Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident.

A criticality accident occurred at the uranium conversion plant in Tokaimura, Ibaraki Prefecture, Japan on 30 September 1999. When uranyl nitrate was overloaded to a critical mass level, uncontrolled fission reaction occurred. A procedure was carried out according to the JCO manual, although not an officially approved manual. Three workers were heavily exposed to neutrons andγ-rays produced by nuclear fission, and they subsequently developed acute radiation syndrome (ARS). The average doses to the whole body of the three workers were approximately 25, 9, and 3 GyEq (biologically equivalent dose ofγ-exposure), respectively; dose distribution analysis later revealed extreme heterogeneity of these doses in two workers. They were triaged according to the predicted clinical needs. Two of these workers developed severe bone marrow failure and received haematopoietic stem cell transplantation: one with peripheral stem cell transplantation from his Human Leukocyte Antigen compatible sister and the other with umbilical cord blood transplantation. The graft was initially successful in both workers; autologous haematopoietic recovery was observed after donor/recipient mixed chimerism in one of them. Despite of all medical efforts available including haematopoietic stem cell transplantation, investigational drugs, skin graft, two workers died of multiple organ involvement and failure 83 and 211 days after the accident, respectively. Clinically as well as pathologically, the direct cause of death was deemed to be intractable gastrointestinal (GI) bleeding in one, and thoraco-abdominal compartment syndrome due to dermal fibrosis/sclerosis in the other. The third worker also developed bone marrow suppression but was treated with granulocyte colony-stimulating factor. He recovered without major complications and is now under periodical medical follow-up. These experiences suggest that treatment of bone marrow is not a limiting factor for saving the life of ARS victims severely exposed. Successful treatment of other organs such as lungs, skin, and GI tract is also essential. Furthermore, the whole-body dose may not always reflect the prognosis of ARS victims because of the nature of accidental exposure, heterogenous exposure.

Tuning Wall Thicknesses in Mesoporous Silica Films for Optimization of Optical Anti-Reflective Properties.

This work reports the fabrication of mesoporous silica films with controllable wall thicknesses by spin coating of precursor solutions consisting of polystyrene-block-polybutadiene-block-polystyrene based triblock copolymers (Hydrogenated methyl Styrene Ethylene Butadiene methyl Styrene, HmSEBmS) and tetraethyl orthosilicate (TEOS) followed by calcination in air at 600 °C, for optical anti-reflection films. By changing the relative weight of the triblock polymer to TEOS, the pore-to-pore distance in the mesoporous silica film can be controlled without significantly affecting the size of the mesopores, thus, enabling effective control of the refractive index and porosity of the films. In terms of optical properties, the transmittance of the fabricated mesoporous silica film is approximately 3.3% higher than that of the uncoated glass substrate in the wavelength range of 400 to 750 nm.

Antisense peptide nucleic acid­peptide conjugates for functional analyses of genes in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the most common and clinically important pathogens because of its resistance to a wide variety of antibiotics. A number of treatments of P. aeruginosa have been developed, but there is still no definitive one. Antisense drugs have a great potential to treat multidrug-resistant P. aeruginosa because this technology, in principle, can inhibit the expression of any essential genes. Nucleic Acid Ther.2012, 22, 323 reported that peptide nucleic acid (PNA) antisenses conjugated to the carrier peptide (RXR)4 and targeted to ftsZ and acpP (essential genes) had antibacterial activity in P. aeruginosa. However, growth inhibition was also found with peptide-PNA antisense conjugates of mismatched sequences (negative controls), and hence there remains a possibility for considerable enhancement of basal level activity due to the general toxicity. To assess the true potential of peptide-PNA conjugates, we measured sequence-dependent knockdown of the (RXR)4-PNA conjugates by using a scrambled sequence as a negative control. In addition, we evaluated (RXR)4-PNA antisenses against three other essential genes (lepB, lptD and mraY) and a non-essential gene (PA1303), and confirmed that multiple sequences targeting only the essential genes showed antimicrobial activity in P. aeruginosa PAO1 cells. We also conducted a rescue experiment and confirmed that the antimicrobial activity of anti-mraY antisenses was an on-target effect, not due to general toxicity. These findings indicate that the (RXR)4­PNA antisense should be a useful tool for target validation of a specific gene and could be a therapeutic platform capable of targeting a variety of genes in P. aeruginosa.

Sepsis caused by peripelvic soft tissue infections in critically injured patients with multiple injuries and unstable pelvic fracture.

