radionuclides. Such an approach could be used to quickly determine internal exposure in instances of a radiological dispersal device or a radiation accident. MATERIALS AND METHODS: We evaluated whole blood samples from five patients with castration-resistant prostate cancer and multiple bone metastases (without visceral or nodal involvement), who underwent treatment with the alpha emitting isotope Radium-223 dichloride (Ra-223, Xofigo®). Patients received about 4 MBq per cycle and, depending on survival and treatment tolerance, were followed for six months. We collected 24 blood samples approximately monthly corresponding to treatment cycle. RESULTS: Firstly, we conducted whole genome screening of mRNAs (mRNA seq) and small RNAs (small RNA seq) using next generation sequencing in one patient at eight different time points during all six cycles of Ra-223-therapy. We identified 1900 mRNAs and 972 small RNAs (222 miRNAs) that were differentially up- or down-regulated during follow-up after the first treatment with Ra-223. Overall candidate RNA species inclusion criteria were a general (≥|2|-fold) change or with peaking profiles (≥|5|-fold) at specific points in time. Next we chose 72 candidate mRNAs and 101 small RNAs (comprising 29 miRNAs) for methodologic (n = 8 samples, one patient) and independent (n = 16 samples, four patients) validation by qRT-PCR. In total, 15 mRNAs (but no small RNAs) were validated by methodologic and independent testing. However, the deregulation occurred at different time points, showing a large inter-individual variability in response among patients. CONCLUSIONS: This proof of concept provides support for the applicability of gene expression measurements to detect internalized alpha-emitting radionuclides, but further work is needed with a larger sample size. While our approach has merit for internal deposition monitoring, it was complicated by the severe clinical condition of the patients we studied.

Estimation of radiation-induced health hazards from a "dirty bomb" attack with radiocesium under different assault and rescue conditions.

In the case of a terrorist attack by a "dirty bomb", blast injuries, external irradiation and the incorporation of radioactivity are to be expected. Departing from information about the radiological attack scenario with cesium-137 in the U.S. National Scenario Planning Guide, we estimated the radiological doses absorbed. Similar calculations were performed for a smaller plume size and a detonation in a subway. For conditions as described in the U.S. scenario, the committed effective dose amounted to a maximum of 848 mSv, even for very unfavorable conditions. Red bone marrow equivalent doses are insufficient to induce acute radiation sickness (ARS). In the case of a smaller plume size, the ARS threshold may be exceeded in some cases. In a subway bombing, doses are much higher and the occurrence of ARS should be expected. The health hazards from a dirty bomb attack will depend on the location and the explosive device. The derived Haddon matrix indicates that preparing for such an event includes education of all the medical staff about radiation effects, the time lines of radiation damages and the treatment priorities. Further determinants of the outcome include rapid evacuation even from difficult locations, the availability of a specific triage tool to rapidly identify victims at risk for ARS, the availability of an antidote stockpile and dedicated hospital beds to treat seriously irradiated victims.

Preparing for a "dirty bomb" attack: the optimum mix of medical countermeasure resources.

BACKGROUND: In radiological emergencies with radionuclide incorporation, decorporation treatment is particularly effective if started early. Treating all people potentially contaminated ("urgent treatment") may require large antidote stockpiles. An efficacious way to reduce antidote requirements is by using radioactivity screening equipment. We analyzed the suitability of such equipment for triage purposes and determined the most efficient mix of screening units and antidote daily doses. METHODS: The committed effective doses corresponding to activities within the detection limits of monitoring portals and mobile whole-body counters were used to assess their usefulness as triage tools. To determine the optimal resource mix, we departed from a large-scale scenario (60,000 victims) and based on purchase prices of antidotes and screening equipment in Germany, we calculated efficiencies of different combinations of medical countermeasure resources by data envelopment analysis. Cost-effectiveness was expressed as the costs per life year saved and compared to risk reduction opportunities in other sectors of society as well as the values of a statistical life. RESULTS: Monitoring portals are adequate instruments for a sensitive triage after cesium-137 exposure with a high screening throughput. For the detection of americium-241 whole-body counters with a lower daily screening capacity per unit are needed. Assuming that 1% of the potentially contaminated patients actually need decorporation treatment, an efficient resource mix includes 6 monitoring portals and 25 mobile whole-body counters. The optimum mix depends on price discounts and in particular the fraction of victims actually needing treatment. The cost-effectiveness of preparedness for a "dirty bomb" attack is less than for common health care, but costs for a life year saved are less than for many risk-reduction interventions in the environmental sector. CONCLUSION: To achieve economic efficiency a high daily screening capacity is of major importance to substantially decrease the required amount of antidote doses. Among the determinants of the number of equipment units needed, the fraction of the potentially contaminated victims that actually needs treatment is the most difficult to assess. Judging cost-effectiveness of the preparedness for "dirty bomb" attacks is an issue of principle that must be dealt with by political leaders.

