The Mu story: how a maverick phage moved the field forward.
This article traces the pioneering contributions of phage Mu to our current knowledge of how movable elements move/transpose. Mu provided the first molecular evidence of insertion elements in E. coli, postulated by McClintock to control gene activity in maize in the pre-DNA era. An early Mu-based model successfully explained all the DNA rearrangements associated with transposition, providing a blueprint for navigating the deluge of accumulating reports on transposable element activity. Amplification of the Mu genome via transposition meant that its transposition frequencies were orders of magnitude greater than any rival, so it was only natural that the first in vitro system for transposition was established for Mu. These experiments unraveled the chemistry of the phosphoryl transfer reaction of transposition, and shed light on the nucleoprotein complexes within which they occur. They hastened a similar analysis of other transposons and ushered in the structural era where many transpososomes were crystallized. While it was a lucky break that the mechanism of HIV DNA integration turned out to be similar to that of Mu, it is no accident that current drugs for HIV integrase inhibitors owe their discovery to trailblazing experiments done with Mu. Shining the light on how movable elements restructure genomes, Mu has also given of itself generously to understanding the genome.


A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.
Alzheimer's disease is a form of localized amyloidosis characterized by cerebral cortical amyloid plaques, neurofibrillary tangles, and amyloid deposits within the walls of leptomeningeal vessels. Although most cases of Alzheimer's disease are sporadic, kindreds with autosomal-dominant inheritance of the syndrome suggest that a single mutation may be important in pathogenesis. Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein. This mutation correlates with the presence of Alzheimer's disease in all patients in this study, and may be the inherited factor causing both amyloid fibril formation and dementia.


Generating Visually Aligned Sound from Videos.
We focus on the task of generating sound from natural videos, and the sound should be both temporally and content-wise aligned with visual signals. This task is extremely challenging because some sounds generated outside a camera can not be inferred from video content. The model may be forced to learn an incorrect mapping between visual content and these irrelevant sounds. To address this challenge, we propose a framework named REGNET. In this framework, we first extract appearance and motion features from video frames to better distinguish the object that emits sound from complex background information. We then introduce an innovative audio forwarding regularizer that directly considers the real sound as input and outputs bottlenecked sound features. Using both visual and bottlenecked sound features for sound prediction during training provides stronger supervision for the sound prediction. The audio forwarding regularizer can control the irrelevant sound component and thus prevent the model from learning an incorrect mapping between video frames and sound emitted by the object that is out of the screen. During testing, the audio forwarding regularizer is removed to ensure that REGNET can produce purely aligned sound only from visual features. Extensive evaluations based on Amazon Mechanical Turk demonstrate that our method significantly improves both temporal and contentwise alignment. Remarkably, our generated sound can fool the human with a 68.12% success rate. Code and pre-trained models are publicly available at https://github.com/PeihaoChen/regnet.


Triacylglycerol hydrolase: role in intracellular lipid metabolism.
Recent scientific advances have revealed the identity of several enzymes involved in the synthesis, storage and catabolism of intracellular neutral lipid storage droplets. An enzyme that hydrolyzes stored triacylglycerol (TG), triacylglycerol hydrolase (TGH), was purified from porcine, human and murine liver microsomes. In rodents, TGH is highly expressed in liver as well as heart, kidney, small intestine and adipose tissues, while in humans TGH is mainly expressed in the liver, adipose and small intestine. TGH localizes to the endoplasmic reticulum and lipid droplets. The TGH genes are located within a cluster of carboxylesterase genes on human and mouse chromosomes 16 and 8, respectively. TGH hydrolyzes stored TG, and in the liver, the lipolytic products are made available for VLDL-TG synthesis. Inhibition of TGH activity also inhibits TG and apolipoprotein B secretion by primary hepatocytes. A role for TGH in basal TG lipolysis in adipocytes has been proposed. TGH expression and activity is both developmentally and hormonally regulated. A model for the function of TGH is presented and discussed with respect to tissue specific functions.


Supramolecular metalloglycodendrimers selectively modulate lectin binding and delivery of Ru(ii) complexes into mammalian cells.
A host-guest interaction between Ru(ii)-complexes and sugar-capped β-cyclodextrin was employed to synthesize metalloglycodendrimers. These glycodendrimers demonstrated selective carbohydrate-protein interactions and controlled the delivery of the Ru(ii) complexes into cancer cells, which may facilitate cell-specific apoptosis. Lectin binding assay revealed micromolar range IC50 values with different plant lectins. Cell viability assay and confocal imaging studies of Ru(ii) complexes exhibited cytotoxic activities in cancer cells compared to normal cells with IC50 values close to other literature Ru(ii) complexes. The cell death inducer was found to accumulate favorably to the endoplasmic reticulum (ER) and induced ER stress in cells. The upregulation of CHOP, caspase-3 and caspase-12 disturbed the ER morphology initiating the apoptosis pathway.


Testicular cancer: a narrative review of the role of socioeconomic position from risk to survivorship.
Testicular cancer (TC) is one of the most curable cancers. Given survival rates of close to 100% with appropriate therapy, ensuring proper treatment is essential. We reviewed and summarized the literature on the association of socioeconomic position (SEP) along the cancer control spectrum from risk factors to survivorship. We searched PubMed from 1966 to 2011 using the following terms: testicular cancer, testicular neoplasm, poverty, and socioeconomic factors, retrieving 119 papers. After excluding papers for the non-English (10) language and non-relevance (46), we reviewed 63 papers. We abstracted information on socioeconomic position (SEP), including occupation, education, income, and combinations of the 3. Five areas were examined: risk factors, diagnosis, treatment, survival, and survivorship. Most studies examined area-based measures, not individual measures of SEP. The majority of studies found an increased risk of developing TC with high SEP though recent papers have indicated increased risk in low-income populations. Regarding diagnosis, recent papers have indicated that lower levels of education and SEP are risk factors for later-stage TC diagnosis and hence higher TC mortality. For treatment, 1 study that examined the use of radiation therapy (RT) in stage I seminoma reported that living in a county with lower educational attainment led to lower use of RT. For survival (mortality), several studies found that men living in lower SEP geographic areas experience lower survival and higher mortality. The strongest evidence for SEP impact on testicular germ cell tumor (TGCT) was found for the risk of developing cancer as well as survival. The association of SEP with TGCT risk appears to have changed over the last decade. Given the highly curable nature of TGCT, more research is needed to understand how SEP impacts diagnosis and treatment for TGCT and to design interventions to address disparities in TGCT outcomes and SEP.


Pulse contour analysis and transesophageal echocardiography: a comparison of measurements of cardiac output during laparoscopic colon surgery.
Pulse wave analysis (PWA) allows cardiac output (CO) measurement after calibration by transpulmonary thermodilution. A PWA system that does not require previous calibration, the FloTrac/Vigileo (FTV), has been recently developed. We compared determinations of CO made with the FTV to simultaneous measurements using transesophageal echocardiography (TEE). Ten ASA I-II patients scheduled for laparoscopic colorectal surgery were studied. A radial 20-gauge cannula was inserted and connected to a hemodynamic monitor and a FTV system for PWA and determination of CO (CO(PWA)). TEE CO (CO(TEE)) was determined as previously described. Measurements were made after intubation, 5 min after establishing the lithotomy position, 5 min after establishing pneumoperitoneum, every 30 min, or each time mean arterial blood pressure decreased below basal values. Statistical analysis was made with the Bland and Altman method. Eighty-eight measurements were compared. The CO(TEE) values ranged from 3.23 to 12 Lt/min (mean 6.21 +/- 1.85). Values for CO(PWA) ranged from 2.9 to 8.5 Lt/min (mean 4.84 +/- 1.14). Bias was 1.17 and limits of agreement -2.02 and 4.37. The percentage error between all CO(TEE) and CO(PWA) measurements was 40% (27%-50%) mean (range). During laparoscopic colon surgery, clinically important differences were observed between CO determinations made with TEE and FTV.


