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Background: A landmark legal judgment in March 2015 (Montgomery) changed the test for determining negligence due to failing to inform patients before consent, by moving away from asking what a reasonable doctor should disclose and asking instead what a reasonable patient would expect to know., Aim: We sought to determine the effect Montgomery has had on settled claims due to failure to inform compared with claims for other reasons and whether legal firms are adding contributory claims of failure to inform to other principal allegations of negligence., Methods: A Freedom of Information request to NHS Resolution provided data on the number of settled claims against the NHS (2005-19) for any cause and where failure to inform before consent was the principal or contributory cause. Time-series regression was used to compare trends before and after 31 March 2015., Results: The trend in claims/year increased 4-fold for failure to inform (an increase of 9.8/year before 2015 vs. 39.5/year after 2015, P < 0.01), 2.7-fold when failure to inform was the principal cause (7.9/year vs. 21.2/year, P = 0.02) and 9.9-fold as a contributory cause (1.9/year vs. 18.3/year, P < 0.01). There was no material difference in claims due to other causes (334/year vs. 318/year, P = 0.84)., Conclusions: Montgomery has led to a substantial increase in settled claims of failure to inform before consent, with no coincident change in claims for other causes. The increase in contributory compared with principal causes suggests that lawyers are using the judgment to increase the chances of a successful claim against the NHS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Emergency medicine is a profession that requires good leadership skills. Emergency physicians must be able to instill confidence in both the staff and patients, inspire the best in others, have the enthusiasm to take on a surplus of responsibilities, and maintain calmness during unexpected circumstances. Accordingly, residency program directors look carefully for leadership qualities and potential among their applicants. Although some people do have a predisposition to lead, leadership can be both learned and taught. In this article, we provide medical students with the tools that will help them acquire those qualities and thus make them more desirable by program directors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The age of tissues and cells can be accurately estimated by DNA methylation analysis. The multitissue DNA methylation (DNAm) age predictor combines the DNAm levels of 353 CpG dinucleotides to arrive at an age estimate referred to as DNAm age. Recent studies based on short-term observations showed that the DNAm age of reconstituted blood following allogeneic hematopoietic stem cell transplantation (HSCT) reflects the age of the donor. However, it is not known whether the DNAm age of donor blood remains independent of the recipient's age over the long term. Importantly, long-term studies including child recipients have the potential to clearly reveal whether DNAm age is cell-intrinsic or whether it is modulated by extracellular cues in vivo. Here, we address this question by analyzing blood methylation data from HSCT donor and recipient pairs who greatly differed in chronological age (age differences between 1 and 49 years). We found that the DNAm age of the reconstituted blood was not influenced by the recipient's age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder. However, the DNAm age of recipients with relapse of leukemia was unstable. These data are consistent with our previous findings concerning the abnormal DNAm age of cancer cells, and it can potentially be exploited to monitor the health of HSCT recipients. Our data demonstrate that transplanted human hematopoietic stem cells have an intrinsic DNAm age that is unaffected by the environment in a recipient of a different age., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

One of the hardest decisions a medical student has to make is the choice of specialty. Many studies have explored what influences the choice of emergency medicine (EM) as a specialty. In this article, we elaborate on the most important incentives, including the diversity in patients' presentations, having a defined and flexible schedule, the plasticity in choosing and changing a practice location, and the acuity of care and trauma experience. Additionally, we tackle some of the challenges that emergency physicians face. For instance, having to follow a different thought process than most other physicians, as well as the patients' quality and expectations. We also address some of the concerns regarding the specialty, specifically burnout, stress, and the fear associated with maintaining a career in EM. Finally, we provide students interested in EM with some resources that can provide them with further guidance to decide whether EM is the right choice for them., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules.

Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation., (Copyright © 2018 Ferrata Storti Foundation.)

GS87 is a novel, highly specific GSK3 inhibitor, which has shown to induce extensive differentiation of acute myeloid leukemia (AML) cells in early mouse studies and has great potential for therapeutic advancement. This work described the development and validation of an LC-MS/MS method for quantitative determination of GS87 in mouse plasma. In this method, GS87 and T6447952 (a structural analog used as internal standard) were extracted from plasma using hexane as extraction solvent, and separated isocratically on a Waters XTerra ® MS C8 column (2.1 × 50 mm, 3.5 μm) using a mobile phase consisting of acetonitrile and 5.00 mM ammonium formate (35:65, v/v) pumped at a flow rate of 0.200 mL min -1 . Quantitation of GS87 was done by positive electrospray ionization tandem mass spectrometry operated in multiple-reaction-monitoring (MRM) mode. The method has been validated in accordance with the US Food and drug administration guidelines for bioanalytical method validation. It has linear calibration range of 2.50-250 ng mL -1 with correlation coefficient of >0.999. The intra- and inter- assay accuracy and precision were ≤ ±5 and ≤6%, respectively. The IS normalized recovery of GS87 was 103-106%. The stability studies showed that GS87 was stable under all tested conditions. The method developed has been successfully applied to the measurement of GS87 concentrations in mouse plasma samples from an animal study, and may be useful for further preclinical investigation of GS87., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Competing Interests: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