Heterogeneous nuclear ribonucleoprotein K is overexpressed and contributes to radioresistance irrespective of HPV status in head and neck squamous cell carcinoma.

Radiotherapy is a major treatment option for head and neck squamous cell carcinoma (HNSCC). However, the success of radiotherapy is limited by tumor cell resistance to ionizing radiation (IR). Clinical studies have demonstrated an overall improved prognosis and higher susceptibility to radiotherapy of high­risk human papillomavirus (HPV)­associated HNSCC compared with classic HNSCC, as well as worse overall survival for male HNSCC patients. Overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) K has been associated with resistance to radiotherapy in melanoma and colorectal carcinoma. The aim of the present study was to analyze the impact of hnRNP K expression on the aggressiveness and radioresistance of HNSCC with respect to patient sex and HPV status. Immunohistochemical staining of HNSCC tissue specimens revealed elevated hnRNP K levels compared with those in the non­neoplastic epithelium. Cytoplasmic hnRNP K accumulation was associated with advanced tumor stage and male sex. Exposure of HNSCC cells to IR was followed by rapid upregulation of hnRNP K at the protein level, along with re­localization from the tumor cell nucleus to the cytoplasm. siRNA­based knockdown of hnRNP K induced apoptosis and abolished tumor formation after xenotransplantation of HNSCC cells onto the chick egg chorioallantoic membrane (CAM). The observed effects were independent of the respective HPV status of the cell lines. These results indicated a tumorigenic and anti­apoptotic role of hnRNP K in HNSCC, which appeared to be enhanced in male patients and contributed to the radioresistance of these tumors. However, the radioprotective effects of hnRNP K were found to be independent of the tumor's HPV status.

A comparison of thyroidal protection by stable iodine or perchlorate in the case of acute or prolonged radioiodine exposure.

In the case of a nuclear power plant accident, repetitive/prolonged radioiodine release may occur. Radioiodine accumulates in the thyroid and by irradiation enhances the risk of cancer. Large doses of non-radioactive iodine may protect the thyroid by inhibiting radioiodine uptake into the gland (iodine blockade). Protection is based on a competition at the active carrier site in the cellular membrane and the Wolff-Chaikoff effect, the latter being, however, only transient (24-48 h). Perchlorate may alternatively provide protection by a carrier competition mechanism only. Perchlorate has, however, a stronger affinity to the carrier than iodide. Based on an established biokinetic-dosimetric model developed to study iodine blockade, and after its extension to describe perchlorate pharmacokinetics and the inhibition of iodine transport through the carrier, we computed the protective efficacies that can be achieved by stable iodine or perchlorate in the case of an acute or prolonged radioiodine exposure. In the case of acute radioiodine exposure, perchlorate is less potent than stable iodine considering its ED50. A dose of 100 mg stable iodine has roughly the same protective efficacy as 1000 mg perchlorate. For prolonged exposures, single doses of protective agents, whether stable iodine or perchlorate, offer substantially lower protection than after acute radioiodine exposure, and thus repetitive administrations seem necessary. In case of prolonged exposure, the higher affinity of perchlorate for the carrier in combination with the fading Wolff-Chaikoff effect of iodine confers perchlorate a higher protective efficacy compared to stable iodine. Taking into account the frequency and seriousness of adverse effects, iodine and perchlorate at equieffective dosages seem to be alternatives in case of short-term acute radioiodine exposure, whereas preference should be given to perchlorate in view of its higher protective efficacy in the case of longer lasting radioiodine exposures.

