The Implant-Induced Foreign Body Response Is Limited by CD13-Dependent Regulation of Ubiquitination of Fusogenic Proteins.

Implanted medical devices, from artificial heart valves and arthroscopic joints to implantable sensors, often induce a foreign body response (FBR), a form of chronic inflammation resulting from the inflammatory reaction to a persistent foreign stimulus. The FBR is characterized by a subset of multinucleated giant cells (MGCs) formed by macrophage fusion, the foreign body giant cells (FBGCs), accompanied by inflammatory cytokines, matrix deposition, and eventually deleterious fibrotic implant encapsulation. Despite efforts to improve biocompatibility, implant-induced FBR persists, compromising the utility of devices and making efforts to control the FBR imperative for long-term function. Controlling macrophage fusion in FBGC formation presents a logical target to prevent implant failure, but the actual contribution of FBGCs to FBR-induced damage is controversial. CD13 is a molecular scaffold, and in vitro induction of CD13KO bone marrow progenitors generates many more MGCs than the wild type, suggesting that CD13 regulates macrophage fusion. In the mesh implant model of FBR, CD13KO mice produced significantly more peri-implant FBGCs with enhanced TGF-ß expression and increased collagen deposition versus the wild type. Prior to fusion, increased protrusion and microprotrusion formation accompanies hyperfusion in the absence of CD13. Expression of fusogenic proteins driving cell-cell fusion was aberrantly sustained at high levels in CD13KO MGCs, which we show is due to a novel CD13 function, to our knowledge, regulating ubiquitin/proteasomal protein degradation. We propose CD13 as a physiologic brake limiting aberrant macrophage fusion and the FBR, and it may be a novel therapeutic target to improve the success of implanted medical devices. Furthermore, our data directly implicate FBGCs in the detrimental fibrosis that characterizes the FBR.

Computational modeling of phagocyte transmigration for foreign body responses to subcutaneous biomaterial implants in mice.

BACKGROUND: Computational modeling and simulation play an important role in analyzing the behavior of complex biological systems in response to the implantation of biomedical devices. Quantitative computational modeling discloses the nature of foreign body responses. Such understanding will shed insight on the cause of foreign body responses, which will lead to improved biomaterial design and will reduce foreign body reactions. One of the major obstacles in computational modeling is to build a mathematical model that represents the biological system and to quantitatively define the model parameters. RESULTS: In this paper, we considered quantitative inter connections and logical relationships among diverse proteins and cells, which have been reported in biological experiments and literature. Based on the established biological discovery, we have built a mathematical model while unveiling the key components that contribute to biomaterial-mediated inflammatory responses. For the parameter estimation of the mathematical model, we proposed a global optimization algorithm, called Discrete Selection Levenberg-Marquardt (DSLM). This is an extension of Levenberg-Marquardt (LM) algorithm which is a gradient-based local optimization algorithm. The proposed DSLM suggests a new approach for the selection of optimal parameters in the discrete space with fast computational convergence. CONCLUSIONS: The computational modeling not only provides critical clues to recognize current knowledge of fibrosis development but also enables the prediction of yet-to-be observed biological phenomena.

Immunobiology of foreign body response to composite PLACL/gelatin electrospun nanofiber meshes with mesenchymal stem/stromal cells in a mouse model: Implications in pelvic floor tissue engineering and regeneration.