High hepatitis B viral load predicts recurrence of small hepatocellular carcinoma after curative resection.
A retrospective cohort study was conducted to identify risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. A total of 317 patients who had received curative resection of pathologically proven small HCC (< or = 3 cm in diameter) were analyzed to ascertain the factors affecting recurrence. The median follow-up period was 33.7 months. Cumulative recurrence rates at 1, 3, and 5 years after resection were 23.5%, 49.5%, and 65.5%, respectively. Male sex, alpha-fetoprotein (AFP) > or = 400 ng/mL, HBV DNA level > or = 4 log(10) copies/mL, prolonged prothrombin time, tumor size > or = 2 cm, microvascular invasion, absence of capsular formation, moderate/poor tumor differentiation, and absence of postoperative interferon-alpha (IFN-alpha) treatment were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV DNA level > or = 4 log(10) copies/mL (P < 0.001, hazard ratio (HR) 2.110), AFP > or = 400 ng/mL (P = 0.011, HR 1.574), microvascular invasion (P < 0.001, HR 1.767), and postoperative IFN-alpha treatment (P = 0.022, HR 0.562) remained to be independently associated with HCC recurrence. Those contributing to late recurrence (>2 years) were older age and HBV DNA level > or = 4 log(10) copies/mL. Patients with persistent HBV DNA level > or = 4 log(10) copies/mL at resection and follow-up had the highest recurrence risk (P < 0.001, HR 4.129). HBV DNA level > or = 4 log(10) copies/mL at the time of resection was the most important risk factor for recurrence. Postoperative IFN-alpha treatment significantly decreased the recurrence risk after resection.


Super-Coulombic atom-atom interactions in hyperbolic media.
Dipole-dipole interactions, which govern phenomena such as cooperative Lamb shifts, superradiant decay rates, Van der Waals forces and resonance energy transfer rates, are conventionally limited to the Coulombic near-field. Here we reveal a class of real-photon and virtual-photon long-range quantum electrodynamic interactions that have a singularity in media with hyperbolic dispersion. The singularity in the dipole-dipole coupling, referred to as a super-Coulombic interaction, is a result of an effective interaction distance that goes to zero in the ideal limit irrespective of the physical distance. We investigate the entire landscape of atom-atom interactions in hyperbolic media confirming the giant long-range enhancement. We also propose multiple experimental platforms to verify our predicted effect with phonon-polaritonic hexagonal boron nitride, plasmonic super-lattices and hyperbolic meta-surfaces as well. Our work paves the way for the control of cold atoms above hyperbolic meta-surfaces and the study of many-body physics with hyperbolic media.


Dyserythropoiesis in the diagnosis of the myelodysplastic syndromes and other myeloid neoplasms: problem areas.
An evaluation of the significance of specified dyserythropoietic features in suspected myelodysplastic syndrome (MDS) and acute myeloid leukaemia with erythroid dysplasia was made by means of evaluation of 100 electronic images of bone marrow erythroblasts from each of 20 subjects: 11 with a myeloid neoplasm, six with another condition that could cause erythroid dysplasia and three healthy controls. The evaluation was carried out independently by seven experienced haematologists/haematopathologists who were blinded to the diagnosis. The majority of the dyserythropoietic features listed in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues were validated, although karyorrhexis was found to be infrequent and lacking in specificity; multinuclearity and megaloblastosis were more often observed but also lacked specificity. Good majority agreement on the identification of dysplastic features was obtained. Despite this, it was demonstrated that a reliable diagnosis of MDS can often not be made on the basis of erythroid morphology alone. Interpretation of dyserythropoiesis must be carried out with full knowledge of other clinicopathological features and with a constant awareness of the other conditions that can be confused with MDS. An iron stain is essential, as cases with ring sideroblasts may otherwise not be recognised as having MDS.


[Preface: intuitive visualization of medical information].
Information technology(IT), visualization, and manipulation will be the key words for next generation surgery. In other words, it is awaited to make good use of intuitive visualization of medical information management by extensive use of IT in which medical science and engineering are merged and incorporated and of the process management or the visualization of treatment course using three-dimensional intraoperative images and simulation data base. In order to put it into practice, it is inevitable to establish a treatment strategy system that certainly enables surgeons to provide constantly high quality medicine. This means that to achieve the goal while optimizing the strategy toward the goal(a road map) by monitoring real-timely the pre- and intraoperative surgical planning and the operating condition of surgical devices under the control of the surgical strategy system.


Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression.
Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4(+) and CD8(+)T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS(+)TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor(+)CD4(+)T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN(+) and CD83(+)B-cells in SPMS. ICOS(+)TFH-cells and DC-SIGN(+)B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4(+)T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.


Physiological responses of ponderosa pine in western Montana to thinning, prescribed fire and burning season.
Low-elevation ponderosa pine (Pinus ponderosa Dougl. ex. Laws.) forests of the northern Rocky Mountains historically experienced frequent low-intensity fires that maintained open uneven-aged stands. A century of fire exclusion has contributed to denser ponderosa pine forests with greater competition for resources, higher tree stress and greater risk of insect attack and stand-destroying fire. Active management intended to restore a semblance of the more sustainable historic stand structure and composition includes selective thinning and prescribed fire. However, little is known about the relative effects of these management practices on the physiological performance of ponderosa pine. We measured soil water and nitrogen availability, physiological performance and wood radial increment of second growth ponderosa pine trees at the Lick Creek Experimental Site in the Bitterroot National Forest, Montana, 8 and 9 years after the application of four treatments: thinning only; thinning followed by prescribed fire in the spring; thinning followed by prescribed fire in the fall; and untreated controls. Volumetric soil water content and resin capsule ammonium did not differ among treatments. Resin capsule nitrate in the control treatment was similar to that in all other treatments, although burned treatments had lower nitrate relative to the thinned-only treatment. Trees of similar size and canopy condition in the three thinned treatments (with and without fire) displayed higher leaf-area-based photosynthetic rate, stomatal conductance and mid-morning leaf water potential in June and July, and higher wood radial increment relative to trees in control units. Specific leaf area, mass-based leaf nitrogen content and carbon isotope discrimination did not vary among treatments. Our results suggest that, despite minimal differences in soil resource availability, trees in managed units where basal area was reduced had improved gas exchange and growth compared with trees in unmanaged units. Prescribed fire (either in the spring or in the fall) in addition to thinning, had no measurable effect on the mid-term physiological performance and wood growth of second growth ponderosa pine.


Timing of surgery and radiotherapy in the management of metastatic spine disease: a systematic review.
The last decade has witnessed a dramatic change in management of metastatic spine disease, with an increased role for surgery and emerging use of stereotactic radiotherapy, often in combination. Patients may be treated with radiotherapy followed by surgery, or have surgery and then adjuvant radiotherapy. In both cases, the surgeon and oncologist need to select the optimal timing for surgery and radiotherapy to minimize wound complications while obtaining maximum oncolytic effects. The purpose of this review was to determine the optimal timing of surgery and radiotherapy in patients surgically treated for spinal metastases. A systematic review utilizing Medline, Embase, Paper First, Web of Science, Google Scholar, and the Cochrane Database of Systematic Reviews was performed. References were screened to further identify relevant studies and basic science literature reviewed. A total of 46 reports discussing the timing of surgery after radiotherapy, describing experience in 5836 patients, were identified. Only one retrospective study addressed the research question and suggested that surgery within seven days of radiation increases the rate of postoperative wound complications. Timing of adjuvant radiotherapy following surgery was addressed in 51 reports describing 7090 patients. None of the studies specifically answered the research question. The time interval between radiotherapy and surgery was reported as 5-21 days in nine studies. Based on this systematic review together with the understanding of general principles of wound healing and effects of radiation on wound healing, the optimal radiotherapy-surgery/surgery-radiotherapy time interval should be at least one week to minimize wound complications.


Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma.
Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma.


Riverscape genetics identifies replicated ecological divergence across an Amazonian ecotone.
Ecological speciation involves the evolution of reproductive isolation and niche divergence in the absence of a physical barrier to gene flow. The process is one of the most controversial topics of the speciation debate, particularly in tropical regions. Here, we investigate ecologically based divergence across an Amazonian ecotone in the electric fish, Steatogenys elegans. We combine phylogenetics, genome scans, and population genetics with a recently developed individual-based evolutionary landscape genetics approach that incorporates selection. This framework is used to assess the relative contributions of geography and divergent natural selection between environments as biodiversity drivers. We report on two closely related and sympatric lineages that exemplify how divergent selection across a major Amazonian aquatic ecotone (i.e., between rivers with markedly different hydrochemical properties) may result in replicated ecologically mediated speciation. The results link selection across an ecological gradient with reproductive isolation and we propose that assortative mating based on water color may be driving the divergence. Divergence resulting from ecologically driven selection highlights the importance of considering environmental heterogeneity in studies of speciation in tropical regions. Furthermore, we show that framing ecological speciation in a spatially explicit evolutionary landscape genetics framework provides an important first step in exploring a wide range of the potential effects of spatial dependence in natural selection.


A regional consensus recommendation on brain atrophy as an outcome measure in multiple sclerosis.
Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory and neurodegenerative processes leading to irreversible neurological impairment. Brain atrophy occurs early in the course of the disease at a rate greater than the general population. Brain volume loss (BVL) is associated with disability progression and cognitive impairment in patients with MS; hence its value as a potential target in monitoring and treating MS is discussed. A group of MS neurologists and neuro-radiologists reviewed the current literature on brain atrophy and discussed the challenges in assessing and implementing brain atrophy measurements in clinical practice. The panel used a voting system to reach a consensus and the votes were counted for the proposed set of questions for cognitive and brain atrophy assessments. The panel of experts was able to identify recent studies, which demonstrated the correlation between BVL and future worsening of disability and cognition. The current evidence revealed that reduction of BVL could be achieved with different disease-modifying therapies (DMTs). BVL provided a better treatment and monitoring strategy when it is combined to the composite measures of "no evidence of disease activity" (NEDA). The panel recommended a set of cognitive assessment tools and MRI methods and software applications that may help in capturing and measuring the underlying MS pathology with high degree of specificity. BVL was considered to be a useful measurement to longitudinally assess disease progression and cognitive function in patients with MS. Brain atrophy measurement was recommended to be incorporated into the concept of NEDA. Consequently, a consensus recommendation was reached in anticipation for implementation of the use of cognitive assessment and brain atrophy measurements on a regional level.


Broadly neutralizing antibodies abrogate established hepatitis C virus infection.
In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs-AR3A, AR3B, and AR4A-delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection.


A Novel Mutation in DMD (c.10797+5G>A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability.
Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy. The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD. Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.


Comparing neural correlates of configural processing in faces and objects: an ERP study of the Thatcher illusion.
In the Thatcher illusion, a face with inverted eyes and mouth looks abnormal when upright but not when inverted. Behavioral studies have shown that thatcherization of an upright face disrupts perceptual processing of the local configuration. We recorded high-density EEG from normal observers to study ERP correlates of the illusion during the perception of faces and nonface objects, to determine whether inversion and thatcherization affect similar neural mechanisms. Observers viewed faces and houses in four conditions (upright vs. inverted, and normal vs. thatcherized) while detecting an oddball category (chairs). Thatcherization delayed the N170 component over occipito-temporal cortex to faces, but not to houses. This modulation matched the illusion as it was larger for upright than inverted faces. The P1 over medial occipital regions was delayed by face inversion but unaffected by thatcherization. Finally, face thatcherization delayed P2 over occipito-temporal but not over parietal regions, while inversion affected P2 across categories. All effects involving thatcherization were face-specific. These results indicate that effects of face inversion and feature inversion (in thatcherized faces) can be distinguished on a functional as well as neural level, and that they affect configural processing of faces in different time windows.


Peer Feedback, Learning, and Improvement: Answering the Call of the Institute of Medicine Report on Diagnostic Error.
In September 2015, the Institute of Medicine (IOM) published a report titled "Improving Diagnosis in Health Care," in which it was recommended that "health care organizations should adopt policies and practices that promote a nonpunitive culture that values open discussion and feedback on diagnostic performance." It may seem counterintuitive that a report addressing a highly technical skill such as medical diagnosis would be focused on organizational culture. The wisdom becomes clearer, however, when examined in the light of recent advances in the understanding of human error and individual and organizational performance. The current dominant model for radiologist performance improvement is scoring-based peer review, which reflects a traditional quality assurance approach, derived from manufacturing in the mid-1900s. Far from achieving the goals of the IOM, which are celebrating success, recognizing mistakes as an opportunity to learn, and fostering openness and trust, we have found that scoring-based peer review tends to drive radiologists inward, against each other, and against practice leaders. Modern approaches to quality improvement focus on using and enhancing interpersonal professional relationships to achieve and maintain high levels of individual and organizational performance. In this article, the authors review the recommendations set forth by the recent IOM report, discuss the science and theory that underlie several of those recommendations, and assess how well they fit with the current dominant approach to radiology peer review. The authors also offer an alternative approach to peer review: peer feedback, learning, and improvement (or more succinctly, "peer learning"), which they believe is better aligned with the principles promoted by the IOM. © RSNA, 2016.


A critical appraisal of 2007 American College of Occupational and Environmental Medicine (ACOEM) Practice Guidelines for Interventional Pain Management: an independent review utilizing AGREE, AMA, IOM, and other criteria.
Today, with the growing interest of the medical community and others in practice guidelines, there is greater emphasis on formal procedures and methods for arriving at a widely scrutinized and endorsed consensus than ever before. Conflicts in terminology and technique are notable for the confusion that guidelines create and for what they reflect about differences in values, experiences, and interests among different parties. While public and private development activities continue to multiply, the means for coordinating these efforts to resolve inconsistencies, fill in gaps, track applications and results, and assess the soundness of particular guidelines continue to be limited. In this era of widespread guideline development by private organizations, the American College of Occupational and Environment Medicine (ACOEM) has developed guidelines that evaluate areas of clinical practice well beyond the scope of occupational medicine and yet fail to properly involve physicians expert in these, especially those in the field of interventional pain management. As the field of guidelines suffers from imperfect and incomplete scientific knowledge as well as imperfect and uneven means of applying that knowledge without a single or correct way to develop guidelines, ACOEM guidelines have been alleged to hinder patient care, reduce access to interventional pain management procedures, and transfer patients into a system of disability, Medicare, and Medicaid. To critically appraise occupational medicine practice guidelines for interventional pain management by an independent review utilizing the Appraisal of Guidelines for Research and Evaluation (AGREE), American Medical Association (AMA), Institute of Medicine (IOM), and other commonly utilized criteria. Revised chapters of ACOEM guidelines, low back pain and chronic pain, developed in 2007 and 2008 are evaluated, utilizing AGREE, AMA, IOM instruments, and Shaneyfelt et al's criteria, were independently reviewed by 4 appraisers. Critical appraisal utilizing the AGREE instrument found that both chapters scored less than 10% in 3 of the 6 domains, less than 20% in one domain, over 30% in one domain, and over 70% in one domain. Global assessment also scored below 30% with a recommendation from AGREE, "not recommended or suitable for use in practice." Based on AMA key attributes, both chapters of ACOEM guidelines met only one of the 6 key attributes, only 3 of the 8 attributes were met by IOM criteria, and based on the criteria described by Shaneyfelt et al, overall only 28% of criteria were met. Both the low back pain and chronic pain chapters of the ACOEM guidelines may not be ideal for clinical use based on the assessment by the AGREE instrument, AMA attributes, and criteria established by Shaneyfelt et al. They also scored low on IOM criteria (37.5%). These guidelines may not be applicable for clinical use.


