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Purpose Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE). There is no radiation medical countermeasure approved by the U.S. Food and Drug Administration which can be used prior to radiation exposure to protect exposed individuals. Different formulations containing synthetic genistein (BIO 300) are being developed to counter the harmful effects of radiation exposure. Materials and methods We investigated the efficacy of a BIO 300 Oral Powder (OP) formulation as a prophylactic radiation medical countermeasure against a lethal dose of cobalt-60 gamma-radiation in CD2F1 male mice while comparing to other formulations of BIO 300 and Neulasta (PEGylated filgrastim), a standard of care drug for H-ARS. Results BIO 300 OP provided significant radioprotection against ionizing radiation in mice when administered twice per day for six days prior to total-body radiation exposure. Its radioprotective efficacy in the murine model was comparable to the efficacy of a single subcutaneous (sc) injection of Neulasta administered after total-body radiation exposure. Conclusions Our results demonstrate that BIO 300 OP, which can be administered orally, is a promising prophylactic radiation countermeasure for H-ARS.

To date, the United States Food and Drug Administration (FDA) has approved four drugs to mitigate hematopoietic acute radiation syndrome and all four are repurposed radiomitigators. There are several additional drug candidates currently under evaluation that may also be helpful for use during a widespread emergency. One possible candidate is Ex-Rad, also known as ON01210, a chlorobenzyl sulfone derivative (organosulfur compound), which is a novel, small-molecule kinase inhibitor with demonstrated efficacy in the murine model. In this study, we have evaluated the metabolomic and lipidomic profiles in serum samples of nonhuman primates (NHPs) treated with Ex-Rad after exposure to ionizing radiation. Two different dose administration schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation), were used and evaluated using a global molecular profiling approach. We observed alterations in biochemical pathways relating to inflammation and oxidative stress after radiation exposure that were alleviated in animals that received Ex-Rad I or Ex-Rad II. The results from this study lend credence to the possible radiomitigative effects of this drug possibly via a dampening of metabolism-based tissue injury, thus aiding in recovery of vital, radiation-injured organ systems.

Hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE) are detrimental health effects that occur after exposure to high doses of ionizing radiation. BIO 300, a synthetic genistein nanosuspension, was previously proven safe and effective against H-ARS when administered (via the oral (po) or intramuscular (im) route) prior to exposure to lethal doses of total-body radiation. In this study, we evaluated the proteomic changes in serum of nonhuman primates (NHP) after administering BIO 300 by different routes (po and im). We utilized nanoflow-ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (NanoUPLC-MS/MS) methods for comprehensive global profiling and quantification of serum proteins. The results corroborate previous findings that suggest a very similar metabolic profile following both routes of drug administration. Furthermore, we observed minor alterations in protein levels, 2 hours after drug administration, which relates to the Cmax of BIO 300 for both routes of administration. Taken together, this assessment may provide an insight into the mechanism of radioprotection of BIO 300 and a reasonable illustration of the pharmacodynamics of this radiation countermeasure.

Acute exposure to high-dose ionizing irradiation has the potential to severely injure the hematopoietic system and its capacity to produce vital blood cells that innately serve to ward off infections and excessive bleeding. Developing a medical radiation countermeasure that can protect individuals from the damaging effects of irradiation remains a significant, unmet need and an area of great public health interest and concern. Despite significant advancements in the field of radiation countermeasure development to find a nontoxic and effective prophylactic agent for acute radiation syndrome, no such drug has yet been approved by the Food and Drug Administration. This study focuses on examining the metabolic corrections elicited by amifostine, a potent radioprotector, on tissues of vital body organs, such as the heart, spleen, and kidney. Our findings indicate that prophylaxis with this drug offers significant protection against potentially lethal radiation injury, in part, by correction of radiation-induced metabolic pathway perturbations.

The availability of safe and effective radiation countermeasures for the military and civilian population represents a significant unmet medical need. To expedite the development of countermeasures for life-threating situations, the United States Food and Drug Administration (US FDA) has implemented the “Animal Rule” which applies to the development and evaluation of drugs and biologics to reduce or prevent life-threatening conditions caused by exposure to lethal or permanently disabling agents where human efficacy trials are neither feasible nor ethical. In addition, the FDA has introduced several incentives (fast track, orphan drug status, and emergency use authorization [EUA]) to attract drug sponsors to develop such agents for human use. Repurposing is vital to make drugs available for life-threatening conditions. Drugs are commonly repurposed for new indications not originally envisioned. By repurposing a drug, it can be made available for human use much quicker, but this pathway also involves issues such as intellectual property rights as corporations are reluctant to expose their blockbuster pharmaceuticals to additional scientific scrutiny. Two radiomitigators for hematopoietic acute radiation syndrome (H-ARS) (Neupogen and Neulasta) have been approved by the FDA through repurposing. The EUA is a legal means for the FDA to approve new drugs or new indications for the previously approved drugs for use during a declared emergency and is a valid way to expedite drug development. Several promising agents with and without FDA investigational new drug (IND) status for ARS are under advanced development. In the next few years, we expect that the FDA will approve a few radioprotectors for H-ARS as well as gastrointestinal ARS via Animal Rule.

The possible detonation of a radiological dispersal device or improvised nuclear device in a metropolitan city, or the accidental exposures to a radiation source, nuclear accidents, or the all-to-often threats of radiological/nuclear terrorism have led to the urgent need to develop essential analytic tools to assess such radiation exposures, especially radiation doses to exposed individuals. This exposure-assessing work using biological samples, and discipline, is known as biodosimetry. As of late, this field has progressed significantly as it has made use of the advances within newer areas of biologic analytics, namely omics (genomics, proteomics, metabolomics, and transcriptomics), lymphocyte kinetics, optically stimulated luminescence, and electron paramagnetic resonance technology in addition to conventional cytogenetic techniques. The use of automated high throughput platforms and the planning for laboratory surge capacity during the time of need are the latest developments in the field of biomarkers for biodosimetry. Such biomarkers are also needed for radiation exposure/dose conversion estimates that are essential for the development and application of radiation countermeasures, from animals to humans and that are currently being developed following the US Food and Drug Administration Animal Rule. Here, we present and discuss the current status of various biomarkers for assessing radiation dose after radiation exposure. It is anticipated that with the advent of improved biomarkers and associated biomarker platforms for the acute radiation syndrome, exposed victims can be more efficiently triaged and appropriately treated than is currently allowable. The latest advances in the field, and identify the areas where improvement is needed are also listed and discussed.