Pelvic Organ Prolapse (POP) is a common gynaecological disorder where pelvic organs protrude into the vagina. While transvaginal mesh surgery using non-degradable polymers was a commonly accepted treatment for POP, it has been associated with high rates of adverse events such as mesh erosion, exposure and inflammation due to serious foreign body response and therefore banned from clinical use after regulatory mandates. This study proposes a tissue engineering strategy using uterine endometrium-derived mesenchymal stem/stromal cells (eMSC) delivered with degradable poly L-lactic acid-co-poly ε-caprolactone (PLACL) and gelatin (G) in form of a composite electrospun nanofibrous mesh (P + G nanomesh) and evaluates the immunomodulatory mechanism at the material interfaces. The study highlights the critical acute and chronic inflammatory markers along with remodelling factors that determine the mesh surgery outcome. We hypothesise that such a bioengineered construct enhances mesh integration and mitigates the Foreign Body Response (FBR) at the host interface associated with mesh complications. Our results show that eMSC-based nanomesh significantly increased 7 genes associated with ECM synthesis and cell adhesion including, Itgb1, Itgb2, Vcam1, Cd44, Cdh2, Tgfb1, Tgfbr1, 6 genes related to angiogenesis including Ang1, Ang2, Vegfa, Pdgfa, Serpin1, Cxcl12, and 5 genes associated with collagen remodelling Col1a1, Col3a1, Col6a1, Col6a2, Col4a5 at six weeks post-implantation. Our findings suggest that cell-based tissue-engineered constructs potentially mitigate the FBR response elicited by biomaterial implants. From a clinical perspective, this construct provides an alternative to current inadequacies in surgical outcomes by modulating the immune response, inducing angiogenesis and ECM synthesis during the acute and chronic phases of the FBR.

Altered anesthetic requirements and carbon dioxide setpoint in chronic airway obstruction.

Accidental ingestion of a foreign body into either tracheobronchial tree or esophagus is not an uncommon occurrence. However, there is limited literature available on sequelae of post foreign body ingestion--carbon dioxide set point and apneic threshold due to chronic respiratory acidosis. We report a case of chronic airway obstruction in a 14-month-old boy with prior history of battery ingestion and share our experience in the management.

Mapping Macrophage Polarization and Origin during the Progression of the Foreign Body Response to a Poly(ethylene glycol) Hydrogel Implant.

Poly(ethylene glycol) (PEG) hydrogels hold promise for in vivo applications but induce a foreign body response (FBR). While macrophages are key in the FBR, many questions remain. This study investigates temporal changes in the transcriptome of implant-associated monocytes and macrophages. Proinflammatory pathways are upregulated in monocytes compared to control monocytes but subside by day 28. Macrophages are initially proinflammatory but shift to a profibrotic state by day 14, coinciding with fibrous capsule emergence. Next, this study assesses the origin of macrophages responsible for fibrous encapsulation using wildtype, C-C Motif Chemokine Receptor 2 (CCR2)-/- mice that lack recruited macrophages, and Macrophage Fas-Induced Apoptosis (MaFIA) mice that enable macrophage ablation. Subpopulations of recruited and tissue-resident macrophages are identified. Fibrous encapsulation proceeds in CCR2-/- mice similar to wildtype mice. However, studies in MaFIA mice indicate that macrophages are necessary for fibrous capsule formation. These findings suggest that macrophage origin impacts the FBR progression and provides evidence that tissue-resident macrophages and not the recruited macrophages may drive fibrosis in the FBR to PEG hydrogels. This study demonstrates that implant-associated monocytes and macrophages have temporally distinct transcriptomes in the FBR and that profibrotic pathways associated with macrophages may be enriched in tissue-resident macrophages.

Extraovarian conditions mimicking ovarian cancer: a single center experience of 15 years.