Bardoxolone-Methyl (CDDO-Me) Impairs Tumor Growth and Induces Radiosensitization of Oral Squamous Cell Carcinoma Cells.

Radiotherapy represents a common treatment strategy for patients suffering from oral squamous cell carcinoma (OSCC). However, application of radiotherapy is immanently limited by radio-sensitivity of normal tissue surrounding the tumor sites. In this study, we used normal human epithelial keratinocytes (NHEK) and OSCC cells (Cal-27) as models to investigate radio-modulating and anti-tumor effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid methyl ester (CDDO-Me). Nanomolar CDDO-Me significantly reduced OSCC tumor xenograft-growth in-ovo applying the chick chorioallantoic membrane (CAM) assay. In the presence of CDDO-Me reactive oxygen species (ROS) were found to be reduced in NHEK when applying radiation doses of 8 Gy, whereas ROS levels in OSCC cells rose significantly even without radiation. In parallel, CDDO-Me was shown to enhance metabolic activity in malignant cells only as indicated by significant accumulation of reducing equivalents NADPH/NADH. Furthermore, antioxidative heme oxygenase-1 (HO-1) levels were only enhanced in NHEK and not in the OSCC cell line, as shown by immunoblotting. Clonogenic survival was left unchanged by CDDO-Me treatment in NHEK but revealed to be abolished almost completely in OSCC cells. Our results indicate anti-cancer and radio-sensitizing effects of CDDO-Me treatment in OSCC cells, whereas nanomolar CDDO-Me failed to provoke clear detrimental consequences in non-malignant keratinocytes. We conclude, that the observed differential aftermath of CDDO-Me treatment in malignant OSCC and non-malignant skin cells may be utilized to broaden the therapeutic range of clinical radiotherapy.

Development of New Biokinetic-Dosimetric Models for the Simulation of Iodine Blockade in the Case of Radioiodine Exposure in Man.

In the case of nuclear incidents, radioiodine may be liberated. After incorporation it accumulates in the thyroid and by internal irradiation enhances the risk of cancer occurrence. By administering a large dose of non-radioactive iodine the uptake of radioiodine into the gland can be inhibited ("iodine blockade"). Biokinetic models using first order kinetics are not suited to simulate iodine blockade, as the uptake into the gland is mediated by a saturable active transport. Therefore, we integrated an uptake mechanism described by a Michaelis-Menten kinetic into a simple ICRP biokinetic model. We moreover added a total uptake blocking mechanism representing the Wolff-Chaikoff effect becoming active when the gland is saturated with iodine. The validity of the model was ascertained by comparison with IMBA software. The competition of radioiodine and stable iodine at the membrane carrier site was modeled according to the rate law for monomolecular reactions for competing substrates. Our simulations show that competition for the uptake at the membrane carrier site accounts for about 60% and the saturation of the gland with iodine for over 35% of the total protective efficacy that exceeds 95%. Following acute radioiodine exposure, it is preferable to administer a single large dose of stable iodine. In the case of continuous radioiodine exposure, a single dose of stable iodine is less effective than after an acute exposure and splitting the total available dose and shortening the dosage intervals enhance efficacy. Model-based simulations may be a useful tool to develop antidote dosage schemes for uncommon emergencies.

Pharmacological treatment of inhalation injury after nuclear or radiological incidents: The Chinese and German approach.