Introduction: A number of medical schools have developed capstone courses to help prepare medical students for their transition to residency training. As part of our capstone program, we developed a Night on Call experience for graduating medical students to simulate the experience of an intern physician responding to medical emergencies in the hospital setting., Methods: Our 2-hour program incorporates high-fidelity simulation in a four-station format (four clinical cases) with semistructured debriefing at the conclusion of the experience., Results: The program has been well received. The majority of students report that the exercise achieves its learning objectives and has been a valuable experience. In addition, the students note that our cases offer a realistic experience., Discussion: A program such as this allows the faculty an opportunity to observe and provide formative feedback to the students regarding their clinical performance when caring for patients in a simulated inpatient setting., Competing Interests: None to report.

More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts. We found that actively proliferating leukemia cells inhibited normal hematopoietic stem and progenitor cell (HSPC) proliferation and homing to the perivascular region. In addition, leukemia development was accompanied by the suppression of the endosteum-lining osteoblast population. We further demonstrated that aberrant Notch activation in the stroma plays an important role in negatively regulating the expression of CXLC12 on osteoblasts and their differentiation. Notch blockade reversed attenuated HSPC cycling, leukemia-associated abnormal blood lineage distribution, and thrombocytopenia as well as recovered osteoblast and HSPC abundance and improved the hematopoietic-supportive functions of osteoblasts. Finally, we confirmed that reduced osteoblast frequency and enhanced Notch signaling were also features of the marrow stroma of human ALL tissues. Collectively, our findings suggest that therapeutically targeting the leukemia-infiltrated hematopoietic niche may restore HSPC homeostasis and improve the outcome of ALL patients., (©2016 American Association for Cancer Research.)

Mitochondria are the site of iron utilization, wherein imported iron is incorporated into heme or iron-sulfur clusters. Previously, we showed that a cytosolic siderophore, which resembles a bacterial siderophore, facilitates mitochondrial iron import in eukaryotes, including zebrafish. An evolutionarily conserved 3-hydroxy butyrate dehydrogenase, 3-hydroxy butyrate dehydrogenase 2 (Bdh2), catalyzes a rate-limiting step in the biogenesis of the eukaryotic siderophore. We found that inactivation of bdh2 in developing zebrafish embryo results in heme deficiency and delays erythroid maturation. The basis for this erythroid maturation defect is not known. Here we show that bdh2 inactivation results in mitochondrial dysfunction and triggers their degradation by mitophagy. Thus, mitochondria are prematurely lost in bdh2-inactivated erythrocytes. Interestingly, bdh2-inactivated erythroid cells also exhibit genomic alterations as indicated by transcriptome analysis. Reestablishment of bdh2 restores mitochondrial function, prevents premature mitochondrial degradation, promotes erythroid development, and reverses altered gene expression. Thus, mitochondrial communication with the nucleus is critical for erythroid development.

Normal human hematopoietic stem and progenitor cells (HPC) lose expression of MLH1 , an important mismatch repair (MMR) pathway gene, with age. Loss of MMR leads to replication dependent mutational events and microsatellite instability observed in secondary acute myelogenous leukemia and other hematologic malignancies. Epigenetic CpG methylation upstream of the MLH1 promoter is a contributing factor to acquired loss of MLH1 expression in tumors of the epithelia and proximal mucosa. Using single molecule high-throughput bisulfite sequencing we have characterized the CpG methylation landscape from -938 to -337 bp upstream of the MLH1 transcriptional start site (position +0), from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing MLH1 . We identify a correlation between MLH1 promoter methylation and loss of MLH1 expression. Additionally, using the CpG site methylation frequencies obtained in this study we were able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as has been previously described for many tumor cell types, we report for the first time a correlation between the loss of MLH1 expression and increased MLH1 promoter methylation in CFC derived from CD34 + selected hematopoietic stem and progenitor cells.

Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts., (Copyright © 2015, American Association for the Advancement of Science.)