OBJECTIVE: This study aims to review cases of extra-ovarian conditions that resembled ovarian malignancy and thus, to evaluate the distribution of primary pathology mimicking ovarian malignancy. METHODS: A retrospective review of women, with final pathology of extra-ovarian diseases mimicking ovarian malignancy, which were managed at Zekai Tahir Burak Women's Health Education and Research Hospital, from January 1995 to April 2010 was undertaken. RESULTS: Among the 2,210 women treated during the study period, extra-ovarian diseases accounted for 5.11% (113/2,210) of all the cases. Of the 113 extra-ovarian diseases, 42 (37.17%) were peritoneal tuberculosis, 25 (22.13%) were gastrointestinal malignancies, 20 (17.70%) were pelvic abscess, 8 (7.08%) were pelvic echinococcosis, 8 (7.08) were schwannoma and other retroperitoneal tumors, 4 (3.53%) were malignant lymphoma, 2 (1.77%) were chronic ectopic pregnancy, gossypiboma, and mesenteric cyst, respectively. CONCLUSION: Medical awareness of infectious diseases such as peritoneal tuberculosis, pelvic abscess, and pelvic echinococcosis in the differential diagnosis of ovarian malignancy is still lacking, especially in developing countries. In addition, in case of a pelvic mass, gastrointestinal and retroperitoneal tumors and malignant lymphoma should always be considered to avoid pitfalls in diagnosis and therapy.

Recombinant sugarcane cystatin CaneCPI-5 down regulates inflammation and promotes angiogenesis and collagen deposition in a mouse subcutaneous sponge model.

Cystatins are natural inhibitors of cysteine peptidases that are found practically in all living organisms. CaneCPI-5 is a sugarcane cystatin with inhibitory activity against human cathepsins B, K and L, which are cysteine proteases highly expressed in a variety of pathological conditions, usually marked by persistent inflammation and processing of the extracellular matrix. This work evaluated the effects of daily administration of the recombinant cystatin CaneCPI-5 [0.01, 0.1 or 1.0 µg in 10 µL of Phosphate-Buffered Saline (PBS)] on the inflammatory, angiogenic and fibrogenic components during chronic inflammatory response induced by subcutaneous sponge implants. The anti-inflammatory effect of treatment with CaneCPI-5 was confirmed by reduction of the levels of the pro-inflammatory mediators TNF-α, CXCL1 and CCL2/JE/MCP-1, as well as the activity of the myeloperoxidase and n-acetyl-ß-D-glucosaminidase. Treatment with CaneCPI-5 promoted angiogenesis in the implants, increasing the production of cytokines VEGF and FGF and the formation of new blood vessels. Finally, the administration of the recombinant cystatin favored the production of the pro-fibrogenic cytokine TGF-ß1 and collagen deposition next to the implants. Together, these results show the potential therapeutic application of CaneCPI-5 as an anti-inflammatory agent, capable of favoring angiogenesis and fibrogenesis processes, necessary for tissue repair.

Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) disruption in acute Utah electrode array implants and the effect of deferoxamine as an iron chelator on acute foreign body response.

The use of intracortical microelectrode arrays has gained significant attention in being able to help restore function in paralysis patients and study the brain in various neurological disorders. Electrode implantation in the cortex causes vasculature or blood-brain barrier (BBB) disruption and thus elicits a foreign body response (FBR) that results in chronic inflammation and may lead to poor electrode performance. In this study, a comprehensive insight into the acute molecular mechanisms occurring at the Utah electrode array-tissue interface is provided to understand the oxidative stress, neuroinflammation, and neurovascular unit (astrocytes, pericytes, and endothelial cells) disruption that occurs following microelectrode implantation. Quantitative real time polymerase chain reaction (qRT-PCR) was used to quantify the gene expression at acute time-points of 48-hr, 72-hr, and 7-days for factors mediating oxidative stress, inflammation, and BBB disruption in rats implanted with a non-functional 4 × 4 Utah array in the somatosensory cortex. During vascular disruption, free iron released into the brain parenchyma can exacerbate the FBR, leading to oxidative stress and thus further contributing to BBB degradation. To reduce the free iron released into the brain tissue, the effects of an iron chelator, deferoxamine mesylate (DFX), was also evaluated.

Tattoo image composed of radiopaque deposits demonstrated by postmortem computed tomography.