Inhalation injury is often associated with burns and significantly increases morbidity and mortality. The main toxic components of fire smoke are carbon monoxide, hydrogen cyanide, and irritants. In the case of an incident at a nuclear power plant or recycling facility associated with fire, smoke may also contain radioactive material. Medical treatments may vary in different countries, and in this paper, we discuss the similarities and differences in the treatments between China and Germany. Carbon monoxide poisoning is treated by 100% oxygen administration and, if available, hyperbaric oxygenation in China as well as in Germany. In addition, antidotes binding the cyanide ions and relieving the respiratory chain are important. Methemoglobin-forming agents (e.g., nitrites, dimethylaminophenol) or hydroxocobalamin (Vitamin B12) are options. The metabolic elimination of cyanide may be enhanced by sodium thiosulfate. In China, sodium nitrite with sodium thiosulfate is the most common combination. The use of dimethylaminophenol instead of sodium nitrite is typical for Germany, and hydroxocobalamin is considered the antidote of choice if available in cases of cyanide intoxications by fire smoke inhalation as it does not further reduce oxygen transport capacity. Systematic prophylactic use of corticosteroids to prevent toxic pulmonary edema is not recommended in China or Germany. Stable iodine is indicated in the case of radioiodine exposure and must be administered within several hours to be effective. The decorporation of metal radionuclides is possible with Ca (DTPA) or Prussian blue that should be given as soon as possible. These medications are used in both countries, but it seems that Ca (DTPA) is administered at lower dosages in China. Although the details of the treatment of inhalation injury and radionuclide(s) decorporation may vary, the general therapeutic strategy is very similar in China and Germany.

Medical management of victims contaminated with radionuclides after a "dirty bomb" attack.

A wide spectrum of scenarios may lead to radiation incidents and the liberation of radioactive material. In the case of a terrorist attack by a "dirty bomb", there is a risk of mechanical and thermal trauma, external irradiation, superficial contamination and incorporation of radioactive material. The first treatment priority must be given to the care of trauma patients with life-threatening injuries, as the health effects of radiation occur with latency. Radionuclide incorporation will lead to a longer-lasting irradiation from inside the body, associated with a higher risk of stochastic radiation effects (e.g., occurrence of tumors) in the long run. It must be expected that victims with potentially incorporated radionuclides will far outnumber trauma patients. The elimination of radionuclides can be enhanced by the administration of decorporation agents such as (Ca) Diethylenetriaminepentaacetic acid (DTPA) or Prussian blue, reducing the radiological burden of the body. There is still no consensus whether decorporation treatment should be started immediately based only on a suspicion of radionuclide incorporation ("urgent approach") or if the results of internal dosimetry confirming the necessity of a treatment should be awaited, accepting the delay caused by the measurements and computations ("precautionary approach"). As the therapeutic effectiveness may be substantially decreased if treatment initiation is delayed only by several days, depending on the radionuclide, the physicochemical properties of the compounds involved and the route of absorption, we favor an "urgent approach" from a medical point of view. In doubt, it seems justified to treat victims by precaution, as the adverse effects of the medication seem minimal. However, in the case of a high number of victims, an "urgent treatment approach" may require a large number of daily doses of antidotes, and therefore, adequate investments in preparedness and antidote stockpiling are necessary.

Anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related human papillary thyroid carcinoma after the Chernobyl accident.

Childhood radiation exposure has been associated with increased papillary thyroid carcinoma (PTC) risk. The role of anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related PTC remains unclear, but STRN-ALK fusions have recently been detected in PTCs from radiation exposed persons after Chernobyl using targeted next-generation sequencing and RNA-seq. We investigated ALK and RET gene rearrangements as well as known driver point mutations in PTC tumours from 77 radiation-exposed patients (mean age at surgery 22.4 years) and PTC tumours from 19 non-exposed individuals after the Chernobyl accident. ALK rearrangements were detected by fluorescence in situ hybridisation (FISH) and confirmed with immunohistochemistry (IHC); point mutations in the BRAF and RAS genes were detected by DNA pyrosequencing. Among the 77 tumours from exposed persons, we identified 7 ALK rearrangements and none in the unexposed group. When combining ALK and RET rearrangements, we found 24 in the exposed (31.2%) compared to two (10.5%) in the unexposed group. Odds ratios increased significantly in a dose-dependent manner up to 6.2 (95%CI: 1.1, 34.7; p = 0.039) at Iodine-131 thyroid doses >500 mGy. In total, 27 cases carried point mutations of BRAF or RAS genes, yet logistic regression analysis failed to identify significant dose association. To our knowledge we are the first to describe ALK rearrangements in post-Chernobyl PTC samples using routine methods such as FISH and IHC. Our findings further support the hypothesis that gene rearrangements, but not oncogenic driver mutations, are associated with ionising radiation-related tumour risk. IHC may represent an effective method for ALK-screening in PTCs with known radiation aetiology, which is of clinical value since oncogenic ALK activation might represent a valuable target for small molecule inhibitors.