This study was designed to evaluate the possible potentiation of survival protection afforded by relatively low-dose amifostine prophylaxis against total body irradiation in combination with a protective, less toxic agent, gamma-tocotrienol (GT3). Mice were administered amifostine and/or GT3, then exposed to 9.2 Gy 60Co γ-irradiation and monitored for survival for 30 days. To investigate cytokine stimulation, mice were administered amifostine or GT3; serum samples were collected and analyzed for cytokines. Survival studies show single treatments of GT3 or amifostine significantly improved survival, compared to the vehicle, and combination treatments resulted in significantly higher survival compared to single treatments. In vivo studies with GT3 confirmed prior work indicating GT3 induces granulocyte colony-stimulating factor (G-CSF). This approach, the prophylactic combination of amifostine and GT3, which act through different mechanisms, shows promise and should be investigated further as a potential countermeasure for acute radiation syndrome.

There is a large literature of numerical methods for phase field models from materials science. The prototype models are the Allen-Cahn and Cahn-Hilliard equations. We present four benchmark problems for these equations, with numerical results validated using several computational methods with different spatial and temporal discretizations. Our goal is to provide the scientific community with a reliable reference point for assessing the accuracy and reliability of future software for this important class of problem.

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co &gamma, radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.

The threat of chemical, biological, radiological, and nuclear (CBRN) warfare has been addressed as the uppermost risk to national security since the terrorist attacks on 11 September 2001. Despite significant scientific advances over the past several decades toward the development of safe, non-toxic and effective countermeasures to combat CBRN threats, relatively few countermeasures have been approved by the US Food and Drug Administration (US FDA). Therefore, countermeasures capable of protecting the population from the effects of CBRN attack remain a significant unmet medical need. Chemical and biological (CB) threat agents can be particularly hazardous due to their effectiveness in small quantities and ease of distribution. Area covered: This article reviews the development of countermeasures for CB threats and highlights specific threats for which at least one countermeasure has been approved following the FDA Animal Rule. Patents of CB countermeasures since 2010 have been included. Expert opinion: Nine CB countermeasures have received FDA approval for use in humans following the Animal Rule, and a number of promising CB countermeasures are currently under development. In the next few years, we should expect to have multiple countermeasures approved by the FDA for each indication allowing for more flexible and effective treatment options.

The use of urinary iodine as an indicator of iodine status relies in part on the accuracy of the analytical measurement of iodine in urine. Likewise, the use of dietary iodine intake as an indicator of iodine status relies in part on the accuracy of the analytical measurement of iodine in dietary sources, including foods and dietary supplements. Similarly, the use of specific serum biomarkers of thyroid function to screen for both iodine deficiency and iodine excess relies in part on the accuracy of the analytical measurement of those biomarkers. The National Institute of Standards and Technology has been working with the NIH Office of Dietary Supplements for several years to develop higher-order reference measurement procedures and Standard Reference Materials to support the validation of new routine analytical methods for iodine in foods and dietary supplements, for urinary iodine, and for several serum biomarkers of thyroid function including thyroid-stimulating hormone, thyroglobulin, total and free thyroxine, and total and free triiodothyronine. These materials and methods have the potential to improve the assessment of iodine status and thyroid function in observational studies and clinical trials, thereby promoting public health efforts related to iodine nutrition.

The 15th International Symposium on Biological and Environmental Reference Materials (BERM-15), organized by BAM, took place at in Berlin in September 2018. An overview on main topics of the conference is given.

The development of radiation countermeasures for acute radiation syndrome (ARS) has been underway for the past six decades, leading to the identification of multiple classes of radiation countermeasures. However, to date, only two growth factors (Neupogen and Neulasta) have been approved by the United States Food and Drug Administration (US FDA) for the mitigation of hematopoietic acute radiation syndrome (H-ARS). No radioprotector for ARS has been approved by the FDA yet. Gamma-tocotrienol (GT3) has been demonstrated to have radioprotective efficacy in murine as well as nonhuman primate (NHP) models. Currently, GT3 is under advanced development as a radioprotector that can be administered prior to radiation exposure. We are studying this agent for its safety profile and efficacy using the NHP model. In this study, we analyzed global metabolomic and lipidomic changes using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in serum samples of NHPs administered GT3. Our study, using 12 NHPs, demonstrates that alterations in metabolites manifest only 24 h after GT3 administration. Furthermore, metabolic changes are associated with transient increase in the bioavailability of antioxidants, including lactic acid and cholic acid and anti-inflammatory metabolites 3 deoxyvitamin D3, and docosahexaenoic acid. Taken together, our results show that the administration of GT3 to NHPs causes metabolic shifts that would provide an overall advantage to combat radiation injury. This initial assessment also highlights the utility of metabolomics and lipidomics to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3.

Since 2005, the National Institute of Standards and Technology (NIST) has collaborated with the National Institutes of Health (NIH), Office of Dietary Supplements (ODS) to improve the quality of measurements related to human nutritional markers of vitamin Dstatus. In support of the NIH-ODS Vitamin D Initiative, including the Vitamin D Standardization Program (VDSP), NIST efforts have focused on (1) development of validated analytical methods, including reference measurement procedures (RMPs); (2) development of Standard ReferenceMaterials (SRMs); (3) value assignment of critical study samples using NIST RMPs; and (4) development and coordination of laboratory measurement QA programs. As a result of this collaboration, NIST has developed RMPs for 25-hydroxyvitamin D2 [25(OH)D2], 25(OH)D3, and 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3]; disseminated serum-based SRMs with values assigned for 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3, and 24R,25(OH)2D3; assigned values for critical samples for VDSP studies, including an extensive interlaboratory comparison and reference material commutability study; provided an accuracy basis for the Vitamin D External Quality Assurance Scheme; coordinated the first accuracy-based measurement QA program for the determination of 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 in human serum/plasma; anddeveloped methods and SRMs for the determination of vitamin D and 25(OH)D in food and supplement matrix SRMs. The details of these activities and their benefit and impact to the NIH-ODS Vitamin D Initiative are described.

The Vitamin D Standardization Program (VDSP) coordinated an interlaboratory study to assess the comparability of measurements of total 25-hydroxyvitamin D [25(OH)D] in human serum, which is the primary marker of vitamin D status. A set of 50 individual donor samples were analyzed by 15 different laboratoriesrepresenting national nutrition surveys, assay manufacturers, and clinical and/or research laboratories to provide results for total 25(OH)D using both immunoassays (IAs) and LC tandem MS (MS/MS). The resultswere evaluated relative to bias compared with the target values assigned based on a combination of measurements at Ghent University (Belgium) and the U.S. National Institute of Standards and Technology using reference measurement procedures for the determination of 25(OH)D2 and 25(OH)D3. CV and mean bias for each laboratory and assay platform were assessed and compared with previously established VDSP performance criteria, namely CV ≤ 10% and mean bias ≤ 5%. Nearly all LC-MS/MS results achieved VDSP criteria, whereas only 50% of IAs met the criterion for a ≤10% CV and only three of eight IAs achieved the ≤5% bias. These results establish a benchmark for the evaluation of 25(OH)D assay performance and standardization activities in the future.