Postmortem computed tomography (PMCT) is becoming used more commonly in routine forensic investigation. CT is sensitive for detection of metal foreign bodies. Here we report a case of suicide due to self-ignition of kerosene that the victim had poured over herself. Prior to autopsy, PMCT detected tiny radiopaque particles arranged in a row in the surface of the back and either thigh, together with a series of similar particles under the skin lateral to the breasts or the bilateral inguinal region. At autopsy, external examination revealed third-degree burns involving charred tissues all over the body except for the head. Tattoos were visible on the back and on either thigh. The tattoos had colored designs, and the red portions corresponded to the radiopaque particles in the surface of the body. Internal examination demonstrated swelling of the axillary and inguinal lymph nodes, which corresponded to the radiopaque particles. A wave length-dispersive X-ray spectroscopy revealed deposition of mercury and titanium in the inguinal lymph nodes. Thus, it was plausible that the ink could have contributed to the radiopaque particles found by PMCT in the surface of the back and thighs, as well in the lymph nodes. The present case was able to provide clues for interpretation of radiopaque particles revealed by PMCT in the surface of the body.

Graphene oxide enhances alginate encapsulated cells viability and functionality while not affecting the foreign body response.

The combination of protein-coated graphene oxide (GO) and microencapsulation technology has moved a step forward in the challenge of improving long-term alginate encapsulated cell survival and sustainable therapeutic protein release, bringing closer its translation from bench to the clinic. Although this new approach in cell microencapsulation represents a great promise for long-term drug delivery, previous studies have been performed only with encapsulated murine C2C12 myoblasts genetically engineered to secrete murine erythropoietin (C2C12-EPO) within 160 µm diameter hybrid alginate protein-coated GO microcapsules implanted into syngeneic mice. Here, we show that encapsulated C2C12-EPO myoblasts survive longer and release more therapeutic protein by doubling the micron diameter of hybrid alginate-protein-coated GO microcapsules to 380 µm range. Encapsulated mesenchymal stem cells (MSC) genetically modified to secrete erythropoietin (D1-MSCs-EPO) within 380 µm-diameter hybrid alginate-protein-coated GO microcapsules confirmed this improvement in survival and sustained protein release in vitro. This improved behavior is reflected in the hematocrit increase of allogeneic mice implanted with both encapsulated cell types within 380 µm diameter hybrid alginate-protein-coated GO microcapsules, showing lower immune response with encapsulated MSCs. These results provide a new relevant step for the future clinical application of protein-coated GO on cell microencapsulation.

Beyond foreign-body-induced carcinogenesis: impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression.

Foreign-body-induced carcinogenesis is a traditional, maybe old, way of understanding cancer development. A number of novel approaches are available today to elucidate cancer development. However, there are things we learn from the old, and thus I bring out some examples of various clinical cases and experimental models of foreign-body-induced tumorigenesis. What is notable is that the foreign bodies themselves are unrelated to each other, whereas commonly underlying in them is to induce inflammatory reaction, especially stromal proliferation, where those exogenous materials are incorporated and undigested. Such foreign-body-induced carcinogenesis is also recognized in the step of tumor progression, the final step of carcinogenesis that tumor cells acquire malignant phenotypes including metastatic properties. And the phenomenon is universally observed in several cell lines of different origins. In this review I would like to show the evidence that tumor development and progression are accelerated inevitably by inflammation caused from foreign bodies, and that reactive oxygen species derived from inflammatory cells are one of the most important genotoxic mediators to accelerate the process.

Morphological findings and energy dispersive X-ray microanalysis of oral amalgam tattoos.