Brain death induces renal expression of heme oxygenase-1 and heat shock protein 70.
Kidneys derived from brain dead donors have lower graft survival and higher graft-function loss compared to their living donor counterpart. Heat Shock Proteins (HSP) are a large family of stress proteins involved in maintaining cell homeostasis. We studied the role of stress-inducible genes Heme Oxygenase-1 (HO-1), HSP27, HSP40, and HSP70 in the kidney following a 4 hour period of brain death. Brain death was induced in rats (n=6) by inflating a balloon catheter in the epidural space. Kidneys were analysed for HSPs using RT-PCR, Western blotting, and immunohistochemistry. RT-PCR data showed a significant increase in gene expression for HO-1 and HSP70 in kidneys of brain dead rats. Western blotting revealed a massive increase in HO-1 protein in brain dead rat kidneys. Immunohistochemistry confirmed these findings, showing extensive HO-1 protein expression in the renal cortical tubules of brain dead rats. HSP70 protein was predominantly increased in renal distal tubules of brain dead rats treated for hypotension. Renal stress caused by brain death induces expression of the cytoprotective genes HO-1 and HSP70, but not of HSP27 and HSP40. The upregulation of these cytoprotective genes indicate that renal damage occurs during brain death, and could be part of a protective or recuperative mechanism induced by brain death-associated stress.


Risk of Invasive Pneumococcal Disease in Children with Sickle Cell Disease in England: A National Observational Cohort Study, 2010-2015.
To describe the clinical presentation, risk factors, serotype distribution and outcomes of invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in the UK. Prospective national newborn screening for SCD and enhanced national IPD surveillance. Children with SCD born in England between 1 September 2010 and 31 August 2014 who developed laboratory-confirmed IPD by 31 December 2015. Risk of IPD in children with SCD compared with children without SCD during the surveillance period. Eleven children homozygote for haemoglobin S (HbSS) and one double heterozygote for haemoglobin S and C (HbSC) developed IPD. Septicaemia (n=7) and lower respiratory tract infection (n=4) were the main clinical presentations, and serogroup 15 (not present in PCV13) was responsible for 73% (8/11) of cases. Three children with HbSS (27%) died compared with <5% nationally. Children with HbSS had a 49-fold (95% CI 27 to 89, P<0.001) higher risk of IPD compared with their peers without SCD. Children with SCD remain at increased risk of IPD despite national newborn screening, early penicillin prophylaxis and high pneumococcal vaccine uptake. They are also more likely to die of their infection compared with their peers without SCD. Most IPD cases are now due to serotypes not covered by PCV13. Healthcare professionals need to work more closely with families with SCD and local communities to emphasise the importance of penicillin prophylaxis, explore barriers, allay misguided beliefs and facilitate rapid access to healthcare.


Birth of a Father: Fathering in the First 1,000 Days.
As a result of societal changes, fathers participate more actively in child care than they used to. In this article, we propose a context-dependent biobehavioral model of emergent fatherhood in which sociocultural, behavioral, hormonal, and neural factors develop and interact during the first 1,000 days of fatherhood. Sociocultural factors, including different expectations of fathers and varying opportunities for paternal caregiving through paid paternal leave, influence paternal involvement. Levels of hormones (e.g., testosterone, vasopressin, oxytocin, cortisol) predict fathers' parenting behaviors, and involvement in caregiving in turn affects their hormones and brain responses to infant stimuli. The birth of the first child marks the transition to fatherhood and may be a critical period in men's lives, with a smoother transition to fatherhood predicting more optimal involvement by fathers in subsequent years. A focus on prenatal and early postnatal fathering may pave the way for developing interventions that effectively support fathering during pregnancy and in the first years of their children's lives.


Etomidate infusion at low doses is an effective and safe treatment for severe Cushing's syndrome outside intensive care.
Intravenous etomidate infusion is effective to rapidly lower cortisol levels in severe Cushing's syndrome (CS) in the intensive care unit (ICU). Recently, etomidate treatment has also been proposed at lower doses in non-ICU wards, but it is not yet clear how this approach compares to ICU treatment. We compared data from patients with severe CS treated with high starting doses of etomidate (median: 0.30 mg/kg BW/day) in ICU or with lower starting doses (median: 0.025 mg/kg BW/day) in non-ICU medical wards. Fourteen patients were included, among which ten were treated with low starting doses (LD) and four with high starting doses etomidate (HD). All patients had severe and complicated CS related to adrenal carcinoma (n = 8) or ectopic ACTH secretion (n = 6). Etomidate was effective in reducing cortisol levels below 500 nmol/L in a median of 1 day in the HD group compared to 3 days in the LD group (P = 0.013). However, all patients of the HD group had etomidate-induced cortisol insufficiency and needed frequent monitoring, while no patient from the LD group required hydrocortisone supplementation. No patient in either group died from complications of CS or etomidate treatment, but final outcome was poor as six patients in the LD group and all four patients in the HD group died from their cancer during follow-up. Our study suggests that, for patients with severe CS who do not require intensive organ-supporting therapy, the use of very low doses of etomidate in medical wards should be considered.


Improved methods and assumptions for estimation of the HIV/AIDS epidemic and its impact: Recommendations of the UNAIDS Reference Group on Estimates, Modelling and Projections.
UNAIDS and WHO produce biannual country-specific estimates of HIV/AIDS and its impact. These estimates are based on methods and assumptions that reflect the best understanding of HIV epidemiology and demography at the time. Where significant advances are made in epidemiological and demographic research, the methods and assumptions must evolve to match these advances. UNAIDS established an Epidemiology Reference Group in 1999 to advise them and other organisations on HIV epidemiology and methods for making estimates and projections of HIV/AIDS. During the meeting of the reference group in 2001, four priority areas were identified where methods and assumptions should be reviewed and perhaps modified: a) models of the HIV epidemic, b) survival of adults with HIV-1 in low and middle income countries, c) survival of children with HIV-1 in low and middle income countries, and d) methods to estimate numbers of AIDS orphans. Research and literature reviews were carried out by Reference Group members and invited specialists, prior to meetings held during 2001-2. Recommendations reflecting the consensus of the meeting participants on the four priority areas were determined at each meeting. These recommendations were followed in UNAIDS and WHO development of country-specific estimates of HIV/AIDS and its impact for end of 2001.