Introduction: Since 2011 two online, validated exams for fourth-year emergency medicine (EM) students have been available (National EM M4 Exams). In 2013 the National Board of Medical Examiners offered the Advanced Clinical Examination in Emergency Medicine (EM-ACE). All of these exams are now in widespread use; however, there are no data on how they correlate. This study evaluated the correlation between the EM-ACE exam and the National EM M4 Exams., Methods: From May 2013 to April 2014 the EM-ACE and one version of the EM M4 exam were administered sequentially to fourth-year EM students at five U.S. medical schools. Data collected included institution, gross and scaled scores and version of the EM M4 exam. We performed Pearson's correlation and random effects linear regression., Results: 305 students took the EM-ACE and versions 1 (V1) or 2 (V2) of the EM M4 exams (281 and 24, respectively) [corrected].The mean percent correct for the exams were as follows: EM-ACE 74.9 (SD-9.82), V1 83.0 (SD-6.39), V2 78.5 (SD-7.70) [corrected]. Pearson's correlation coefficient for the V1/EM-ACE was 0.53 (0.43 scaled) and for the V2/EM-ACE was 0.58 (0.41 scaled) [corrected]. The coefficient of determination for V1/ EM-ACE was 0.73 and for V2/EM-ACE 0.71 (0.65 and .49 for scaled scores) [ERRATUM]. The R-squared values were 0.28 and 0.30 (0.18 and 0.13 scaled), respectively [corrected]. There was significant cluster effect by institution., Conclusion: There was moderate positive correlation of student scores on the EM-ACE exam and the National EM M4 Exams.

(-)-Securinine (SE) is a major alkaloid found in plant Securinega suffruticosa, which has a wide range of pharmacological activities including anticancer, anti-parasitic and central nervous system stimulating effects, etc. To aid the pharmacological study of SE, we developed an LC-MS/MS method for quantitative determination of SE in mouse plasma. In this method, plasma samples were first prepared with salting-out assisted liquid-liquid extraction using cold acetonitrile (-20°C) and 2.00 M ammonium acetate. Separation of SE and the internal standard (IS) from sample matrix was achieved on a Gemini Nx C18 column using 40% acetonitrile and 60% 10.0mM ammonium acetate at a flow rate of 0.200 mL min(-1). Quantification of SE was accomplished with positive electrospray ionization tandem mass spectrometry using mass transitions m/z 218.1→84.1 for SE, and m/z 204.1→70.2 for the IS. This method has a lower limit of quantitation (LLOQ) of 0.600 ng mL(-1) and a linear calibration range up to 600 ng mL(-1) in mouse plasma. The intra- and inter-run accuracy (%RE) and precision (%CV) were ≤ ± 6% and 6%, respectively. The IS normalized matrix factors from six lots of plasma matrices ranged 0.92-1.07, and the recoveries of plasma SE were 99-109%. The validated method has been applied to the measurement of SE in plasma samples of a mouse study., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: In epidemiological studies, measures of body fat generally are obtained through anthropometric indices such as the body mass index (BMI), waist (WC), and hip circumferences (HC). Such indices, however, can only provide estimates of a person's true body fat content, overall or by adipose compartment, and may have limited accuracy, especially for the visceral adipose compartment (VAT)., Objective: To determine the extent to which different body adipose tissue compartments are adequately predicted by anthropometry, and to identify anthropometric measures alone, or in combination to predict overall adiposity and specific adipose tissue compartments, independently of age and body size (height)., Methods: In a sub-study of 1,192 participants of the German EPIC (European Prospective Investigation into Cancer and Nutrition) cohorts, whole-body MRI was performed to determine adipose and muscle tissue compartments. Additional anthropometric measurements of BMI, WC and HC were taken., Results: After adjusting for age and height, BMI, WC and HC were better predictors of total body volume (TBV), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) than for VAT, coronary adipose tissue (CAT) and skeletal muscle tissue (SMT). In both sexes, BMI was the best predictor for TBV (men: r = 0.72 [0.68-0.76], women: r = 0.80 [0.77-0.83]) and SMT (men: r = 0.52 [0.45-0.57], women: r = 0.48 [0.41-0.54]). WC was the best predictor variable for TAT (r = 0.48 [0.41-0.54]), VAT (r = 0.44 [0.37-0.50]) and CAT (r = 0.34 [0.26-0.41]) (men), and for VAT (r = 0.42 [0.35-0.49]) and CAT (r = 0.29 [0.22-0.37]) (women). BMI was the best predictor for TAT (r = 0.49 [0.43-0.55]) (women). HC was the best predictor for SAT (men (r = 0.39 [0.32-0.45]) and women (r = 0.52 [0.46-0.58]))., Conclusions: Especially the volumes of internal body fat compartments are poorly predicted by anthropometry. A possible implication may be that associations of chronic disease risks with the sizes of internal body fat as measured by BMI, WC and HC may be strongly underestimated.