Oral amalgam tattoos (AT) are distinct pigmentations of the oral mucosa resulting from accidental incorporation of dental amalgam in the oral soft tissues. Dental amalgams and in particular mercury, one of the constituents of dental amalgams, have for long been considered toxic. Oral ATs are easily accessible to study soft tissue reaction to amalgam and its degradation products. In this study, 17 oral ATs were examined by transmission electron microscopy and energy dispersive X-ray microanalysis. Ultrastructurally, in the ATs, three kinds of electron-dense particles were observed. The largest particles ranged in size from 0.5 up to several 100 microm. Smaller electron-dense inclusions (0.5-0.1 microm) were seen extracellularly associated with meshworks of elastic fibers and collagen bundles. The third and smallest type of particles (5-30 nm in diameter) was found with basement membranes of small vessels and pericytes and particularly decorating collagen bundles. Element analysis regularly revealed the presence of silver, sulphur, copper and lead in the AT decay products. Mercury was found in only one instance. Tissue reactions due to ATs seem to be minimal. No acute inflammatory changes were seen. Larger inclusions occasionally were surrounded by macrophages and multinucleated cells. TEM and element analysis may in specific cases be helpful in the differential diagnosis of pigmented lesions of the oral mucosa.

USTUR whole body case 0262: 33-y follow-up of PuO2 in a skin wound and associated axillary node.

This whole body donation case (USTUR Registrant) involved two suspected PuO2 inhalation intakes, each indicated by a measurable Pu alpha activity in a single urine sample, followed about 1(1/2) y later by a puncture wound to the thumb while working in a Pu glovebox. The study is concerned with modelling simultaneously the biokinetics of deposition and retention in the respiratory tract and at the wound site; and the biokinetics of Pu subsequently transferred to other body organs, until the donor's death. Urine samples taken after the wound incident had readily measurable Pu alpha activity over the next 14 y, before dropping below the minimum detectable excretion rate (<0.4 mBq d(-1)). The Registrant died about 33 y after the wound intake, at the age of 71, from hepatocellular carcinoma with extensive metastases. At autopsy, all major soft tissue organs were harvested for analysis of their 238Pu, 239+240Pu and 241Am content. The amount of 239+240Pu retained at the wound site was 68 +/- 7 Bq (1 SD), measured by low-energy planar Ge spectrometry. A further 56.0 +/- 1.2 Bq was retained in an associated axillary lymph node, measured by radiochemistry. Simultaneous mathematical analysis (modelling) of all in vivo urinary excretion data, together with the measured lung, thoracic lymph node, wound, axillary lymph node and systemic tissue contents at death, yielded estimated intake amounts of 757 and 1504 Bq, respectively, for the first and second inhalation incidents, and 204 Bq for the total wound intake. The inhaled Pu material was highly insoluble, with an estimated long-term absorption rate from the lungs of 2 x 10(-5) d(-1). The Pu material deposited at the wound site was mixed: approximately 14% was rapidly absorbed, approximately 49% was absorbed at the rate of about 6 x 10(-5) d(-1), and the remainder ( approximately 37%) was absorbed extremely slowly (at the rate of about 5 x 10(-6) d(-1)). Thus, it was estimated that only approximately 40% of the Pu initially deposited in the wound had been absorbed systemically over the 33-y period until the donor's death. The biokinetic modelling also indicated that, in this individual case, some of the parameter values (rate constants) incorporated in the ICRP Publication 67 Pu model were up to a factor of 2 different from ICRP's recommended values (for reference man).

Percutaneous penetration of uranium in rats after a contamination on intact or wounded skin.

The aim of this work is to assess in vivo in a hairless rat model, the percutaneous diffusion of uranium through intact or wounded rat skin. Six types of wounds were simulated by excoriation and burns with 10 N HF, 2, 5 and 14 N HNO3 and 10 N NaOH on anaesthetised hairless rats. Percutaneous penetration through wounded skin towards blood and subsequent urinary excretion of uranium was followed in vivo during 24 h. The influence of the physicochemical form (solution or powder) of uranyl nitrate (UN) on its percutaneous diffusion was also investigated. UN, even as a powder, can diffuse through intact skin. The presence of uranium in blood is more persistent and its urinary elimination is slower after an HF burn than after an HNO3 burn. Excoriation increases dramatically percutaneous absorption of UN. Thus, percutaneous diffusion of UN is largely dependent on skin barrier integrity with a particular importance of stratum corneum.