Effect of glycosylphosphatidylinositol (GPI)-phospholipase D overexpression on GPI metabolism.
GPI-PLD [glycosylphosphatidylinositol (GPI)-specific phospholipase D (PLD)] is a secreted mammalian enzyme that specifically cleaves GPI-anchored proteins. In addition, the enzyme has been shown to cleave GPI anchor intermediates in cell lysates. The biosynthesis of the GPI anchor is well characterized; however, the mechanisms by which the levels of GPI anchor intermediates are regulated are still unknown. To investigate whether GPI-PLD plays a role in this regulation, we isolated stable HeLa cells overexpressing the enzyme. GPI-PLD-HeLa (GPI-PLD-transfected HeLa) cells showed a 3-fold increase in intracellular GPI-PLD activity and drastically decreased the levels of GPI-anchored proteins when compared with untransfected HeLa controls. Intracellular cleavage of GPI-anchored proteins has been suggested to occur early in the secretory pathway and, in agreement with this proposal, GPI-PLD activity in GPI-PLD-HeLa cells was detected not only in the endoplasmic reticulum and Golgi apparatus, but also in the plasma membrane. The enzyme was also active in lipid rafts, membrane microdomains in which GPI-anchored proteins and GPI anchor intermediates are concentrated, indicating that intracellular GPI-PLD cleavage may also occur in this compartment. Pulse-chase paradigms revealed the turnover rate of the last intermediate of the GPI anchor pathway in GPI-PLD-HeLa cells to be accelerated compared with the controls. Furthermore, 1,10-phenanthroline, a GPI-PLD inhibitor, reversed this effect. Our studies demonstrated that GPI-PLD can cleave not only GPI-anchored proteins, but also GPI anchor intermediates intracellularly. This observation opens the possibility that GPI-PLD can influence the steady-state levels of GPI-anchored proteins by hydrolysing the anchor before and after its attachment to proteins.


Age-related macular degeneration (AMD): Alzheimer's disease in the eye?
Age-related macular degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with Alzheimer's disease (AD), including stress stimuli such as oxidative stress and inflammation. In both diseases, the detrimental intra- and extracellular deposits have many similarities. Aging, hypercholesterolaemia, hypertension, obesity, arteriosclerosis, and smoking are risk factors to develop AMD and AD. Cellular aging processes have similar organelle and signaling association in the retina and brain tissues. However, it seems that these diseases have a different genetic background. In this review, differences and similarities of AMD and AD are thoroughly discussed.


Effect of intermittent weight bearing on soleus fiber force-velocity-power and force-pCa relationships.
Rat permeabilized type I soleus fibers displayed a 33% reduction in peak power output and a 36% increase in the free Ca2+ concentration required for one-half maximal activation after 14 days of hindlimb non-weight bearing (NWB). We examined the effectiveness of intermittent weight bearing (IWB; consisting of four 10-min periods of weight bearing/day) as a countermeasure to these functional changes. At peak power output, type I fibers from NWB animals produced 54% less force and shortened at a 56% greater velocity than did type I fibers from control weight-bearing animals while type I fibers from the IWB rats produced 26% more absolute force than did fibers from the NWB group and shortened at a velocity that was only 80% of the NWB group mean. As a result, no difference was observed in the average peak power of fibers from the IWB and NWB animals. Hill plot analysis of force-pCa relationships indicated that fibers from the IWB group required similar levels of free Ca2+ to reach half-maximal activation in comparison to fibers from the weight-bearing group. However, at forces < 50% of peak force, the force-pCa curve for fibers from the IWB animals clearly fell between the relationships observed for the other two groups. In summary, IWB treatments 1) attenuated the NWB-induced reduction in fiber Ca2+ sensitivity but 2) failed to prevent the decline in peak power that occurs during NWB because of opposing effects on fiber force (an increase vs. NWB) and shortening velocity (a decrease vs. NWB).


Decreased number of interneurons and increased seizures in neuropilin 2 deficient mice: implications for autism and epilepsy.
Clinically, perturbations in the semaphorin signaling system have been associated with autism and epilepsy. The semaphorins have been implicated in guidance, migration, differentiation, and synaptic plasticity of neurons. The semaphorin 3F (Sema3F) ligand and its receptor, neuropilin 2 (NPN2) are highly expressed within limbic areas. NPN2 signaling may intimately direct the apposition of presynaptic and postsynaptic locations, facilitating the development and maturity of hippocampal synaptic function. To further understand the role of NPN2 signaling in central nevous system (CNS) plasticity, structural and functional alterations were assessed in NPN2 deficient mice. In NPN2 deficient mice, we measured seizure susceptibility after kainic acid or pentylenetetrazol, neuronal excitability and synaptic throughput in slice preparations, principal and interneuron cell counts with immunocytochemical protocols, synaptosomal protein levels with immunoblots, and dendritic morphology with Golgi-staining. NPN2 deficient mice had shorter seizure latencies, increased vulnerability to seizure-related death, were more likely to develop spontaneous recurrent seizure activity after chemical challenge, and had an increased slope on input/output curves. Principal cell counts were unchanged, but GABA, parvalbumin, and neuropeptide Y interneuron cell counts were significantly reduced. Synaptosomal NPN2 protein levels and total number of GABAergic synapses were decreased in a gene dose-dependent fashion. CA1 pyramidal cells showed reduced dendritic length and complexity, as well as an increased number of dendritic spines. These data suggest the novel hypothesis that the Sema 3F signaling system's role in appropriate placement of subsets of hippocampal interneurons has critical downstream consequences for hippocampal function, resulting in a more seizure susceptible phenotype.


Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer.
Dysregulation of cell cycle control, in particular G(1)-S-phase transition, is implicated in the pathogenesis of most human cancers, including epithelial ovarian cancer (EOC). However, the prognostic significance of aberrant cell cycle gene expression in EOC remains unclear. The expression of selected genes from the pRb pathway that regulates G(1)-S-phase progression, including cyclin D1, p16(Ink4a), cyclin E, p27(Kip1), p21(Waf1/Cip1), and p53, was examined in a consecutive series of 134 serous EOC using immunohistochemistry and the results correlated to disease outcome. Molecular markers predictive of reduced overall survival in univariate analysis were overexpression of cyclin D1 (P = 0.03) and p53 (P = 0.03) and reduced expression of p27(Kip1) (P = 0.05) and p21(Waf1/Cip1) (P = 0.02), with the latter three also being prognostic for a shorter progression-free interval. In addition, patients displaying overexpression of p53 with concurrent loss of p21(Waf1/Cip1) had a significantly shorter overall (P = 0.0008) and progression-free survival (P = 0.0001). On multivariate analysis, overexpression of cyclin D1 and combined loss of p21(Waf1/Cip1) in the presence of p53 overexpression were independent predictors of overall survival. Similarly, the combination of p21(Waf1/Cip1) loss and p53 overexpression was independently predictive of a shorter progression-free interval. Overexpression of p53 and cyclin E and reduced expression of p27(Kip1) and p21(Waf1/Cip1) were significantly associated with increasing tumor grade. This study confirms that dysregulation of cell cycle genes is common in EOC, and that aberrant expression of critical cell cycle regulatory proteins can predict patient outcome in serous EOC.


Selective activation of the probasin androgen-responsive region by steroid hormones.
Glucocorticoid and androgen receptors have been shown to function through the same palindromic glucocorticoid response element (GRE) and yet have differential effects on gene transcription. In this study, we examined the functional and structural relationship of the androgen and glucocorticoid receptors with the androgen responsive region (ARR) of the probasin (PB) gene containing two androgen receptor binding sites, ARBS-1 and ARBS-2. Transfection studies indicated that one copy of each cis-acting DNA element was essential for maximal androgen-induced chloramphenicol acetyltransferase (CAT) activity and that androgen selectivity was maintained when multiple copies of the minimal wild type (wt) androgen responsive region containing both ARBS-1 and ARBS-2 (-244 to -96) were subcloned in front of the thymidine kinase promoter. Furthermore, replacing the androgen response region with 1, 2 or 3 copies of either ARBS-1 or ARBS-2 restored less than 4% of the biological activity seen with the wt PB ARR. Multiple copies of either ARBS-1 or ARBS-2 did not result in glucocorticoid-induced CAT gene activity. By comparison, 1 or 2 copies of the tyrosine aminotransferase (TAT) GRE, as well as the mouse mammary tumour virus GRE, were strong inducers of CAT activity in response to both androgen and glucocorticoid treatment. In addition, band shift assays demonstrated that although the synthetic glucocorticoid receptor, GR-DNA binding domain (GR-DBD), and the synthetic androgen receptor, AR2, could interact with the TAT GRE (dissociation constants Kd of 63.9 and 14.1 respectively), only AR2 but not GR-DBD binding could be detected on ARBS-1 and ARBS-2. Our findings provide further evidence that androgen-induced regulation of gene transcription can occur through androgen-specific DNA binding sites that are distinct from the common GRE.