The Vitamin D Standardization Program (VDSP) coordinated a study in 2012 to assess the commutability of reference materials and proficiency testing/external quality assurance materials for total 25-hydroxyvitamin D [25(OH)D] in human serum, the primary indicator of vitamin D status. A set of 50 single-donor serum samples as well as 17 reference and proficiency testing/external quality assessment materials wereanalyzed by participating laboratories that used either immunoassay or LC-MS methods for total 25(OH)D. The commutability test materials included National Institute of Standards and Technology Standard Reference Material 972a Vitamin D Metabolites in Human Serum as well as materials from the College of AmericanPathologists and the Vitamin D External Quality Assessment Scheme. Study protocols and data analysis procedures were in accordance with Clinical and Laboratory Standards Institute guidelines. The majority of the test materials were found to be commutable with the methods used in this commutability study. These results provide guidance for laboratories needing tochoose appropriate reference materials and select proficiency or external quality assessment programs and will serve as a foundation for additional VDSP studies.

Recent years have seen a substantial increase in demand for 25-hydroxyvitamin D (25-OHD) assays. DEQAS (the Vitamin D External Quality Assessment Scheme) has been monitoring the performance of these assays since 1989. The first DEQAS distribution was in June 1989 and results were submitted by 13 laboratories in the UK, two of which used HPLC/UV; the rest used ligand binding assays with a tritium tracer. Inter-laboratory CVs (ALTM) ranged from 29.3% (42.7nmol/L) to 53.7% (20.0nmol/L). Currently the scheme has participants in 56 countries using 30 methods or variants of methods. In January 2017, 918 participants returned results and inter-laboratory CVs (ALTM) ranged from 10.3% (73.1nmol/L) to 15.3% (29.4nmol/L). Over the last 27 years, there have been a number of significant milestones in assay development. The first major advance was the development of an iodinated 25-OHD tracer by Hollis and Napoli in 1992, subsequently used in an RIA kit marketed by DiaSorin. This and other commercial radioimmunoassays that followed brought 25-OHD assays within reach of many more non-specialist routine laboratories. With the introduction of fully automated non-isotopic assays without solvent extraction, measurement of 25-OHD became available to any clinical chemistry laboratory with an appropriate analytical platform. However, as the limitations of these non-extraction assays became apparent more laboratories started using LC-MS/MS methodology. Meanwhile the variable accuracy of 25-OHD methods has been addressed by the Vitamin D Standardization Program (VDSP) which encourages manufacturers to produce methods traceable to the reference measurement procedures (RMPs) of NIST, University of Ghent and the Centers for Disease Control and Prevention (CDC). DEQAS changed to an accuracy-based scheme in 2013 and now assesses assay accuracy against the NIST RMP. This review will use DEQAS results and statistics to chart the historical development in 25-OHD assay technology and highlight some of the problems encountered in obtaining reliable results for this most challenging of analytes.

Introduction Despite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government. Area covered This article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures. Emphasis is placed on the advanced development of existing agents since 2011 and new agents identified as radiation countermeasure for ARS during this period. Expert opinion A number of promising radiation countermeasures are currently under development, seven of which have received US FDA investigational new drug status for clinical investigation. Four of these agents, CBLB502, Ex-RAD, HemaMax and OrbeShield, are progressing with large animal studies and clinical trials. G-CSF has high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the US FDA in the future.

The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised individuals exposed to acute, high-dose ionizing irradiation to recover and to survive. CD2F1 mice were irradiated acutely with high doses causing severe, potentially fatal hematopoietic or gastrointestinal injuries and then transfused intravenously with progenitor-enriched, whole blood, or peripheral blood mononuclear cells from mice injected with tocopherol succinate- and AMD3100- (a chemokine receptor anatogonist used to improve the yield of mobilized progenitors). Survival of these mice over a 30-d period was used as the primary measured endpoint of therapeutic effectiveness. The authors demonstrate that tocopherol succinate and AMD3100 mobilize progenitors into peripheral circulation and that the infusion of mobilized progenitor enriched blood or mononuclear cells acts as a bridging therapy for lymphohematopoietic system recovery in mice exposed to whole-body ionizing irradiation. The results demonstrate that infusion of whole blood or blood mononuclear cells from tocopherol succinate (TS)- and AMD3100-injected mice improved the survival of mice receiving high radiation doses significantly. The efficacy of TS-injected donor mice blood or mononuclear cells was comparable to that of blood or cells obtained from mice injected with granulocyte colony-stimulating factor. Donor origin-mobilized progenitors were found to localize in various tissues. The authors suggest that tocopherol succinate is an optimal agent for mobilizing progenitors with significant therapeutic potential. The extent of progenitor mobilization that tocopherol succinate elicits in experimental mice is comparable quantitatively to clinically used drugs such as granulocyte-colony stimulating factor and AMD3100. Therefore, it is proposed that tocopherol succinate be considered for further translational development and ultimately for use in humans.

Introduction The incidence of acute deep venous thrombosis as a result of penetrating proximity extremity trauma (PPET) to the thigh has been demonstrated to be 16% in a single report. The purpose of the current study is to demonstrate the incidence and clinical significance of venous injury as a result of proximity trauma to the thigh in a large cohort screened with colour flow duplex (CFD) ultrasound and to identify factors predictive of defining a wound in proximity to a major vascular structure. Patients and methods A prospective observational study was conducted from January 1st, 2010 to January 1st, 2012 on all patients presenting with penetrating extremity trauma. Data on injury location, mechanism, associated extremity and non-extremity injuries, use and results of CFD, as well as the admitting trauma surgeon were recorded and analysed. Results 220 thigh wounds with a normal physical examination were identified, of which 167 (75.9%) underwent CFD due to proximity. The incidence of acute venous injury was 4.8% (8/167). 37.5% (3/8) of these injuries resulted in morbidity. Injury mechanism and which attending physician was on call were predictive of a wound being defined as in proximity, whereas an injury with an associated fracture was a negative predictor. Conclusions Occult venous injuries as a result of PPET occur in 4.8% of patients with thigh wounds in proximity to a major vascular structure. The designation of a wound as being in “proximity” was influenced by injury mechanism, associated fractures, and the judgement of the on-call attending. Colour flow duplex is a valuable tool with the ability to identify not only occult arterial injuries, but also venous injuries with the potential to cause significant morbidity as well.