BACKGROUND: In critically injured patients with multiple injuries and unstable pelvic fracture, late mortality almost invariably results from sepsis. METHODS: We analyzed the clinical features of 11 patients with sepsis caused by soft tissue infections surrounding the fractured pelvis, of 830 patients with pelvic fracture after blunt trauma treated at our level I trauma center over the past 25 years. Soft tissue infection was defined as abscess formation in subcutaneous tissue or muscle diagnosed by computed tomography or an operation. RESULTS: Mean injury severity score was 48, and mean systolic blood pressure on arrival was 66 mm Hg. All patients had multiple concomitant injuries and prolonged hemorrhagic shock. Open pelvic fracture was present in five patients. Mean blood transfusion volume within 24 hours was 12,611 mL. Intra-aortic balloon occlusion was performed in three patients and transcatheter angiographic embolization in nine patients. Embolic sites of transcatheter angiographic embolization were bilateral internal iliac arteries (n = 9), lumbar artery (n = 5), median sacral artery (n = 2), and circumflex femoral artery (n = 2). Infection sites included the gluteal (n = 11), femoral (n = 6), sacral (n = 4), lumbar (n = 4), anterior iliac (n = 2), inguinal (n = 1), and perineal (n = 1) regions. Necrotic changes of infected soft tissue were found in all patients. They underwent open drainage and daily debridement with pulsatile irrigation followed by intravenous antibiotics. All patients developed severe sepsis, five of whom subsequently died of multiple organ failure. CONCLUSIONS: In critically injured patients with multiple injuries and unstable pelvic fracture, peripelvic soft tissue infections occasionally cause sepsis. Peripelvic infections are often accompanied by necrotic changes and easily develop into severe sepsis or multiple organ failure. Identifying high-risk patients and early diagnosis with prompt surgical treatment are indispensable for the patients' survival.

Characterization of novel non-peptide thrombopoietin mimetics, their species specificity and the activation mechanism of the thrombopoietin receptor.

A series of non-peptide small compounds discovered to be thrombopoietin receptor agonists showed species specificity to humans. Compound I could induce megakaryocyte lineage from human bone marrow cells, but not from mouse, guinea pig or cynomolgus monkey bone marrow cells. To elucidate the mechanism, we identified the pivotal amino acid residue for the receptor activation by compound I by taking advantage of its species specificity. The response of compound I to three human/mouse chimeric receptors indicated the importance of the transmembrane domain. Comparison of amino acid sequences of the transmembrane domain of the thrombopoietin receptor between human and three animal species led us to hypothesize that histidine 499 is necessary for the reactivity to the thrombopoietin mimetics. We verified the hypothesis using two mutant receptors: the human thrombopoietin receptor mutant His499Leu and the mouse thrombopoietin receptor mutant Leu490His. These results should be helpful for structure-activity relationship studies and conducting in vivo studies of thrombopoietin mimetics.

Pathological changes in the gastrointestinal tract of a heavily radiation-exposed worker at the Tokai-mura criticality accident.

Gastrointestinal syndrome after high-dose acute radiation whole body exposure is difficult to treat, although it is a well-known complication. In this report, we describe the clinical and pathological features of a patient who died after the criticality accident which occurred in Japan on 30 September 1999. The patient was estimated to have been exposed to 16-25 Gy equivalent of gamma ray, and died of multiple organ failure after acute radiation syndrome, especially gastrointestinal syndrome, on day 82. The stomach and small intestine contained a large amount of blood clots and the gastrointestinal epithelial cells were almost totally depleted at autopsy. In addition, the degree of the mucosal damage was dependent on the segment of the gastrointestinal tract; the mucosa of stomach, ileum and ascending colon was entirely depleted, but the esophagus, descending and sigmoid colon and rectum retained a small portion of the epithelial cells. From the posture of the patient at the time of exposure, the absorbed dose was presumed to be highest in the right-anterior abdomen. This agreed with the pathological differences in the mucosal damage by the position in the abdomen, which depended presumably on the radiation dose. This is the first report documenting the relationship between the absorbed dose and the severity of gastrointestinal damages in vivo.

Effects of sarin on the nervous system of subway workers seven years after the Tokyo subway sarin attack.