Identification of glycoproteins in human cerebrospinal fluid with a complementary proteomic approach.
Biomarkers are pressingly needed to assist with the clinical diagnosis of neurodegenerative diseases and/or the monitoring of disease progression. Glycoproteins are enriched in bodily fluids such as human cerebrospinal fluid (CSF), an ideal source for discovering biomarkers due to its proximity to the central nervous system (CNS), and consequently can serve as diagnostic and/or therapeutic markers for CNS diseases. We report here an in-depth identification of glycoproteins in human CSF using a complementary proteomic approach which integrated hydrazide chemistry and lectin affinity column for glycoprotein enrichment, followed by multidimensional chromatography separation and tandem mass spectrometric analysis. Using stringent criteria, a total of 216 glycoproteins, including many low-abundance proteins, was identified with high confidence. Approximately one-third of these proteins was already known to be relevant to the CNS structurally or functionally. This investigation, for the first time, not only categorized many glycoproteins in human CSF but also expanded the existing overall CSF protein database.


Patterns of indocyanine green videoangiography of choroidal tumours.
Indocyanine green video-angiography is a recently popularised technique for imaging the retina and choroid. Little is known about the value of this technique in the evaluation of choroidal tumours. Indocyanine green video-angiograms of 51 patients with choroidal tumours, including 32 with choroidal melanoma, five with choroidal naevus, four with choroidal metastasis, four with choroidal haemangioma, one with choroidal osteoma, one with choroidal vortex vein varix, and four with irradiated choroidal melanoma were reviewed in a masked fashion. The choroidal melanoma group achieved maximal fluorescence at an average of 18.2 (range 0.4 to 60) minutes after injection. At maximum fluorescence, the pattern varied from hypofluorescent in 17 cases, to isofluorescent in eight cases, and hyperfluorescent in seven cases. Non-pigmented choroidal melanoma generally showed an earlier average onset of fluorescence than the pigmented choroidal melanoma (mean 28 versus 185 seconds, respectively) (p = 0.04). The two subgroups otherwise overlapped substantially in angiography characteristics. The choroidal metastasis group demonstrated maximal fluorescence at an average of 8.9 (range 1.7 to 13) minutes. All choroidal metastases had a homogeneous diffuse fluorescence with late isofluorescence. The choroidal metastases allowed a subtle blurred perception of the normal choroidal pattern through the tumour. The choroidal haemangioma group revealed very characteristic findings with an onset of filigree fluorescence at an average of 0.6 (range 0.4 to 0.7) minutes with little variation. The maximal fluorescence was typically hyperintense in all cases and was achieved at an average of 1.2 minutes and was reached by 1.8 minutes in all cases. In these cases the fluorescence appeared as a lacy diffuse 'fluorescent mulberry' pattern with visibility of the vascular channels and demonstrated 'washout' of the dye in the late frames. Indocyanine green may be a useful adjunct in the differentiation of amelanotic choroidal melanoma, choroidal metastasis, and choroidal haemangioma. The different patterns of fluorescence may be explained by the intrinsic choroidal vascular architecture in these three tumours.


Pan-Arctic soil moisture control on tundra carbon sequestration and plant productivity.
Long-term atmospheric CO2 concentration records have suggested a reduction in the positive effect of warming on high-latitude carbon uptake since the 1990s. A variety of mechanisms have been proposed to explain the reduced net carbon sink of northern ecosystems with increased air temperature, including water stress on vegetation and increased respiration over recent decades. However, the lack of consistent long-term carbon flux and in situ soil moisture data has severely limited our ability to identify the mechanisms responsible for the recent reduced carbon sink strength. In this study, we used a record of nearly 100 site-years of eddy covariance data from 11 continuous permafrost tundra sites distributed across the circumpolar Arctic to test the temperature (expressed as growing degree days, GDD) responses of gross primary production (GPP), net ecosystem exchange (NEE), and ecosystem respiration (ER) at different periods of the summer (early, peak, and late summer) including dominant tundra vegetation classes (graminoids and mosses, and shrubs). We further tested GPP, NEE, and ER relationships with soil moisture and vapor pressure deficit to identify potential moisture limitations on plant productivity and net carbon exchange. Our results show a decrease in GPP with rising GDD during the peak summer (July) for both vegetation classes, and a significant relationship between the peak summer GPP and soil moisture after statistically controlling for GDD in a partial correlation analysis. These results suggest that tundra ecosystems might not benefit from increased temperature as much as suggested by several terrestrial biosphere models, if decreased soil moisture limits the peak summer plant productivity, reducing the ability of these ecosystems to sequester carbon during the summer.


The 30-day versus in-hospital and 90-day mortality after esophagectomy as indicators for quality of care.
To describe causes of death in the first year after esophagectomy and determine the time frame that should be used for measurement of quality of surgery. A case-mix adjustment model was developed for the comparison between hospitals. The time period in which postoperative mortality should be measured as a performance indicator is debated. Cause of death was identified for patients in a tertiary referral hospital who died within 1 year after surgery and classified as surgery related or not surgery related. Sensitivity and specificity for detecting deaths related to surgery were calculated for different periods of follow-up. Case-mix adjustment models for 30-day mortality (30DM), in-hospital mortality, and 90-day mortality (90DM) were developed. In total, 1282 patients underwent esophagectomy. 30DM was 2.9%, the in-hospital mortality rate was 5.1% and 90DM was 7%. Beyond 30 days, a substantial number of deaths were related to the operation, especially due to anastomotic leakage. Postdischarge nononcological mortality was most frequently caused by sudden death. One in 5 patients died because of recurrent disease, being the most important threat in the first year after surgery. The 30DM had a sensitivity for detecting surgery-related deaths of 33% and a specificity of 100%. The 90DM had a sensitivity of 74% and a specificity of 96%. A period of postoperative follow-up longer than 30 days needs to be considered when comparing surgical performance between institutes. In the case-mix adjustment model for 90DM, no other variables have to be taken into account compared to those involved in 30DM.


Identification of lymphoma-associated antigens using SEREX.
Serological analysis of recombinant complementary deoxyribonucleic acid (cDNA) expression libraries (SEREX) is a powerful approach to identify immunogenic cancer-associated proteins using antibodies that are naturally present in the serum of cancer patients. This technique involves the screening of a relevant cDNA expression library with patient serum that has been cleaned to remove any antibodies that may recognize bacterial and/or viral proteins. Once antigens have been identified and their reactivity has been confirmed with a second round of screening, the gene encoding the protein can be sequenced and identified. Antigens can then be screened with a panel of allogenic sera from other patients and control individuals. This identifies disease-specific antigens, which may be useful diagnostic markers or, alternatively, targets for immunotherapy. This chapter describes the SEREX methodology in full.