A journal devoted to publishing advances in analytical and bioanalytical chemistry, such as Analytical and Bioanalytical Chemistry (ABC), generally focuses on reporting new analytical methods or the application of methods to new analytical problems. Frequently, the necessary concepts and ‘tools’ for producing analytical data that are sufficiently reliable for making important decisions, in addition to satisfying scientific curiosity, are somewhat undervalued. This is also demonstrated in various papers reporting new analytical methods when it comes to method validation. There are still analytical communities that focus such method validation studies only on the characterization of the achievable method precision, but do not consider a suitable evaluation of the trueness of the results. It is recognized that it can be very challenging to assess the latter when appropriate certified reference materials (CRM) are not available to assist in the validation process. Therefore, this special paper collection is intended to address a number of the current challenges regarding BReference Materials for Chemical Analysis^. Building on a legacy initiated with Fresenius’ Zeitschrift fur Analytische Chemie (later called Fresenius’ Journal of Analytical Chemistry), ABC has had a long association with papers related to the production and use of reference materials. Since 1987, collections of papers concerning reference materials had been associated with papers presented at the International Symposium for Biological and Environmental Reference Materials (BERM). For this topical collection on reference materials, however, we specifically invited contributions from producers of CRMs worldwide, primarily from the National Institutes of Metrology (NMIs) in various countries. The response to our invitation was enthusiastic and overwhelming with 57 papers submitted. This topical collection illustrates the global involvement in the development of reference materials with contributions from authors working in 17 countries, the European Commission, and the Bureau International des Poids et Mesures (BIPM). The metrology institutes contributing to this paper collection include: Institute for Reference Materials and Measurements (IRMM), Federal Institute for Materials Research and Testing (BAM) in Germany, Physikalisch-Technische Bundesanstalt (PTB) in Germany, LGC Limited (LGC) in the UK, Laboratoire National de Metrologie et d’Essais (LNE) in France, National Metrology Institute of Japan (NMIJ), National Institute of Metrology (NIM) in China, National Measurement Institute Australia (NMIA), Government Laboratory Hong Kong (GLHK), Korea Research Institute for Science and Standards (KRISS), National Metrology Institute of South Africa (NMISA), National Institute of Metrology, Quality and Technology (INMETRO) in Brazil, National Research Council of Canada (NRCC), and the National Institute of Standards and Technology (NIST) in USA. International cooperation among metrology institutes and other government and academic organizations to produce CRMs is illustrated by several papers (e.g., H. Emteborg et al., L. Wu et al.). This impressive number of manuscript submissions covers a broad range of topics related to CRMs, from their Published in the topical collection Reference Materials for Chemical Analysis with guest editors Hendrik Emons and Stephen A. Wise.

Standard Reference Material 3280 Multivitamin/ Multielement Tablets was issued by the National Institute of Standards and Technology in 2009, and has certified and reference mass fraction values for 13 vitamins, 26 elements, and two carotenoids. Elements were measured using two or more analytical methods at NIST with additional data contributed by collaborating laboratories. This reference material is expected to serve a dual purpose: to provide quality assurance in support of a database of dietary supplement products and to provide a means for analysts, dietary supplement manufacturers, and researchers to assess the appropriateness and validity of their analytical methods and the accuracy of their results.

Background Although the incidence of injury to the upper extremity screened with angiography as a result of proximity penetrating trauma is similar to that of the lower extremity, intervention rates seem to be higher. However, studies evaluating the incidence of injury as a result of proximity penetrating trauma have primarily focused on the lower extremity. This study shows the incidence and clinical significance of vascular injury as a result of proximity trauma to the upper extremity in a large cohort of patients screened with color-flow duplex. Materials and Methods A retrospective study was conducted from January 1, 2005 to January 1, 2012 on all patients undergoing color-flow duplex as a result of proximity penetrating trauma to the upper extremity. Data on injury location, mechanism, associated extremity and nonextremity injuries, and use and results of color-flow duplex were recorded and analyzed. Results A total of 341 patients were identified who underwent color-flow duplex because of proximity penetrating trauma to the upper extremity. Injuries occurred in 370 extremities, with 253 located in the upper arm and 117 in the forearm. Overall, 18 (4.9%) injuries were identified on screening duplex ultrasound, of which 12 (3.2%) were arterial and 5 (1.4%) were venous. The therapeutic intervention rate for detected injuries to the upper arm was 1.6% (4/253), whereas no injuries of the forearm were identified that necessitated intervention. Conclusions Although color-flow duplex is an inexpensive and noninvasive means of detecting injuries as a result of proximity penetrating trauma, screening upper extremity wounds is unlikely to detect clinically significant arterial injuries in need of therapeutic intervention. Venous injuries in the form of deep venous thromboses were detected in only 1.4% of patients. These findings suggest that screening for proximity penetrating trauma of the upper extremity is unlikely to detect injuries at a rate that would prove cost-effective on formal decision analysis.

The purpose of this study was to elucidate the role of alpha-tocopherol succinate (TS)- and AMD3100-mobilized progenitors in mitigating combined injury associated with acute radiation exposure in combination with secondary physical wounding. CD2F1 mice were exposed to high doses of cobalt-60 gamma-radiation and then transfused intravenously with 5 million peripheral blood mononuclear cells (PBMCs) from TS- and AMD3100-injected mice after irradiation. Within 1 h after irradiation, mice were exposed to secondary wounding. Mice were observed for 30 d after irradiation and cytokine analysis was conducted by multiplex Luminex assay at various time-points after irradiation and wounding. Our results initially demonstrated that transfusion of TS-mobilized progenitors from normal mice enhanced survival of acutely irradiated mice exposed 24 h prior to transfusion to supralethal doses (11.5-12.5 Gy) of (60)Co gamma-radiation. Subsequently, comparable transfusions of TS-mobilized progenitors were shown to significantly mitigate severe combined injuries in acutely irradiated mice. TS administered 24 h before irradiation was able to protect mice against combined injury as well. Cytokine results demonstrated that wounding modulates irradiation-induced cytokines. This study further supports the conclusion that the infusion of TS-mobilized progenitor-containing PBMCs acts as a bridging therapy in radiation-combined-injury mice. We suggest that this novel bridging therapeutic approach involving the infusion of TS-mobilized hematopoietic progenitors following acute radiation exposure or combined injury might be applicable to humans.