Modelling of bioassay data from a Pu wound treated by repeated DTPA perfusions: biokinetics and dosimetric approaches.

The aim of this study is to model plutonium (Pu) excretion from the analysis of a well-documented Pu wound case involving repeated diethylene-triamine-penta-acetic acid (DTPA) perfusions up to 390 d and monitoring up to 3109 d. Three modelling approaches were simultaneously applied involving: (1) release of soluble Pu from the wound, estimated with the ICRP66 dissolution model, (2) systemic behaviour of Pu by using ICRP67 model, but also two new models recently reported and (3) additional 'Pu-DTPA' compartments which transfer Pu directly to urinary compartment from blood, interstitial fluids and liver. The best fit of simulations to biological data was obtained by using the new Leggett's systemic model and assuming the presence of three DTPA compartments. Calculations have shown that DTPA treatments have contributed to a 3-fold reduction of the effective dose. Thus, reduction of doses associated with the DTPA treatments can be estimated by modelling which is useful to improve the efficacy of a DTPA treatment schedule based on a diminution of risk.

Consequence of body packing of illicit drugs.

BACKGROUND: During the last decade, increased rates of drug traffic have led the smugglers to use various methods. One of these methods of illicit drug smuggling is body packing. Smuggling by intra-abdominal concealment is called "body packing". In this research, mortality rate was investigated due to body packing in Tehran. METHODS: A descriptive study (case series) was designed on all corpses referred to the Forensic Medicine Organization of Tehran between April 1999 - December 2000. Demographic data such as sex, age, marital status, addiction, job, education level, type of opioid and the weight, number of packets, and results of blood and urine morphine tests by thin-layer chromatographic method were investigated. RESULTS: Continental system of law is used in Iran and 0.06% of the referred corpses to Forensic Medicine Organization of Tehran were body packers. There were 12 cases, all of them were men. The mean age of body packers was 43 years (range 20 - 62). The minimum weight of the packets was 20 g and the maximum weight was 1400 g (mean = 501 g). The minimum number of the packets was one and the maximum number of the packets was 48. Twenty five percent of the corps were putrefied and one corpse was mummified. None of the body packers had academic education nor were employed. Nine of them lived in cities. Twenty five percent of them were intravenous addicts. The corpses were found mostly in terminals (17%), roads (58%), and cities (25%). CONCLUSION: Hospital physicians may neglect this type of gastrointestinal foreign body if they are not aware of the body packer syndrome. Body packing should be suspected in anyone with signs of drug-induced toxic effects after a recent arrival on city terminals or when there is no history of recreational drug use.

Fatal heroin intoxication in body packers in northern Thailand during the last decade: two case reports.

A body packer is an important means of drug trafficking. While drug packets are inside the body, they can leak or rupture causing acute substance toxicity. Most of the reports of body packer syndrome have come from Europe and North America, which are destination targets. In the present study, the authors reported two cases of fatal heroin body packers from the northern part of Thailand. Both cases were foreign tourists who came to Chiang Mai and stayed in a hotel or a guesthouse room in which the deaths occurred. The autopsy findings revealed rupturing of heroin packages in the stomach. The packaging used in both cases was not sophisticated. The powder was packed inside condoms without extra covering, as observed in some other professional packers. The amount of heroin transported was about 30-50 gm. The purity of heroin in this powder was about 50-90%. Their destinations were their home countries and not directly to Europe or North America. Deaths occurred just prior to their return. The cause of death was a heroin overdose. A significant level of heroin metabolites, 6-MAM and morphine were detected in the blood and urine.

Metallosis following implantation of magnetically controlled growing rods in the treatment of scoliosis: a case series.