This study was designed to assess the after effects of sarin exposure on the nervous system in victims of the Tokyo Subway Sarin Attack, which occurred on 20 March, 1995. We performed a similar study 3 yr after the disaster. This time, we newly enrolled 36 staff of the Teito Rapid Transit Authority (Tokyo Eidan subway) to assess the 7 yr after effects on the nervous system, and merged previous data including unpublished data to enhance statistical power. New subjects consisted of 23 male exposed subjects and 13 referent subjects matched for age and working types. Neurobehavioral tests for psychomotor function and memory, stabilometry, and Benton visual retention test were performed. As reported previously, the exposed group performed significantly less well in the psychomotor function test (tapping) than the referent group (117.8 +/- 1.2 vs. 105.6 +/- 1.2 msec). Using merged data, this phenomenon was also observed in a dose-dependent manner and the exposed group performed significantly less well in the backward digit span test (4.47 +/- 1.17 vs. 5.11 +/- 1.65 digits). These results indicate that chronic decline of psychomotor function and memory function still exist 7 yr after the sarin exposure.

Neoendothelialization after peripheral blood stem cell transplantation in humans: a case report of a Tokaimura nuclear accident victim.

OBJECTIVES: Neoendothelialization by circulating endothelial progenitor cells has been a topic of recent research. The extent and scale of this process in humans is not well understood. We examined the extent of neoendothelialization of the aorta and peripheral arteries in the case of a patient who underwent peripheral blood stem cell transplantation for acute radiation syndrome. METHODS: Human tissue samples from the aorta and peripheral arteries were obtained at autopsy. Endothelial cells were isolated, confirmed by von Willebrand factor immunostaining, and then subjected to fluorescent in situ hybridization analysis using X- and Y-chromosome specific probes to examine neoendothelialization by donor cells as possible in this case in which the donor and recipient were of different genders. RESULTS: The aorta showed almost 25% of all endothelial cells to be replaced by donor-origin endothelial cells. The peripheral arteries were also replaced but to a lesser extent. DISCUSSION: The present study provides evidence that peripheral blood is a source of endothelial progenitor cells in humans. Neoendothelialization of the aorta occurs to a significant extent under certain conditions suggesting the potential for exploitation of therapeutic neovascularization by transplantation of circulating endothelial progenitor cells.

Synthesis and characterization of Zn-doped mesoporous SnO2 by using thermally-stable block copolymer templates.

By using novel triblock copolymer templates, thermally-stable ordered mesoporous SnO2 thin films are synthesized through a solvent evaporation method. Owing to the high thermal stability of the triblock copolymer, the mesoporous structure is retained even after calcination at 600 °C. After the crystallization, the mesopore walls consist of small crystallite nanoparticles a few nanometers in diameter. By doping Zn species into the SnO2 framework, fine control of the crystallite sizes is successfully achieved. Under the optimized Zn content, the well-defined mesoporous structure is completely maintained after calcination at 600 °C.

First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation.

OBJECTIVE: Hematopoietic syndrome (HS) is a clinical diagnosis assigned to people who present with ≥ 1 new-onset cytopenias in the setting of acute radiation exposure. The World Health Organization convened a panel of experts to evaluate the evidence and develop recommendations for medical countermeasures for the management of HS in a hypothetical scenario involving the hospitalization of 100 to 200 individuals exposed to radiation. The objective of this consultancy was to develop recommendations for treatment of the HS based upon the quality of evidence. METHODS: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to panel members before the meeting and updated during the meeting. Published case series and case reports of individuals with HS, published randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. In cases in which data were limited or incomplete, a narrative review of the observations was made. No randomized controlled trials of medical countermeasures have been completed for individuals with radiation-associated HS. The use of GRADE analysis of countermeasures for injury to hematopoietic tissue was restricted by the lack of comparator groups in humans. Reliance on data generated in nonirradiated humans and experimental animals was necessary. RESULTS: Based upon GRADE analysis and narrative review, a strong recommendation was made for the administration of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor and a weak recommendation was made for the use of erythropoiesis-stimulating agents or hematopoietic stem cell transplantation. CONCLUSIONS: Assessment of therapeutic interventions for HS in humans exposed to nontherapeutic radiation is difficult because of the limits of the evidence.

Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems.

OBJECTIVES: The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature. METHODS: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation system. In cases in which data were limited or incomplete, a narrative review of the observations was made. RESULTS: No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made for the administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/or shock. A strong recommendation is made against the use of systemic steroids in the absence of a specific indication. A weak recommendation is made for the use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and for selective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients. CONCLUSIONS: High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future.