There is an increasing demand to accurately measure the quality of biofuel products (e.g. biodiesel and bio-ethanol). This demand is driven in Europe by directives promoting the use of renewable sources of energy and worldwide by national and international legislation setting out quality requirements for these fuels. Until now, there has been no international consensus on the minimum technical specifications to ensure biofuel quality. Furthermore, it is unclear which reference materials and measurement techniques are needed to provide the quality assurance and quality control framework to underpin these legislative requirements. As part of the European Commission’s 7th Framework Programme, the BIOREMA project (REference MAterials for BIOfuel specifications) demonstrated the feasibility of preparing biodiesel and bio-ethanol reference materials with reference values traceable to the international system of units for a range of parameters at levels relevant to technical specifications. However, the project concluded also that further research is needed to improve the current measurement capabilities for some parameters. Within the BIOREMA project, two global interlaboratory comparisons were carried out, using the biodiesel and bio-ethanol test materials prepared during the feasibility stage of the project, as well as two biodiesel standard reference materials from the National Institute of Standards and Technology (NIST, USA). The exercises showed that the measurement capabilities of the field laboratories were in many cases satisfactory, whereas for other laboratories the availability and regular use of certified reference materials would likely enhance the measurement capabilities for many of the parameters studied. A general overview of the BIOREMA project is presented in this paper. The details of the production of the two types of BIOREMA reference materials, and the results of the interlaboratory comparison for the bio-ethanol and biodiesel study materials, are discussed in parts 2 and 3 of this series of papers.

At the end of July 2016, Professor Kiyokatsu Jinno retired as an editor of Analytical and Bioanalytical Chemistry (ABC). He was one of the six founding editors when the first issue of the journal appeared in January 2002. Kiyokatsu Jinno (Fig. 1) received his BA (1968), MS degree (1970), and PhD (1973) all from Nagoya University in Nagoya, Japan, working with Professor Daido Ishii, a prominent Japanese separation scientist. Professor Jinno’s doctorate degree, however, was in engineering with research in non-destructive elemental analysis using neutron activation analysis. He then spent the next five years as a research scientist in the Integrated Circuit Laboratory at the Toshiba Research and Development Center working on the development of the dry plasma etching process and electron beam lithographic techniques for large-scale integrated circuits, which he described as Ban active and interesting field^ [1]. In 1978 he was invited to become an associate professor in the School of Materials Science at Toyohashi University of Technology (TUT), a new national technical university just opening at the time of his arrival. At TUT he had been expected to work in the area of radiochemistry using an accelerator that was planned to be built on campus. Unfortunately, the accelerator never appeared, and Professor Jinno was left to find a new area of research. Following the advice of his mentor, Professor Ishii, he chose micro-column liquid chromatography (micro-LC) as his area of research. Professor Jinno remained at TUT until his retirement in 2014 as Full Professor and Vice President of the University. Professor Jinno’s decision to move from activation analysis and elemental analysis to the emerging area of LC was monumental, and he soon became an internationally recognized leader in the field of separation science and related sample preparation techniques. His areas of research during his career span the broad scope of separation science including retention mechanisms and molecular recognition in LC, design of novel stationary phases, development of capillary separation techniques, miniaturized sample preparation techniques and their combination with liquid-phase separations, hyphenated techniques in chromatography and spectroscopy, and the use of computers in separation sciences. He has contributed to a wide range of separation techniques, beyond his primary focus in LC, including micro-LC, capillary electrophoresis, supercritical fluid chromatography (SFC) and extraction (SFE), electrochromatography, gas chromatography, gel permeation chromatography, high-performance thin-layer chromatography, chiral chromatography, solid-phase extraction (SPE), and solid-phase microextraction (SPME). Professor Jinno has been a prolific author with over 310 original research papers, 35 review articles, 39 book chapters, and four books (as author and editor). The exceptional number of review articles, book chapters, and books illustrates the broad range of his contributions. He has presented over 90 plenary and invited lectures at international symposia on chromatography and analytical chemistry. In 2001 a book titled A Century of Separation Science was published highlighting the careers and experiences of many of the founding leaders in the field of separation science. In Professor Jinno’s contribution, BMy Life in Separation Science: Study of Separation Mechanisms^ [1], he states that Bhis contribution to the development of separation science can be divided into at least two main categories: hyphenated * Stephen A. Wise stephen.wise@nih.gov

Background There are a large number of clinical studies focusing on the measurement of individual fatty acids in serum or plasma; however, few studies have focused on the interlaboratory comparisons of these measurements. The National Institutes of Standards and Technology (NIST), in collaboration with the National Institutes of Health Office of Dietary Supplements (NIH-ODS) and the Centers for Disease Control and Prevention (CDC), has initiated a quality assurance program for assessing and improving the comparability of individual fatty acid measurements in serum and plasma. Methods This is a performance-based study so participants are encouraged to use their laboratory's methods for the quantification of the individual fatty acids that they typically measure in the unknown serum or plasma samples along with a control material. The control materials used to date are SRM 1950 Metabolites in Human Plasma and SRM 2378 Fatty Acids in Frozen Human Serum. Results To date, two studies of the Fatty Acid Quality Assurance Program (FAQAP) have been completed with 11 and 14 participants, respectively. The agreement among the laboratories for individual fatty acids was within 20% for 70% of the data submitted. Laboratories were also requested to run triplicate analyses for each unknown sample. The precision of the individual laboratory data was generally good, with relative standard deviations Conclusions The results from the first two exercises indicate the need for additional assessment of the comparability among laboratories doing these measurements. Future studies will be conducted with the goals of increasing the number of participating laboratories, increasing awareness of the need to use control materials, and improving the comparability among laboratories.

This article reviews studies of progenitor mobilization with gamma-tocotrienol (GT3), a tocol under advanced development as a radiation countermeasure for acute radiation syndrome (ARS). GT3 protects mice against high doses of ionizing radiation and induces high levels of granulocyte colony-stimulating factor (G-CSF). GT3‐induced G-CSF in conjunction with AMD3100 (a chemokine receptor antagonist clinically used to improve the yield of mobilized progenitors) mobilizes progenitors; these mobilized progenitors mitigate injury when infused to mice exposed to acute, high-dose ionizing radiation. The administration of a G-CSF antibody to GT3‐injected donor mice abrogated the radiomitigative efficacy of blood or peripheral blood mononuclear cells (PBMC) in irradiated recipient mice. The efficacy of GT3‐injected donor mice blood or PBMC was comparable to a recently published article involving blood or mononuclear cells obtained from mice injected with G-CSF. The injected progenitors were found to localize in various tissues of irradiated hosts. The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised mice to recover. This suggests that GT3 is a highly effective agent for radioprotection and mobilizing progenitors with significant therapeutic potential. Therefore, GT3 may be considered for further translational development and ultimately for use in humans.