Although most animal cells contain centrosomes, consisting of a pair of centrioles, their precise contribution to cell division and embryonic development is unclear. Genetic ablation of STIL, an essential component of the centriole replication machinery in mammalian cells, causes embryonic lethality in mice around mid gestation associated with defective Hedgehog signaling. Here, we describe, by focused ion beam scanning electron microscopy, that STIL(-/-) mouse embryos do not contain centrioles or primary cilia, suggesting that these organelles are not essential for mammalian development until mid gestation. We further show that the lack of primary cilia explains the absence of Hedgehog signaling in STIL(-/-) cells. Exogenous re-expression of STIL or STIL microcephaly mutants compatible with human survival, induced non-templated, de novo generation of centrioles in STIL(-/-) cells. Thus, while the abscence of centrioles is compatible with mammalian gastrulation, lack of centrioles and primary cilia impairs Hedgehog signaling and further embryonic development.

Background: Three-dimensional (3D) presentations enhance the understanding of complex anatomical structures. However, it has been shown that two dimensional (2D) "key views" of anatomical structures may suffice in order to improve spatial understanding. The impact of real 3D images (3Dr) visible only with 3D glasses has not been examined yet. Contrary to 3Dr, regular 3D images apply techniques such as shadows and different grades of transparency to create the impression of 3D.This randomized study aimed to define the impact of both the addition of key views to CT images (2D+) and the use of 3Dr on the identification of liver anatomy in comparison with regular 3D presentations (3D)., Methods: A computer-based teaching module (TM) was used. Medical students were randomized to three groups (2D+ or 3Dr or 3D) and asked to answer 11 anatomical questions and 4 evaluative questions. Both 3D groups had animated models of the human liver available to them which could be moved in all directions., Results: 156 medical students (57.7% female) participated in this randomized trial. Students exposed to 3Dr and 3D performed significantly better than those exposed to 2D+ (p < 0.01, ANOVA). There were no significant differences between 3D and 3Dr and no significant gender differences (p > 0.1, t-test). Students randomized to 3D and 3Dr not only had significantly better results, but they also were significantly faster in answering the 11 anatomical questions when compared to students randomized to 2D+ (p < 0.03, ANOVA). Whether or not "key views" were used had no significant impact on the number of correct answers (p > 0.3, t-test)., Conclusion: This randomized trial confirms that regular 3D visualization improve the identification of liver anatomy.

Purpose: The Medical Imaging Interaction Toolkit (MITK) has been available as open-source software for almost 10 years now. In this period the requirements of software systems in the medical image processing domain have become increasingly complex. The aim of this paper is to show how MITK evolved into a software system that is able to cover all steps of a clinical workflow including data retrieval, image analysis, diagnosis, treatment planning, intervention support, and treatment control., Methods: MITK provides modularization and extensibility on different levels. In addition to the original toolkit, a module system, micro services for small, system-wide features, a service-oriented architecture based on the Open Services Gateway initiative (OSGi) standard, and an extensible and configurable application framework allow MITK to be used, extended and deployed as needed. A refined software process was implemented to deliver high-quality software, ease the fulfillment of regulatory requirements, and enable teamwork in mixed-competence teams., Results: MITK has been applied by a worldwide community and integrated into a variety of solutions, either at the toolkit level or as an application framework with custom extensions. The MITK Workbench has been released as a highly extensible and customizable end-user application. Optional support for tool tracking, image-guided therapy, diffusion imaging as well as various external packages (e.g. CTK, DCMTK, OpenCV, SOFA, Python) is available. MITK has also been used in several FDA/CE-certified applications, which demonstrates the high-quality software and rigorous development process., Conclusions: MITK provides a versatile platform with a high degree of modularization and interoperability and is well suited to meet the challenging tasks of today's and tomorrow's clinically motivated research.