Gene Expression Analysis in Human Peripheral Blood Cells after 900 MHz RF-EMF Short-Term Exposure.

Radiofrequency electromagnetic fields (RF-EMF) are a basic requirement of modern wireless communication technology. Statutory thresholds of RF-EMF are established to limit relevant additional heat supply in human tissue. Nevertheless, to date, questions concerning nonthermal biological effects have yet to be fully addressed. New versions of microarrays (8 × 60K v2) provide a higher resolution of whole genome gene expression to display adaptive processes in cells after irradiation. In this ex vivo/ in vitro study, we irradiated peripheral blood cells from five donors with a continuous wave of 900 MHz RF-EMF for 0, 30, 60 and 90 min. Gene expression changes ( P ≤ 0.05 and ≥twofold differences above or below the room temperature control exposed samples) were evaluated with microarray analysis. The results were compared with data from room temperature + 2°C samples. Verification of microarray results was performed using bioinformatic analyses and qRT-PCR. We registered a lack of an EMF-specific gene expression response after applying the false discovery rate adjustment (FDR), using a high-stringency approach. Low-stringency analysis revealed 483 statistically significant deregulated transcripts in all RF-EMF groups relative to the room temperature exposed samples without an association with their corresponding room temperature + 2°C controls. Nevertheless, these transcripts must be regarded as statistical artefacts due to the absence of a targeted biological response, including enrichment and network analyses administered to microarray expressed gene subset profiles. Correspondingly, 14 most promising candidate transcripts examined by qRT-PCR displayed an absence of correlation with respect to the microarray results. In conclusion, these findings indicate that 900 MHz EMF exposure establishing an average specific absorption rate of 9.3 W/kg to whole blood cells is insufficient to induce nonthermal effects in gene expression during short-time exposure up to 90 min.

Benefit-Cost Analysis of Radiocesium Decorporation by a Prussian Blue Treatment and Stockpiling.

In the case of an attack by a "dirty bomb" with cesium-137 there is a risk of internal contamination. The excretion of cesium-137 can be enhanced by Prussian Blue (PB), and thus the committed effective dose be reduced. We analyzed the benefit and costs of PB decorporation treatment. We simulated the reduction of the radiological dose by PB treatment after cesium-137 incorporation by inhalation. The saving of life time was quantified using the monetary "value of a statistical life" (VSL). Treatment costs were based on the market price of PB in Germany. Moreover we considered the holding costs of stockpiling. The benefit of PB treatment increases with its duration up to about 90 days. If treatment initiation is delayed, the maximum achievable benefit is decreased. For a VSL of 1.646 million €, the net benefit of a 90-days treatment started 1 day after the incorporation remains positive up to a stockpiling duration of 10 years. If starting PB treatment as late as the 180th day after incorporation, the costs will surpass the benefit. We conclude that a prompt decision making and early treatment initiation greatly impacts on the medical but also economic efficiency of a PB treatment.

[The Japanese Health Care System: An Analysis of the Funding and Reimbursement System]. / Das japanische Gesundheitssystem: Analyse von Finanzierung und Vergütung.