Background Chest computed tomography (CCT) is a method of screening for intrathoracic injuries in hemodynamically stable patients with penetrating thoracic trauma. The objective of this study was to examine the changes in utilization of CCT over time and evaluate its contribution to guiding therapeutic intervention. Methods A level 1 trauma center registry was queried between 2006 and 2011. Patients undergoing CCT in the emergency department after penetrating thoracic trauma as well as patients undergoing thoracic operations for penetrating thoracic trauma were identified. Patient demographics, operative indications, use of CCT, injuries, and hospital admissions were analyzed. Results In all, 617 patients had CCTs performed, of whom 61.1% (371 of 617) had a normal screening plain chest radiograph (CXR). In 14.0% (51 of 371) of these cases, the CCT revealed findings not detected on screening CXR. The majority of these injuries were occult pneumothoraces or hemothoraces (84.3%; 43 of 51), of which 27 (62.8%) underwent tube thoracostomy. In only 0.5% (2 of 371), did the results of CCT alone lead to an operative indication: exploration for hemopericardium. The use of CCT in our patients significantly increased overall (28.8% to 71.4%) as well as after a normal screening CXR (23.3% to 74.6%) over the study period. Conclusions The use of CCT for penetrating thoracic trauma increased 3.5-fold during the study period with a concurrent increase in findings of uncertain clinical significance. Patients with a normal screening CXR should be triaged with 3-hour delayed CXR, serial physical examinations, and focused assessment with sonography for trauma; and CCT should only be used selectively as a diagnostic modality.

Polycyclic aromatic sulfur heterocycles (PASH) are ubiquitous in fossil fuels and pose risk to the environment due to their toxicity. Some PASH, resistant to degradation in the environment, are used to differentiate pollutant source and weathering. Although retention data exist for some PASH, few mass spectra are available, so misidentification often occurs between isomers in the same family. In this study, the retention behavior of 119 PASH on 14%-cyanopropyl/86%-polydimethylsiloxane (DB-1701ms), trifluoropropylmethylpolysiloxane (Rtx-200ms), 5%-phenyl/95%-dimethyl (Rxi-5ms), and 50%-diphenyl/50%-dimethyl (Rxi-17Sil-ms) are reported along with their mass spectra. This data is guiding on-going research aimed at identifying PASH in coal tar by multidimensional GC-GC/MS for compounds where standards are not available.

The validity of current guidelines regarding resuscitation of patients in traumatic cardiopulmonary arrest (TCPA) and the ability of emergency medical services (EMS) to appropriately apply them have been called into question. The purpose of this study is to demonstrate the consequences of violating the current published guidelines and whether EMS personnel were able to accurately identify patients in TCPA.We conducted a retrospective review of our Level I trauma center's database that identified 294 patients over an 8-year period (January 1, 2003, to December 31, 2010) who suffered prehospital TCPA and met criteria for the withholding or termination of resuscitation based on current guidelines. Patient demographics, prehospital/emergency department physiology, survival, neurologic outcome, and hospital charges were analyzed.One of 294 patients (0.3%) survived to reach hospital discharge with a Glasgow Coma Scale score of 6. The total costs incurred for these 294 patients meeting criteria for withholding or termination of resuscitation were $3,852,446.65. One hundred seventeen (39.8%) patients were evaluated by more than one EMS team. There was 100% agreement on the presence (15 of 15) or absence (102 of 102) of a pulse between the EMS teams.Our data support the current guidelines regarding the withholding or termination of resuscitation of patients in prehospital TCPA and represent the largest series to date on this topic. EMS personnel were able to accurately determine traumatic cardiac arrest in the field in this series. Violation of the current guidelines resulted in six patients being resuscitated to a neurologically devastated state. No loss of neurologically intact survivors would have resulted had strict adherence to the guidelines been maintained.

Background Practice guidelines for the appropriate use of emergency department thoracotomy (EDT) according to current national resuscitative guidelines have been developed by the American College of Surgeons Committee on Trauma (ACS-COT) and published. At an urban level I trauma center we analyzed how closely these guidelines were followed and their ability to predict mortality. Methods Between January 2003 and July 2010, 120 patients with penetrating thoracic trauma underwent EDT at Mount Sinai Hospital (MSH). Patients were separated based on adherence (group 1, n=70) and nonadherence (group 2, n=50) to current resuscitative guidelines, and group survival rates were determined. These 2 groups were analyzed based on outcome to determine the effect of a strict policy of adherence on survival. Results Of EDTs performed during the study period, 41.7% (50/120) were considered outside current guidelines. Patients in group 2 were less likely to have traditional predictors of survival. There were 6 survivors in group 1 (8.7%), all of whom were neurologically intact; there were no neurologically intact survivors in group 2 ( p = 0.04). The presence of a thoracic surgeon in the operating room (OR) was associated with increased survival (p = 0.039). Conclusions A policy of strict adherence to EDT guidelines based on current national guidelines would have accounted for all potential survivors while avoiding the harmful exposure of health care personnel to blood-borne pathogens and the futile use of resources for trauma victims unable to benefit from them. Cardiothoracic surgeons should be familiar with current EDT guidelines because they are often asked to contribute their operative skills for those patients who survive to reach the OR.

Nuclear detonation through either military or terrorist action would most likely lead to a mass-casualty scenario involving victims with varying degrees of exposure to ionizing radiation. As a result of radiation injury to the hematopoietic system, victims would suffer from a lack of red blood cells that deliver oxygen, immune cells that detect and eliminate infectious agents, and blood platelets that promote blood clot formation. In part, these symptoms are generally referred to as acute radiation syndrome (ARS). While some victims of moderate to high levels of radiation will be beyond saving, most will have received enough radiation to injure but not kill their bone marrow cells completely. Such people will recover from their injuries but face a 30–60 day period during which they cannot fully fight infections and are prone to uncontrolled bleeding and anemia. To keep them alive until their hematopoietic system recovers, they must receive supportive care. Recently, using experimental animal models of ARS, transfusion of myeloid progenitor cells have been tried as a bridging therapy for radiation-exposed animals. Such cells have been shown to be effective in protecting animals exposed to lethal doses of radiation. These myeloid progenitors (along with of other hematopoietic progenitor cell types) can be mobilized out of the bone marrow into the blood for the reconstitution of hematopoiesis. This review discusses various approaches to the mobilization of progenitors using different mobilizing agents, and their utility as a bridging therapy for radiation casualties. We suggest that α-tocopherol succinate (TS) is an optimal mobilizing agent for progenitors. The extent of progenitor mobilization TS elicits in experimental mice is comparable to clinically used drugs such as recombinant granulocyte-colony stimulating factor rhG-CSF/Neupogen® and the bicyclam AMD3100 (plerixafor/Mozobil); therefore, we propose that TS be considered for further translational development and, ultimately for use in humans.