Objectives: On March 11, 2011, Japan experienced the largest earthquake in its history. The undersea earthquake launched a tsunami that inundated much of Japan's eastern coastline and damaged nuclear power plants, precipitating multiple reactor meltdowns. We examined open-source disaster situation reports, news accounts, and disaster-monitoring websites to gather event-specific data to conduct a trauma signature analysis of the event., Methods: The trauma signature analysis included a review of disaster situation reports; the construction of a hazard profile for the earthquake, tsunami, and radiation threats; enumeration of disaster stressors by disaster phase; identification of salient evidence-based psychological risk factors; summation of the trauma signature based on exposure to hazards, loss, and change; and review of the mental health and psychosocial support responses in relation to the analysis., Results: Exposure to this triple-hazard event resulted in extensive damage, significant loss of life, and massive population displacement. Many citizens were exposed to multiple hazards. The extremity of these exposures was partially mitigated by Japan's timely, expert-coordinated, and unified activation of an evidence-based mental health response., Conclusions: The eastern Japan disaster was notable for its unique constellation of compounding exposures. Examination of the trauma signature of this event provided insights and guidance regarding optimal mental health and psychosocial responses. Japan orchestrated a model response that reinforced community resilience.

Purpose: To develop an automated method with which to distinguish metabolically different adipose tissues in a large number of subjects using whole-body magnetic resonance imaging (MRI) datasets for improving the understanding of chronic disease risk predictions associated with distinct adipose tissue compartments., Materials and Methods: In all, 314 participants were scanned using a 1.5T MRI-scanner with a 2-point Dixon whole-body sequence. Image segmentation was automated using standard image processing techniques and knowledge-based methods. Abdominal adipose tissue was separated into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) by statistical shape models. Bone marrow was removed to provide a more accurate measurement of adipose tissue. To assess segmentation accuracy, ground-truth segmentations in 52 images were performed manually by one operator. Due to the high effort of manual delineation, manual segmentation was limited to seven slices per volume., Results: Volumetric differences were 3.30 ± 2.97% and 6.22 ± 5.28% for SAT and VAT, respectively. The systematic error shows an overestimation of 4.22 ± 7.01% for VAT and 0.37 ± 4.45% for SAT. Coefficients-of-variation from repeated measurements were: 3.50 ± 2.93% for VAT and 0.35 ± 0.26% for SAT. The approach of removing bone marrow worked well in most body regions. Only occasionally the method failed for knees and/or shinbone, which resulted in an overestimation of SAT by 3.14 ± 1.45%., Conclusion: We developed a fully automatic process to assess SAT and VAT in whole-body MRI data. The method can support epidemiological studies investigating the relationship between excess body fat and chronic diseases., (Copyright © 2012 Wiley Periodicals, Inc.)

Hematopoietic stem and progenitor cells (HPCs) are necessary for long-term survival. Genomic instability and persistent DNA damage may cause loss of adult stem cell function. The mismatch repair (MMR) pathway increases replication fidelity and defects have been implicated in malignant hematopoietic diseases. Little, however, is known about the role MMR pathway failure plays in the aging process of human HPCs. We hypothesized that loss of MMR occurs in HPCs as a process of human aging. We examined microsatellite instability and expression of the MMR genes MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in HPCs and colony-forming cell-derived clones (CFCs) from human donors aged 0 to 86 years. CFCs from donors > 45 years had a greater frequency of microsatellite instability and CD34(+) progenitors lacking MLH1 expression and protein than individuals ≤ 45 years. Loss of MSH2 did not correlate with age. Thus, a potentially early event in the normal human aging process is microsatellite instability accumulation in normal human HPCs associated with the loss of MLH1 protein expression.

A wide variety of cognitive measures, particularly memory measures, have been studied for their ability to detect suspect effort, or biased responding on neuropsychological assessment instruments. However, visual spatial measures have received less attention. The purpose of this study was to evaluate the classification accuracy of several commonly used visual spatial measures, including the Judgment of Line Orientation Test, the Benton Facial Recognition Test, the Hooper Visual Organization Test, and the Rey Complex Figure Test-Copy and Recognition trials. Participants included 491 consecutive referrals who participated in a comprehensive neuropsychological assessment and met study criteria. Participants were divided into two groups identified as either unbiased responding (UR, N = 415) or biased responding (BR, N = 30) based on their performance on two measures of effort. The remaining participants (N = 46) had discrepant performance on the symptom validity measures and were excluded from further analysis. The groups differed significantly on all measures. Additionally, receiver operating characteristic (ROC) analysis indicated all of the measures had acceptable classification accuracy, but a measure combining scores from all of the measures had excellent classification accuracy. Results indicated that various cut-off scores on the measures could be used depending on the context of the evaluation. Suggested cut-off scores for the measures had sensitivity levels of approximately 32-46%, when specificity was at least 87%. When combined, the measures suggested cut-off scores had sensitivity increase to 57% while maintaining the same level of specificity (87%). The results were discussed in the context of research advocating the use of multiple measures of effort.