Googling Stroke ASPECTS to Determine Disability: Exploratory Analysis from VISTA-Acute Collaboration.
The summed Alberta Stroke Program Early CT Score (ASPECTS) is useful for predicting stroke outcome. The anatomical information in the CT template is rarely used for this purpose because traditional regression methods are not adept at handling collinearity (relatedness) among brain regions. While penalized logistic regression (PLR) can handle collinearity, it does not provide an intuitive understanding of the interaction among network structures in a way that eigenvector method such as PageRank can (used in Google search engine). In this exploratory analysis we applied graph theoretical analysis to explore the relationship among ASPECTS regions with respect to disability outcome. The Virtual International Stroke Trials Archive (VISTA) was searched for patients who had infarct in at least one ASPECTS region (ASPECTS ≤ 9, ASPECTS = 10 were excluded), and disability (modified Rankin score/mRS). A directed graph was created from a cross correlation matrix (thresholded at false discovery rate of 0.01) of the ASPECTS regions and demographic variables and disability (mRS > 2). We estimated the network-based importance of each ASPECTS region by comparing PageRank and node strength measures. These results were compared with those from PLR. There were 185 subjects, average age 67.5 ± 12.8 years (55% Males). Model 1: demographic variables having no direct connection with disability, the highest PageRank was M2 (0.225, bootstrap 95% CI 0.215-0.347). Model 2: demographic variables having direct connection with disability, the highest PageRank were M2 (0.205, bootstrap 95% CI 0.194-0.367) and M5 (0.125, bootstrap 95% CI 0.096-0.204). Both models illustrate the importance of M2 region to disability. The PageRank method reveals complex interaction among ASPECTS regions with respects to disability. This approach may help to understand the infarcted brain network involved in stroke disability.


Defining the genomic signature of the parous breast.
It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy. In order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry. We identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis. This study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process.


Estimation of emission properties for silica particles using thermal radiation spectroscopy.
This paper shows that spectrally resolved thermal radiation from silica aggregate particles can be used to extract an emissivity and a temperature in the visible regime. Emissivity of silica aggregate particles at temperatures above 2000 K is measured by the analysis of emission radiation spectra from the particles. Temperature is estimated from the relation between the emission intensity and the wavenumber. Relative emissivities at temperatures from 2150 to 2919 K are presented. Proper knowledge of optical properties for silica aggregate particles will help further the understanding of thermophysics at high temperature.


Treatment of Hereditary Angioedema Attacks with Icatibant and Recombinant C1 Inhibitor During Pregnancy.
Hereditary angioedema (HAE) is a rare disease caused by a C1 inhibitor (C1-INH) deficit. Clinically, HAE is manifested by repeated episodes of localized subcutaneous or submucosal oedema attacks. Managing HAE patients in pregnancy is challenging, since there are only limited data on the safety and efficacy of various therapeutic approaches. We present our clinical experience treating acute HAE attacks during pregnancy in six consecutive patients. During the pregnancies, 79 HAE attacks occurred. The most frequent were abdominal 53 (67.1%) followed by peripheral 21 (26.6%), facial 10 (12.7%), and laryngeal 10 (12.7%) oedemas; 13 (16.5%) attacks were combined. Fifty (63.3%) attacks were treated with recombinant human C1-INH (rhC1-INH); 17 (21.5%) with plasma-derived, pasteurized, nanofiltered C1-INH (pnfC1-INH); 13 (16.5%) with icatibant; and 1 (1.3%) with plasma-derived, nanofiltered C1-INH (nfC1-INH). Treatment had to be repeated in 5 attacks (6.3%). All six deliveries (one caesarean section and five spontaneous vaginal deliveries) were complication free. All pregnancies went to the full term and the patients delivered healthy babies with a birth weight ranging from 2850 to 3690 g. No congenital abnormalities were detected in the neonates. No abortions occurred. Our results show good C1-INH or icatibant treatment efficacy for HAE attacks in pregnancy. The treatment by the first drug used was effective in 93.7% of all attacks. In 6.3% of attacks, a second treatment had to be used. No adverse effects were observed.


The Triform algorithm: improved sensitivity and specificity in ChIP-Seq peak finding.
Chromatin immunoprecipitation combined with high-throughput sequencing (ChIP-Seq) is the most frequently used method to identify the binding sites of transcription factors. Active binding sites can be seen as peaks in enrichment profiles when the sequencing reads are mapped to a reference genome. However, the profiles are normally noisy, making it challenging to identify all significantly enriched regions in a reliable way and with an acceptable false discovery rate. We present the Triform algorithm, an improved approach to automatic peak finding in ChIP-Seq enrichment profiles for transcription factors. The method uses model-free statistics to identify peak-like distributions of sequencing reads, taking advantage of improved peak definition in combination with known characteristics of ChIP-Seq data. Triform outperforms several existing methods in the identification of representative peak profiles in curated benchmark data sets. We also show that Triform in many cases is able to identify peaks that are more consistent with biological function, compared with other methods. Finally, we show that Triform can be used to generate novel information on transcription factor binding in repeat regions, which represents a particular challenge in many ChIP-Seq experiments. The Triform algorithm has been implemented in R, and is available via http://tare.medisin.ntnu.no/triform.


Risk and treatment effect heterogeneity: re-analysis of individual participant data from 32 large clinical trials.
Risk of the outcome is a mathematical determinant of the absolute treatment benefit of an intervention, yet this can vary substantially within a trial population, complicating the interpretation of trial results. We developed risk models using Cox or logistic regression on a set of large publicly available randomized controlled trials (RCTs). We evaluated risk heterogeneity using the extreme quartile risk ratio (EQRR, the ratio of outcome rates in the lowest risk quartile to that in the highest) and skewness using the median to mean risk ratio (MMRR, the ratio of risk in the median risk patient to the average). We also examined heterogeneity of treatment effects (HTE) across risk strata. We describe 39 analyses using data from 32 large trials, with event rates across studies ranging from 3% to 63% (median = 15%, 25th-75th percentile = 9-29%). C-statistics of risk models ranged from 0.59 to 0.89 (median = 0.70, 25th-75th percentile = 0.65-0.71). The EQRR ranged from 1.8 to 50.7 (median = 4.3, 25th-75th percentile = 3.0-6.1). The MMRR ranged from 0.4 to 1.0 (median = 0.86, 25th-75th percentile = 0.80-0.92). EQRRs were predictably higher and MMRRs predictably lower as the c-statistic increased or the overall outcome incidence decreased. Among 18 comparisons with a significant overall treatment effect, there was a significant interaction between treatment and baseline risk on the proportional scale in only one. The difference in the absolute risk reduction between extreme risk quartiles ranged from -3.2 to 28.3% (median = 5.1%; 25th-75th percentile = 0.3-10.9). There is typically substantial variation in outcome risk in clinical trials, commonly leading to clinically significant differences in absolute treatment effects Most patients have outcome risks lower than the trial average reflected in the summary result. Risk-stratified trial analyses are feasible and may be clinically informative, particularly when the outcome is predictable and uncommon.


NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer. Results of a phase II trial.
NSC-631570 (Ukrain) is a semisynthetic compound of thiophosphoric acid and the alkaloid chelidonine from the plant Chelidonium majus. It has been used in complementary herbal medicine for more than 20 years for the treatment of benign and malignant tumors. Between August 1999 and June 2001, 90 patients with histologically proven unresectable pancreatic cancer were randomized in a monocentric, controlled, randomized study. Patients in arm A received 1000 mg gemcitabine/m2, those in arm B received 20 mg NSC-631570, and those in arm C received 1000 mg gemcitabine/m2 followed by 20 mg NSC-631570 weekly. End point of the study was overall survival. In all three arms therapy was well tolerated and toxicity was moderate. At the first re-evaluation in arm A 32%, in arm B 75%, and in arm C 82% showed no change or partial remission according to WHO criteria (arm A versus arm B: P<0.01, arm A versus arm C: P<0.001). Median survival according to Kaplan-Meier analysis was in arm A 5.2 months, in arm B 7.9 months, and in arm C 10.4 months (arm A versus arm B: P<0.01, arm A versus arm C: P<0.01). Actuarial survival rates after 6 months were 26%, 65% and 74% in arms A B and C, respectively (arm A versus arm B: P<0.05, arm A versus arm C P<0.01). We could show that in unresectable advanced pancreatic cancer, NSC-631570 alone and in combination with gemcitabine nearly doubled the median survival times in patients suffering from advanced pancreatic cancer.