Ethnic differences in warfarin maintenance doses have been documented amongst the three major Asian ethnic groups (Chinese, Malay and Indian) in Singapore. Studies have shown that cytochrome P450 2C9 (CYP2C9) polymorphisms alone did not entirely account for these differences. Recent reports suggest that VKORC1 (subunit of vitamin K epoxide reductase) haplotypes are more predictive of warfarin response. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling techniques were employed to characterise the PK and PD of warfarin in a healthy volunteer study of 16 Chinese and Indian subjects following a single 25 mg dose of warfarin. To further investigate the underlying differences in warfarin response, a semi-mechanistic modelling approach (using an indirect response model for PCA activity) incorporating the vitamin K cycle was attempted using population methods with Bayesian inference. All eight Indian subjects had H7H7 VKORC1 haplotypes and three had either *2/wt or *3/wt CYP2C9 genotypes. Six Chinese subjects had H1H1 VKORC1 haplotypes and one had H1H7. All Chinese subjects were homozygous wt/wt for CYP2C9. Simulations to steady state were performed to examine warfarin response in subjects with different CYP2C9 and VKORC1 polymorphisms. The presence of a single *2 or *3 CYP2C9 allele reduced mean [SE (standard error)] S-warfarin clearance by 35% from 0.276 (0.04) to 0.180 (0.11) l/h. Subjects with VKORC1 haplotype groups of H7H7 had increased mean (SE) C 50,S (concentration of S-warfarin required to achieve 50% of maximum effect) of 479 (7.3) compared to 206 (6.7) ng/ml in subjects with the H1H1 groups. For subjects with the H1H7 haplotype, mean (SE) C 50,S increased 1.4 times to 288 (1.3) ng/ml compared to subjects with H1H1 haplotypes. Steady state simulations showed that whilst CYP2C9 polymorphisms affect the PK of warfarin, VKORC1 haplotypes may be better predictors of warfarin response. Since 90% of Chinese subjects had the VKORC1 H1 haplotype and 100% of Indian subjects the H7 haplotype in this study, ethnic differences in warfarin response in this study appear to be linked to differences in VKORC1 haplotypes.

The National Institute of Standards and Technology offers a variety of natural-matrix and solution-based Standard Reference Materials (SRM) that are characterized for fatty acid composition. The natural-matrix SRM are intended primarily for use as control materials, but other uses include method validation, the development of new analytical methods, and use as a component in achieving traceability of measurements. The use of complex-matrix reference materials for instrument calibration is not recommended; solution calibrants are better suited to this task. In addition to calibration, solution SRM can be used as spiking solutions for fortification of samples, in studying extraction recoveries, for developing chromatographic separations, and as authentic standards for identifying constituents in more complex-matrix extracts. The use of SRM to support the measurement of fatty acids is relevant to a broad spectrum of applications including compliance with and accuracy of nutritional labeling, food manufacturing tolerances (e. g., infant formulas), traceability of measurements for food exports, clinical nutritional measurements, and characterization of alternative energy sources (e. g., biodiesel). Currently, nearly 30 SRM are available with certified, reference, and information values reported for fatty acids. Additional SRM are under development that will complement these reference materials by providing fatty acid profiles in different types of matrices.

What is already known about this subject • Only one other study (Becker et al.) has reported on the influence of smoking cessation and smoking resumption on inhaled insulin pharmacokinetics and glucodynamics, concluding that the rapid changes associated with smoking resumption carry the risk for hypoglycaemia and thus should not be used by active smokers. What this study adds • This is the first euglycaemic clamp study on the impact of smoking cessation, acute smoking re-exposure and nicotine replacement on AIR® inhaled insulin pharmacokinetics and glucodynamics. • We demonstrate clinically and statistically significant shifts in glucodynamic response to acute re-exposure to a single cigarette, leading us to conclude that active smokers should be advised against inhaled insulin therapy until smoking abstinence is stable. • Additionally, these results are also the first to demonstrate an apparent independent effect of nicotine replacement therapy on insulin exposure and glucodynamic response. Aims To explore the effects of smoking cessation and acute smoking re-exposure on the pharmacokinetic (PK) and glucodynamic (GD) profiles of AIR® inhaled insulin (AIR Insulin) with or without nicotine replacement therapy (NRT). Methods Nondiabetic smokers (n = 24) with normal pulmonary function completed a two-phase (four-period), open-label, randomized euglycaemic clamp study. During the initial study phase, subjects underwent glucose clamps following AIR Insulin dosing, shortly after smoking, 8–12 h after smoking, or following subcutaneous insulin lispro shortly after smoking. AIR Insulin PK and GD were again assessed during and after a 4-week smoking-cessation period with or without NRT. In the last study period, subjects smoked one cigarette shortly before final AIR Insulin dosing and glucose clamp, to study the effect of acute smoking re-exposure on inhaled insulin PK and GD. Results Compared with the preceding active smoking phase, the administration of AIR Insulin in nondiabetic subjects undergoing a 4-week period of smoking abstinence resulted in a decrease in PK and GD of approximately 25% (P = 0.008 for both), an effect which was greater in subjects using NRT. Following rechallenge with a single cigarette (without NRT), GD response to AIR Insulin increased significantly (P = 0.006) towards precessation levels, relative to smoking abstinence. In subjects using NRT, however, the increase in GD was less pronounced. Conclusion Smoking, smoking cessation and acute re-exposure with a single cigarette are associated with clinically significant alterations in AIR Insulin pharmacokinetics and glucodynamics. AIR Insulin should not be used by smokers or those at risk for recidivism.

The National Institute of Standards and Technology (NIST) environmental specimen banking system consists of two environmental specimen banks (ESBs): the National Biomonitoring Specimen Bank established in 1979, and the Marine Environmental Specimen Bank established in 2002. Both facilities were specifically designed to store environmental specimens over long periods of time (50–100 years) and in such a way that future researchers could use these specimens to answer questions regarding trends in newly recognized environmental contaminants and verification of past analytical results. The NIST environmental banking system maintains collections of human liver specimens, human blood serum and blood spots, human diet samples, marine sediments, fish tissues, mussels, oysters, marine mammal tissues, and bird eggs and feathers collected as part of several monitoring and research programs supported by the U.S. Government. The NIST environmental banking system emphasizes: (1) carefully designed (and publish...