Development of high-throughput spermidine synthase activity assay using homogeneous time-resolved fluorescence.

Spermidine synthase (SPDS) catalyzes transfer of the propylamine group from decarboxylated S-adenosylmethionine (dcSAM) to putrescine to yield methylthioadenosine (MTA) and spermidine. SPDS plays a regulatory role in cell proliferation and differentiation. This article describes the development of a high-throughput SPDS activity assay using homogeneous time-resolved fluorescence (HTRF) based on energy transfer from europium cryptate as a donor to crosslinked allophycocyanin (XL665) as an acceptor. First a highly specific anti-MTA monoclonal antibody, MTA-7H8, was generated, and then a competitive immunoassay for MTA determination was developed using europium cryptate-labeled MTA-7H8 and XL665-labeled MTA. In our homogeneous immunoassay, the percentage molar cross-reactivity of dcSAM with MTA-7H8 was 0.01% and the detection limit of MTA was 2.6 pmol/well. Our HTRF assay uses only one assay plate in which both enzyme reaction and MTA determination can be done successively. Therefore, our method can enable automatic screening of SPDS inhibitors from large numbers of samples.

Iliac vein injuries in hemodynamically unstable patients with pelvic fracture caused by blunt trauma.

BACKGROUND: Major pelvic venous injuries secondary to blunt trauma can be a difficult problem in diagnosis and management. This study aimed to elucidate the clinical significance of iliac vein injuries demonstrated by venography in patients with blunt pelvic injuries who remained unstable even after transcatheter arterial embolization (TAE). METHODS: We reviewed the records of 72 patients with unstable pelvic fracture who presented with shock at our center after blunt trauma from 1999 through 2003. The average Injury Severity Score was 34.3 in this study population. RESULTS: TAE was the first method of choice to control bleeding from pelvic fracture in 61 patients. Thirty-six patients recovered from shock after TAE. Eighteen of 25 who did not recover from shock died. In 11 of these 25, transfemoral venography with a balloon catheter was performed, revealing significant venous extravasation in 9: common iliac vein in 5, internal iliac vein in 3, and external iliac vein in 1. The average Injury Severity Score of patients with iliac vein injury was 45.8. Treatments for venous injuries were laparotomy for hemostasis (n = 1, survivors = 0), retroperitoneal gauze packing (n = 3, survivors = 1), and endovascular stent placement (n = 3, survivors = 3). Two patients suffered from cardiac arrest before treatment for venous injury. External fixations were performed after TAE according to fracture type. CONCLUSION: The iliac vein injury is the principal cause of hemorrhagic shock in some patients with unstable pelvic fractures after blunt trauma. Venography is useful for identifying iliac vein injuries.

The phosphoinositol 3,4-bisphosphate-binding protein TAPP1 interacts with syntrophins and regulates actin cytoskeletal organization.

Syntrophins are scaffold proteins of the dystrophin glycoprotein complex (DGC), which target ion channels, receptors, and signaling proteins to specialized subcellular domains. A yeast two-hybrid screen of a human brain cDNA library with the PSD-95, Discs-large, ZO-1 (PDZ) domain of gamma1-syntrophin yielded overlapping clones encoding the C terminus of TAPP1, a pleckstrin homology (PH) domain-containing adapter protein that interacts specifically with phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)). In biochemical assays, the C terminus of TAPP1 bound specifically to the PDZ domains of gamma1-, alpha1-, and beta2-syntrophin and was required for syntrophin binding and for the correct subcellular localization of TAPP1. TAPP1 is recruited to the plasma membrane of cells stimulated with platelet-derived growth factor (PDGF), a motogen that produces PI(3,4)P(2). Cell migration in response to PDGF stimulation is characterized by a rapid reorganization of the actin cytoskeleton, which gives rise to plasma membrane specializations including peripheral and dorsal circular ruffles. Both TAPP1 and syntrophins were localized to PDGF-induced circular membrane ruffles in NIH-3T3 cells. Ectopic expression of TAPP1 potently blocked PDGF-induced formation of dorsal circular ruffles, but did not affect peripheral ruffling. Interestingly, coexpression of alpha1- or gamma1-syntrophin with TAPP1 prevented the blockade of circular ruffling. In addition to syntrophins, several other proteins of the DGC were enriched in circular ruffles. Collectively, our results suggest syntrophins regulate the localization of TAPP1, which may be important for remodeling the actin cytoskeleton in response to growth factor stimulation.