OBJECTIVE: The modern Japanese health care system was established during the Meiji period (1868-1912) using the example of Germany. In this paper, the funding and remuneration of health services and products in Japan are described. The focus lies on the mechanisms used to implement health policy goals and to control costs. METHOD: Selective literature search. RESULTS: All permanent residents in Japan are enrolled in one of more than 3,000 compulsory health funds. Employees and public servants are covered through company or government-related health insurance schemes. Independent workers, the unemployed and the pensioners are usually assigned to health insurance plans managed by local city governments. The elderly over 75 years are insured through special health funds managed at the prefectural level. To correct the fiscal disparities among the health insurance programs, a risk adjustment is realized by compensatory financial transfers between the funds and substantial subsidies from the central and local governments. The statutory benefits package that is identical for all insurance plans is regulated in a single comprehensive schedule. All the covered health services and products are listed with the fees and compensations, and the conditions for the service providers to be remunerated are also stated. This fee and compensation schedule is regularly revised every 2 years under the leadership of the Ministry of Health, Labor and Welfare. The revisions are intended to contain health expenditures and to set incentives for the achievement of health policy goals. CONCLUSION: The funding of the Japanese health care system and the risk adjustment mechanisms among health funds are well established and show a rather static character. The short- and mid-term development of the system is mainly controlled on the side of the expenditures through the unique and comprehensive fee and compensation schedule. The regular revisions of this schedule permit to react at relatively short notice to evolving situations, and through a policy of small improvements, target an optimization of the system as a whole.

The Incorporation of Radionuclides After Wounding by a "Dirty Bomb": The Impact of Time for Decorporation Efficacy and a Model for Cases of Disseminated Fragmentation Wounds.

Objective: In the case of a terrorist attack by a "dirty bomb" there is a risk of internal contamination with radionuclides through inhalation and wounds. We studied the efficacy of a decorporation treatment depending on the initiation time and duration. Approach: Based on biokinetic models, we simulated the impact of different diethylenetriaminepentaacetic acid treatments on the committed effective dose after the incorporation of plutonium-239. Results: For the same level of radioactivity, the dose was higher after the fast absorption from the wound than after a slow invasion following inhalation. The impact of the treatment initiation time was particularly important in the case of the internal contamination through the wound. Ending the treatment at an early point in time was followed by an augmentation of radioactivity in the blood compartment, reflecting insufficient treatment duration. Treatment efficacy increased only marginally if extended over 90 days. Innovation and Conclusion: For plutonium-239, the committed effective dose and the impact of the treatment initiation time on therapeutic efficacy predominantly depend on the speed of invasion, i.e., the pathway and the physicochemical properties of the compounds involved. Thus, it is prudent to start decorporation therapy as soon as possible, as a loss of efficacy resulting from a delay in treatment initiation cannot be compensated later on. In the case of plutonium-239 incorporation, the treatment must be continued for several months. Multiple fragmentation wounds might be aggregated to a single wound model suited for internal dosimetry calculations by using the "rule of nine."

Baseline MAPK signaling activity confers intrinsic radioresistance to KRAS-mutant colorectal carcinoma cells by rapid upregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K).

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is overexpressed in malignant tumors and involved in DNA damage response upon ionizing radiation (IR). Here, we investigate its role in radioresistance of colorectal carcinoma (CRC) and evaluate a pharmacological approach to enhance CRC radiosensitivity via downregulation of hnRNP K. We show that hnRNP K is overexpressed in CRC tissue specimens and upregulated in response to IR in vitro, which occurs faster in KRAS-mutant CRC cells. HnRNP K knockdown impairs cell survival, cell cycle progression and KRAS-dependent radioresistance and increases apoptosis. Using the chicken chorioallantoic membrane assay, a decrease in xenograft tumor growth and radioresistance upon hnRNP K depletion could be verified in vivo, and comparable effects were achieved by suppression of hnRNP K expression using the MEK inhibitor MEK162 (Binimetinib). In summary, KRAS-mutant CRC shows intrinsic radioresistance along with rapid upregulation of hnRNP K in response to IR that can effectively be targeted by MEK inhibition. Our results point towards a possible use of MAPK pathway inhibitors to decrease radioresistance of KRAS-mutant CRC via downregulation of hnRNP K.