Vitamin C is a potent antioxidant in vitro and has been reported to act as a vasodilator, possibly by increasing nitric oxide bioavailability. This study examined the antioxidant and vascular effects of a single large oral dose of vitamin C in 26 healthy human volunteers. Haemodynamic and oxidative DNA and lipid damage markers were measured for 8 h following an oral dose of 2 g vitamin C or placebo. Vitamin C had no effect on vasodilation (measured by augmentation index (mean change=0.04%, 90% CI=- 2.20% to 2.28%) or forearm blood flow (-0.19%/min (-0.68, 0.30)), in comparison to placebo) or on several markers of oxidative stress including DNA base oxidation products in blood cells, 8-hydroxy-2'-deoxyguanosine (8O HdG) in urine (0.068 (-0.009, 0.144)) or urinary or plasma total F(2)-isoprostanes (-0.005 ng/ml (-0.021, 0.010), -0.153 ng/mg (-0.319, 0.014), respectively).

The National Institute of Standards and Technology (NIST), the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and Center for Food Safety and Applied Nutrition (CFSAN), and the National Institutes of Health (NIH), Office of Dietary Supplements (ODS) are collaborating to produce a series of standard reference materials (SRMs) for dietary supplements. Standard reference material (SRM) 3276 Carrot Extract in Oil is one in this series, with values assigned for trans-alpha-carotene, trans- and total beta-carotene, delta- and gamma-tocopherol, and twelve fatty acids. Results for carotenoids and tocopherols were obtained by use of combinations of liquid chromatography (LC), on columns of differing selectivity, with absorbance and mass spectrometric (MS) detection. Fluorescence detection also was used for the tocopherols. Results for fatty acids were obtained by use of gas chromatography (GC) with both flame-ionization and mass-spectrometric detection. This material is intended for use as a primary control material when assigning values to in-house (secondary) control materials and for validation of analytical methods for measurement of these analytes in similar matrices.

For nearly three decades the National Institute of Standards and Technology (Gaithersburg, MD) has been involved in the development of Standard Reference Materials (SRMs) for the determination of organic contaminants in environmental matrices. Classes of organic contaminants characterized in these materials include polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), chlorinated pesticides, and most recently, brominated flame retardants (polybrominated diphenyl ethers [PBDEs]). Environmental matrices include fossil fuels, air and diesel particulate matter, house dust, coal tar, sediment, mussel and fish tissue, fish oil, and whale blubber. Recent SRM developments and activities have led to a number of environmental SRMs that are useful for assuring quality of analytical measurements in environmental forensics where source profiling of organic contaminants is often conducted in a range of environmental or biological matrices. Particle-related SRM developments include the issue of a ne...

Ruboxistaurin, a specific inhibitor of the beta(1) and beta(2) isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route.To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522.Six healthy subjects (creatinine clearance80 mL/min/1.73 m(2)) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32 mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis.No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)], maximum plasma concentration [C(max)] and elimination half-life [t(1/2)]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p=0.163). Ruboxistaurin was well tolerated in both groups of subjects.These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 μg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUC τ , s s ) and C m i n , s s but caused a 17% decrease in mean plasma digoxin C m a s , s s (1.40 to 1.16 ng/mL) and an increuse in digoxin t m a x , s s (median increase, 2.5 hours). Although the decrease in digoxin C m a x , s s was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

We examined the relationships among IGF binding protein (IGFBP)-1, insulin sensitivity, and leptin in different ethnic groups (Asian Indians, Chinese, and Caucasians) using the euglycemic hyperinsulinemic clamp. Ten healthy, young and nondiabetic subjects of each ethnic group, matched for body mass index, age, and physical activity were studied. A euglycemic clamp was performed on all subjects. IGFBP-1, insulin, and leptin were measured after fasting and during the clamp. Fasting IGFBP-1 concentration was highest in Chinese (P = 0.027). Asian Indians had the lowest insulin sensitivity index (P = 0.006). The ratio of insulin to IGFBP-1 at fasting and throughout the euglycemic clamp was higher in Asian Indians. Fasting IGFBP-1 had a strong negative correlation with fasting leptin levels (r = -0.715, P = 0.001). Multiple linear regression demonstrated that fasting insulin, leptin, ethnicity, and insulin sensitivity were significant predictors for fasting IGFBP-1. IGFBP-1 is independently determined by ethnicity, insulin sensitivity, and leptin in glucose-tolerant men. The presence of relative insulin resistance and low fasting IGFBP-1 levels in Asian Indians may contribute to their higher risk of developing diabetes and cardiovascular disease.

Background/Aims Alamifovir is a purine nucleotide analogue prodrug that shows potent activity against wild type and lamivudine resistant hepatitis B virus in preclinical studies. The aim of this study was to assess the safety and potential antiviral effects of alamifovir in humans. Methods A randomised, placebo controlled, dose escalation study of oral alamifovir was conducted in 66 chronic hepatitis B infected patients who were selected based on stable HBV DNA (>10 5 copies/ml), with no significant liver pathology. They received either placebo or alamifovir at a total daily dose ranging from 2.5 to 20mg in single or divided doses for 28 days and were followed up for approximately 12 weeks after cessation of treatment. Results All doses showed significant antiviral activity, with mean plasma viral load reductions ranging from 1.5 to 2.6 log 10 after 28 days of dosing. Once and twice daily regimen for the same daily dose (5mg BID vs 10mg QD, 10mg BID vs 20mg QD) showed no apparent difference in the rate and extent of viral decline, or viral reduction at day 28. Post-treatment viral suppression was dose dependent. There were no serious adverse events attributable to study drug, nor were significant dose related events identified. Conclusions Alamifovir has shown potent in vivo anti-HBV activity, with a favourable safety profile.

The results of Global Positioning System (GPS) mapping and Geographic Information System (GIS) analysis of Civil War earthworks in Beaufort and Jasper counties, South Carolina, are presented. Most earthworks were part of a defensive system built by Confederate forces over the course of the war to protect the Charleston to Savannah railroad, which itself was part of a vital supply line allowing rapid transport of men and materiel throughout the Confederacy. For most of the war, Union forces were deployed at Port Royal Sound less than 40 km from the railroad. The Confederates met this threat through fixed defenses at strategic locations combined with rapid movement of troops by rail. This strategy and these tactics are understandable within the geographic context provided by GPS/GIS technology and a military context provided by a detailed campaign history.

Aim To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects. Methods Randomized, three-period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived. Results No statistically significant racial differences in the weight-normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5- and 10-mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups. Conclusion The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.