Background: Combination therapy with three classes of drug, antiplatelet, cholesterol and blood pressure lowering treatment markedly reduce the risk of recurrent cardiovascular events in patients with coronary heart disease (CHD). Within each class, generic and branded (patented) drugs are available which have similar efficacy but differ in cost., Aims: (i) To assess the extent to which preventive medical drugs are prescribed in patients with CHD and to examine the reasons for drug omissions and (ii) to assess the relative use of branded and generic drugs and the reasons for drug selection., Methods: The medication charts and hospital notes of consecutive patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) at a large cardiothoracic centre were reviewed over a 3-month period. Interviews with patients, attending cardiologists and general practitioners were undertaken to establish why drugs were and were not prescribed., Results: Among 1008 patients (755 who had PCI and 253 who had CABG) the use of aspirin, statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), beta blockers and calcium channel blockers were, respectively, 97, 98, 81, 76 and 18%. The combination of any 4 classes of drug were used in 65% of patients. Almost all patients who did not receive aspirin or a statin had clinical contraindications and were on alternative drugs. In about 12% of patients without an ACE inhibitor (or ARB) and 7% of patients without a beta blocker, no reason to withhold such treatment was identified. Branded drugs were used in 52% of patients; the most commonly prescribed being atorvastatin in 33%. Clinical reasons for using branded rather than generic drugs were identified in 13% of cases., Conclusion: Our results show a high rate of use of secondary preventive cardiac medications in patients undergoing coronary revascularization procedures, but the use of ACE inhibitors or beta blockers is still overlooked in about 1 in 10 patients. Branded drugs are prescribed in about half of all patients undergoing PCI and CABG, but in almost 90% of cases, a generic equivalent could have been used to achieve similar risk reduction. If our results reflect wider practice, an estimated 11 million pounds a year would be saved by the National Health Service by switching to generic alternative drugs.

Acute myelogenous leukemia (AML) results from a differentiation block of hematopoietic progenitor cells along with uncontrolled proliferation. The cytogenetic abnormality at initial diagnosis is the single most important prognostic factor classifying AML patients into three prognostic categories: favorable, intermediate, and poor risk. Currently, favorable-risk AML patients are usually treated with contemporary chemotherapy, and poor-risk AML patients receive allogeneic stem cell transplantation if suitable stem cell donors exist. The approximately 40% of AML patients without identifiable cytogenetic abnormalities (NC AML) are classified as intermediate risk. The optimal therapeutic strategies for these patients are largely unclear. Emerging data recently suggested that molecular study of the mutations of NPM1, FLT3, MLL, and CEBPalpha and alterations in expression levels of BAALC, MN1, and ERG may identify poor-risk patients with NC AML. Further prospective studies are needed to confirm whether NC AML patients with poor risk have improved clinical outcomes after more aggressive therapy.

Despite constant contact with the large population of commensal bacteria, the colonic mucosa is normally hyporesponsive to these potentially proinflammatory signals. Here we report that the single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a negative regulator for Toll-IL-1R signaling, plays a critical role in gut homeostasis, intestinal inflammation, and colitis-associated tumorigenesis by maintaining the microbial tolerance of the colonic epithelium. SIGIRR-deficient (Sigirr(-/-)) colonic epithelial cells displayed commensal bacteria-dependent homeostatic defects, as shown by constitutive upregulation of inflammatory genes, increased inflammatory responses to dextran sulfate sodium (DSS) challenge, and increased Azoxymethane (AOM)+DSS-induced colitis-associated tumorigenesis. Gut epithelium-specific expression of the SIGIRR transgene in the SIGIRR-deficient background reduced the cell survival of the SIGIRR-deficient colon epithelium, abrogated the hypersensitivity of the Sigirr(-/-) mice to DSS-induced colitis, and reduced AOM+DSS-induced tumorigenesis. Taken together, our results indicate that epithelium-derived SIGIRR is critical in controlling the homeostasis and innate immune responses of the colon to enteric microflora.

The 26 December 2004 Sumatra-Andaman earthquake initiated slowly, with small slip and a slow rupture speed for the first 40 to 60 seconds. Then the rupture expanded at a speed of about 2.5 kilometers per second toward the north northwest, extending 1200 to 1300 kilometers along the Andaman trough. Peak displacements reached approximately 15 meters along a 600-kilometer segment of the plate boundary offshore of northwestern Sumatra and the southern Nicobar islands. Slip was less in the northern 400 to 500 kilometers of the aftershock zone, and at least some slip in that region may have occurred on a time scale beyond the seismic band.

The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.