Analysis of the antidote requirements and outcomes of different radionuclide decorporation strategies for a scenario of a "dirty bomb" attack.

OBJECTIVE: In radiological emergencies, there is a risk of radionuclide incorporation. The radiological doses absorbed can be reduced by decorporation treatment. Antidote requirements depend on the scenario and treatment strategy ("urgent approach": immediate treatment of all patients with possible incorporation; "precautionary approach": treatment only after confirmation of incorporation). We calculated the number of daily antidote doses for different scenarios and the differences in outcome for both treatment strategies. DESIGN: The number of potentially contaminated victims was varied from 1,000 to 60,000 (a maximum that might seem plausible for "dirty bomb" scenarios in Germany), the proportion of patients actually needing decorporation treatment from 0.1 percent to 100 percent, the radioactive screening capacities from 250 to 2,500 people/day and treatment duration from 10 to 90 days. The outcomes were assessed as total statistical lifetime saved assuming an inhalation of 1 mCi cesium-137 and the achievable dose reductions by a Prussian Blue treatment. RESULTS: Assuming 1 percent of the potentially contaminated people actually needing treatment, applying an "urgent approach" the requirements for 1,000 victims range from 1,100 to 3,400 and for 60,000 victims from 489,000 to 4,400,000 daily doses, depending on treatment duration and screening capacities. The "urgent approach" is associated with larger stockpile requirements than the "precautionary approach", up to several hundred times in large-scale scenarios if the proportion of people actually needing treatment is low. The impact of the screening capacities is particularly important in large-scale scenarios, a low proportion of people needing treatment and extended treatment duration. The outcome is better for an "urgent approach" particularly in large-scale scenarios and low screening capacities. CONCLUSIONS: If only a small fraction of the victims actually needs treatment, their timely identification by enhancing screening capacities may be the most efficacious way to reduce antidote requirements. In large-scale scenarios, it might be necessary to abandon the medically preferable "urgent approach" for an antidote-sparing "precautionary approach".

Studies on the cardiotoxicity of noradrenaline in isolated rabbit hearts.

UNLABELLED: The concentration-dependent toxic effects of exogenous noradrenaline (NA, CAS 51-41-2) on acute regional myocardial ischemia (MI) was investigated with and without alpha- and beta-adrenoceptor blockade. Electrically-driven rabbit Langendorff-hearts with depleted catecholamine stores were used (reserpin 7.0 mg/kg i.p. 16-24 h before preparation, constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). Repetitive MI, separated by a reperfusion period of 50 min, was induced by coronary artery branch ligature, and quantitated from epicardial NADH-fluorescence photography. Starting after a reperfusion period of 20 min, hearts were treated with exogenous NA (10(-7), 10(-6) or 10(-5) mol/l). Adrenoceptors were blocked by propranolol (10(-6) mol/l) and phentolamine (10(-6) mol/l). Without adrenoceptor blockers, NA 10(-6) mol/l induced an increase in left ventricular pressure and a reduction in the relative coronary flow. Concomitantly, MI was enhanced. After adrenoceptor blockade, NA 10(-7) or 10(-6) mol/l had no influence on functional parameters. MI was not affected by NA 10(-7) mol/l, but MI was significantly enhanced by NA 10(-6) mol/l. MI enhancement by NA 10(-6) mol/l was completely prevented by superoxide dismutase (30 U/ml). Functional effects of NA 10(-5) mol/l were not completely inhibited by adrenoceptor blockers at the concentrations used, and arrythmias were observed. MI was also enhanced by NA 10(-5) mol/l. CONCLUSION: Deleterious effects on MI, that are independent on functional effects, are induced by NA in a micromolar concentration. These direct toxic effects are mediated by superoxide anion radicals. In lower concentrations (10(-7) mol/l), there is no evidence for direct toxic actions of NA independent of functional effects. MI enhancement by NA 10(-5), or 10(-6) mol/l without adrenoceptor blockers may have been caused in part by functional and arrythmogenic effects and/or through the generation of oxygen free radicals.