AIMS: We present a case series of five patients who had revision surgery following magnetic controlled growing rods (MGCR) for early onset scoliosis. Metallosis was found during revision in four out of five patients and we postulated a mechanism for rod failure based on retrieval analysis. PATIENTS AND METHODS: Retrieval analysis was performed on the seven explanted rods. The mean duration of MCGR from implantation to revision was 35 months (17 to 46). The mean age at revision was 12 years (7 to 15; four boys, one girl). RESULTS: A total of six out of seven rods had tissue metallosis and pseudo-capsule surrounding the actuator. A total of four out of seven rods were pistoning. There were two rods which were broken. All rods had abrasive circumferential markings. A significant amount of metal debris was found when the actuators were carefully cut open. Analytical electron microscopy demonstrated metal fragments of predominantly titanium with a mean particle size of 3.36 microns (1.31 to 6.61). CONCLUSION: This study highlights concerns with tissue metallosis in MCGR. We recommend careful follow-up of patients who have received this implant. Cite this article: Bone Joint J 2016;98-B:1662-7.

Inflammasome components ASC and AIM2 modulate the acute phase of biomaterial implant-induced foreign body responses.

Detailing the inflammatory mechanisms of biomaterial-implant induced foreign body responses (FBR) has implications for revealing targetable pathways that may reduce leukocyte activation and fibrotic encapsulation of the implant. We have adapted a model of poly(methylmethacrylate) (PMMA) bead injection to perform an assessment of the mechanistic role of the ASC-dependent inflammasome in this process. We first demonstrate that ASC(-/-) mice subjected to PMMA bead injections had reduced cell infiltration and altered collagen deposition, suggesting a role for the inflammasome in the FBR. We next investigated the NLRP3 and AIM2 sensors because of their known contributions in recognising damaged and apoptotic cells. We found that NLRP3 was dispensable for the fibrotic encapsulation; however AIM2 expression influenced leukocyte infiltration and controlled collagen deposition, suggesting a previously unexplored link between AIM2 and biomaterial-induced FBR.

Toxicity of uranium and the removal effects of CBMIDA and EHBP in simulated wounds of rats.

We examined the acute toxicity of uranium (99.3% 238U, 0.7% 235U) and the effects of Catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) and Ethane-1-hydroxy-1,1-bisphosphonate (EHBP) on the removal of uranium after intramuscular injection as a simulated wound intake in rats. In this experiment, male Wistar rats, 8 wk old, were injected intramuscularly with uranyl nitrate in the femoral muscles. Experiment I: Rats died from 3 to 7 d after they were injected with five doses of 7.9, 15.8, 31.5, 63, and 126 mg kg(-1) uranium. The uranium retained 8.4-13.6% of the injected doses in the kidneys, showing the relationship between the injected dose and the retained concentration (r = 0.997). The excretion rates of the injected doses in the 63 and 126 mg kg(-1) uranium-injected rats were 1.73% and 3.09% in urine and 0.81% and 1.06% in feces on the first day, and 0.54% and 0.56% in feces on the second day, respectively. Experiment II: The retention of uranium at 1, 3, 6, and 24 h was examined after rats were injected with 63 mg kg(-1) uranium. The concentration of uranium decreased in the plasma, while it increased in the kidneys and femur until 6 h, and it continued to increase in the liver until 24 h. Experiment III: Rats were divided into four groups (n = 10) and were injected with a dose of 2 mg kg(-1) uranium. Two of the groups were then injected intraperitoneally with 240 or 480 mg kg-1 CBMIDA, and one group was injected with 10 mg kg(-1) EHBP once daily for 28 d, beginning 1 h after uranium injection on the first day. The fourth group was the non-treated control group. The survival rates at the end of the experiment were 80% and 40% in the 240 and 480 mg kg(-1) CBMIDA groups, 50% in the EHBP group, and 20% in the non-treated group. The successive administration of chelating agents was effective in decreasing the concentration of uranium in the kidneys, bone, and liver. The results indicated that uranium induces acute death and renal dysfunction by chemical toxicity, and both CBMIDA and EHBP were effective agents to prevent these effects.