Recent studies show that NF-kappa B activator 1 (Act1) functions as an important adapter molecule for CD40-mediated signaling in epithelial cells. To explore the physiological function of the CD40-Act1 axis, we studied the regulation of gene expression of CD40 and Act1 both in vivo and in cell culture models. Although CD40 and Act1 are up-regulated in mouse lung upon LPS stimulation, IL-1 plus IFN-alpha, -beta, or -gamma synergistically up-regulate both CD40 and Act1 gene expression in human epithelial A549 cells. Cycloheximide superinduces the Act1 mRNA, whereas actinomycin D completely abolishes the Act1 mRNA, indicating that the induction of Act1 mRNA is at the transcriptional level and does not require protein synthesis. Promoter sequence analyses identified putative IFN regulatory factor (IRF)-1, C/EBP-beta, and AP-1 transcription factor binding sites in the Act1 promoter. Although mutation of any of the three sites abolished the promoter activity, Abs against IRF-1 and C/EBP-beta, but not AP-1, blocked the formation of the DNA-binding complex induced by IL-1 plus IFN-beta stimulation, suggesting cooperative action between IRF-1 and C/EBP-beta in mediating Act1 promoter activity. Importantly, LPS-induced gene expression of CD40 and Act1 in the mouse lung is abolished in IRF-1(-/-) mice, indicating an essential role of transcription factor IRF-1 in the coordinated regulation of these two genes during airway inflammation. The induced expression of the CD40-Act1 axis by inflammatory cytokines in epithelial cells probably plays an important role in priming these cells for their response to CD40 ligand during airway inflammation.

Interleukin-18 (IL-18), a pleiotropic cytokine produced by activated macrophages, plays significant roles in the immune response, inducing the secretion of IFN-gamma, TNF-alpha and IL-2, enhancing NK cell activity and potentiating the differentiation of Th1 cells. The intercellular signal transduction pathways through which IL-18 functions have not been thoroughly defined. We have generated a mutant cell line, I1A, that lacks the IRAK protein. In this line which has low or no expression of the other known IRAK family members, we find that the IL-1 receptor-associated kinase (IRAK) is essential for the activation of NFkappaB and JNK in response to IL-18. Furthermore, the death domain, but not the kinase activity of IRAK, is necessary for NFkappaB activation in response to IL-18. Interestingly, the N-proximal undetermined region of IRAK is necessary for NFkappaB activation, but not for JNK activation in response to IL-18, indicating IRAK may be a branchpoint in IL-18 signaling. In addition to IRAK, we implicate two other components in IL-18 signaling, TAK1 (TGF-beta-activated kinase 1) and its activator and substrate TAB1. A dominant negative mutant of TAK1 inhibits the IL-18-mediated NFkappaB activation, while IL-18 stimulation leads to the phosphorylation of TAB1. Finally, analysis of IL-18 signaling in IL-1-unresponsive mutant cell lines suggests that the IL-1- and IL-18-mediated pathways are similar, but may not be identical.

Life-threatening cardiac arrhythmias and other peri-infarct complications are often unexpected and commonly present with little warning. The therapeutic procedures reviewed often require immediate implementation and should be second nature to any physician involved in the management of patients with an AMI.

Background: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear., Methods: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued., Results: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical., Conclusions: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

Use of an NF-kappaB-dependent selectable marker facilitated the isolation of a cell line containing a cDNA encoding Act1, an NF-kappaB activator. Act1 associates with and activates IkappaB kinase (IKK), leading to the liberation of NF-kappaB from its complex with IkappaB. Many signaling pathways that liberate NF-kappaB also activate activating transcription factor (ATF) and activator protein 1 (AP-1) through Jun kinase (JNK). Act1 also activates JNK, suggesting that it might be part of a multifunctional complex involved in the activation of both NF-kappaB and JNK. Act1 fails to activate NF-kappaB in an IL-1-unresponsive mutant cell line in which all known signaling components are present, suggesting that it interacts with an unknown component in IL-1 signaling.

The purpose of this study was to investigate the fire risk of laser resurfacing in the presence of supplemental oxygen. This study aims at defining safety parameters of variables such as laser energy level, oxygen flow rate, and "oxygen to laser target distance" when oxygen is delivered through a nasal cannula or nasopharyngeal tube. The typical operating room environment was simulated in the laboratory using the Yucatan minipig animal model. The energy source was a Coherent Ultrapulse CO2 laser. It was found that combustion did not occur at laser settings of 500 mJ, 50 W, 100 kHz, and a density of 5, used in conjunction with an oxygen flow rate of 6 liter/minute with the target area as close as 0.5 cm to the oxygen delivery. A total of 400 computer pattern generator treatments were delivered using this energy setting without observation of any combustion (p < 0.001). This provides evidence that while using even somewhat high laser settings and oxygen flow rate, laser induced fires can be avoided. We conclude that use of the laser in the presence of oxygen is safe, provided the target area is free of combustible fuels. Despite this assurance, laser mishaps are serious because they lead to both morbidity and mortality. It is our recommendation that close attention be constantly paid to all details, thus reducing the hazard potential of laser energy on local factors in an oxygen-rich environment.

Helium is an inert gas with unique physical properties that allow it to be used for various respiratory emergencies. Because of its low specific gravity and low viscosity, the passage of helium through the respiratory tract is smoother, more laminar, and less turbulent than either air or oxygen. These properties have prompted the use of helium and oxygen in patients with airway obstructions due to tumor, foreign body, edema, or bronchoconstriction. Helium-oxygen has been used to facilitate bronchoscopy through small diameter endotracheal tubes and to increase the effectiveness of high-frequency jet ventilation. Helium has been successful in the treatment of spinal cord decompression sickness seen in divers. Helium-oxygen mixtures are commercially available and may be useful in the emergency department to treat patients with airway obstruction. This article reviews literature concerning the use of helium-oxygen gas mixtures in the emergency department. Additional research conducted in the future may further define the use of this unique gas mixture in the emergency department.

Objective: Fine needle aspiration (FNA) is a minimally invasive procedure that is used to obtain cytologic specimens of suspicious lesions in the breast. The goal of this study was to evaluate the logistics and limitations of MR-guided FNA using a prototype breast localization coil., Materials and Methods: MR-guided FNAs were attempted on 18 lesions (detected on mammography and/or palpation) in 16 patients. Patients were prone with their breast compressed mediolaterally between two plates in a circularly polarized RF coil. Lesion position was determined by reference to fiducial markers that corresponded to a grid of holes placed at 5 mm intervals in the compression plate. FNA was performed with a 22G non-ferromagnetic needle., Results: FNA was successful for 11 of 18 lesions (61%). Of the seven unsuccessful cases, there were four in which the lesions were too posteriorly placed to be accessed through the compression plate by the needle. Three cases were too anteriorly placed to be effectively immobilized and, although successfully localized, were insufficiently sampled by the FNA technique., Conclusion: MR-guided FNA is possible using a prototype breast localization device in a select group of patients. Current coil design limits its use in performing MR-guided FNA on the most anteriorly and posteriorly placed breast lesions. Unique requirements of FNA under MR guidance as compared to needle localization and biopsy have been identified. Modifications in localization hardware and cytology aspiration needles should overcome these restrictions.

High-rise flexible-frame buildings are commonly considered to be resistant to shaking from the largest earthquakes. In addition, base isolation has become increasingly popular for critical buildings that should still function after an earthquake. How will these two types of buildings perform if a large earthquake occurs beneath a metropolitan area? To answer this question, we simulated the near-source ground motions of a M(w) 7.0 thrust earthquake and then mathematically modeled the response of a 20-story steel-frame building and a 3-story base-isolated building. The synthesized ground motions were characterized by large displacement pulses (up to 2 meters) and large ground velocities. These ground motions caused large deformation and possible collapse of the frame building, and they required exceptional measures in the design of the base-isolated building if it was to remain functional.

This study was performed to describe and compare the accuracy of weightbearing at three target levels (25, 50, and 75% of body weight) of 14 ambulatory stroke subjects and 14 matched healthy subjects. Weightbearing through a designated lower extremity (stroke subjects-paretic, healthy subjects-randomly selected) was measured with digital scales. No significant difference was found in magnitude of weightbearing (%) between the stroke and healthy groups. Although making significantly greater errors in weightbearing than healthy subjects, stroke subjects did not consistently weightbear under target. Subjects with stroke tested in earlier studies were neither asked to stand symmetrically nor examined to judge whether they were capable of accepting the required weight through the paretic lower extremity. Before assuming that weightbearing asymmetry is a problem in patients with stroke, clinicians should examine weightbearing behavior more specifically.

The euthymic manic-d-pressive patients with therapeutic plasma lithium levels were each given two i.f. infusions of 30 mg of methylphenidate. The infusions were separated by at least 3 days. Before one infusion each patient was given 5 mg of haloperidol i.v. and before the other infusion each was given an identical volume of saline. A psychiatric observer was blind to the nature of the pretreatment and the order of pretreatment was randomized. Saline pretreated patients showed marked activation and euphoriant responses despite therapeutic lithium levels. Haloperidol pretreatment reduced this response in three patients and eliminated the euphoriant and activating response in the remaining seven patients. These results agree with the existence of a dopaminergic step in the induction of methylphenidate-induced activation and euphoria.