Transplantation of autologous Schwann cells for the repair of segmental peripheral nerve defects.
Peripheral nerve injuries are a source of chronic disability. Incomplete recovery from such injuries results in motor and sensory dysfunction and the potential for the development of chronic pain. The repair of human peripheral nerve injuries with traditional surgical techniques has limited success, particularly when a damaged nerve segment needs to be replaced. An injury to a long segment of peripheral nerve is often repaired using autologous grafting of "noncritical" sensory nerve. Although extensive axonal regeneration can be observed extending into these grafts, recovery of function may be absent or incomplete if the axons fail to reach their intended target. The goal of this review was to summarize the progress that has occurred in developing an artificial neural prosthesis consisting of autologous Schwann cells (SCs), and to detail future directions required in translating this promising therapy to the clinic. In the authors' laboratory, methods are being explored to combine autologous SCs isolated using cell culture techniques with axon guidance channel (AGC) technology to develop the potential to repair critical gap length lesions within the peripheral nervous system. To test the clinical efficacy of such constructs, it is critically important to characterize the fate of the transplanted SCs with regard to cell survival, migration, differentiation, and myelin production. The authors sought to determine whether the use of SC-filled channels is superior or equivalent to strategies that are currently used clinically (for example, autologous nerve grafts). Finally, although many nerve repair paradigms demonstrate evidence of regeneration within the AGC, the authors further sought to determine if the regeneration observed was physiologically relevant by including electrophysiological, behavioral, and pain assessments. If successful, the development of this reparative approach will bring together techniques that are readily available for clinical use and should rapidly accelerate the process of bringing an effective nerve repair strategy to patients with peripheral nerve injury prior to the development of pain and chronic disability.


Cocaine by-product detection with metal oxide semiconductor sensor arrays.
A range of n-type and p-type metal oxide semiconductor gas sensors based on SnO2 and Cr2O3 materials have been modified with zeolites H-ZSM-5, Na-A and H-Y to create a gas sensor array able to successfully detect a cocaine by-product, methyl benzoate, which is commonly targeted by detection dogs. Exposure to vapours was carried out with eleven sensors. Upon data analysis, four of these that offered promising qualities for detection were subsequently selected to understand whether machine learning methods would enable successful and accurate classification of gases. The capability of discrimination of the four sensor array was assessed against nine different vapours of interest; methyl benzoate, ethane, ethanol, nitrogen dioxide, ammonia, acetone, propane, butane, and toluene. When using the polykernel function (C = 200) in the Weka software - and just five seconds into the gas injection - the model was 94.1% accurate in successfully classifying the data. Although further work is necessary to bring the sensors to a standard of detection that is competitive with that of dogs, these results are very encouraging because they show the potential of metal oxide semiconductor sensors to rapidly detect a cocaine by-product in an inexpensive way.


A laser-induced mouse model with long-term intraocular pressure elevation.
To develop and characterize a mouse model with intraocular pressure (IOP) elevation after laser photocoagulation on the trabecular meshwork (TM), which may serve as a model to investigate the potential of stem cell-based therapies for glaucoma. IOP was measured in 281 adult C57BL/6 mice to determine normal IOP range. IOP elevation was induced unilaterally in 50 adult mice, by targeting the TM through the limbus with a 532-nm diode laser. IOP was measured up to 24 weeks post-treatment. The optic nerve damage was detected by electroretinography and assessed by semiautomatic counting of optic nerve axons. Effects of laser treatment on the TM were evaluated by histology, immunofluorescence staining, optical coherence tomography (OCT) and transmission electron microscopy (TEM). The average IOP of C57BL/6 mice was 14.5 ± 2.6 mmHg (Mean ± SD). After laser treatment, IOP averaged above 20 mmHg throughout the follow-up period of 24 weeks. At 24 weeks, 57% of treated eyes had elevated IOP with the mean IOP of 22.5 ± 2.5 mmHg (Mean ± SED). The difference of average axon count (59.0%) between laser treated and untreated eyes was statistically significant. Photopic negative response (PhNR) by electroretinography was significantly decreased. CD45+ inflammatory cells invaded the TM within 1 week. The expression of SPARC was increased in the TM from 1 to 12 weeks. Histology showed the anterior chamber angle open after laser treatment. OCT indicated that most of the eyes with laser treatment had no synechia in the anterior chamber angles. TEM demonstrated disorganized and compacted extracellular matrix in the TM. An experimental murine ocular hypertension model with an open angle and optic nerve axon loss was produced with laser photocoagulation, which could be used to investigate stem cell-based therapies for restoration of the outflow pathway integrity for ocular hypertension or glaucoma.


Western blot analysis of sera from dogs with suspected food allergy.
Food allergy is often suspected in dogs with clinical signs of atopic dermatitis. This diagnosis is confirmed with an elimination diet and a subsequent challenge with regular food. Laboratory tests for the diagnosis of food allergy in dogs are unreliable and/or technically difficult. Cyno-DIAL® is a Western blot method that might assist with the selection of an appropriate elimination diet. To evaluate the performance of Cyno-DIAL® for the selection of an elimination diet and diagnosis of food allergy. Thirty eight dogs with atopic dermatitis completed an elimination diet. Combining the results of the diet trials and the challenges, 14 dogs were classified as food allergic (FA), 22 as nonfood-allergic and two as ambiguous cases. Amongst all dogs and amongst dogs with a clinical diagnosis of FA, 3% and 7% (respectively) were positive to Royal Canin Anallergenic® , Vet-Concept Kanguru® or Vet-Concept Dog Sana® ; 8% and 7% to Hill's d/d Duck and Rice® ; 8% and 21% to Hill's z/d Ultra Allergen Free® ; 53% and 64% to Eukanuba Dermatosis FP® ; and 32% and 43% to a home-cooked diet of horse meat, potatoes and zucchini. The specificity and sensitivity of Cyno-DIAL® for diagnosing food allergy were 73% and 71%, respectively. Although Cyno-DIAL® was considered potentially useful for identifying appropriate foods for elimination diet trials, it cannot be recommended for the diagnosis of food allergy. The Cyno-DIAL® test performed better than some previously evaluated ELISA-based tests.


Measurement of the specific airway resistance by plethysmography in young children accompanied by an adult.
The purpose of this study was to evaluate a procedure for measurement of specific airway resistance (sRaw) by whole body plethysmography in young awake children accompanied by an adult. sRaw was measured by a single-step procedure, omitting the measurement of the thoracic gas volume. The frequency dependency of sRaw was investigated and the accuracy of simulating body temperature, atmospheric pressure and saturation with water vapour (BTPS) conditions by electronic compensation was assessed. One hundred and thirty one children with asthma were studied. In 57 children (mean (SD) age 5.6 (1.8) yrs) who performed measurements with and without an accompanying adult, the mean value of sRaw was 1.45 (0.36) and 1.44 (0.38) kPa x s, respectively, with a mean difference of 0.008 (0.152) kPa x s, and mean within-subject coefficients of variations (CV) of 8% and 10%, respectively. In 52 children (mean age 3.3 (0.8) yrs), for whom measurements made only in the presence of an accompanying adult, the CV was 8.5%. No measurements could be obtained in 22 children (17%) (mean age 2.8 (0.5) yrs). Measurements exhibited a significant frequency dependency, and electronic BTPS compensation substantially overestimated SRaw. In conclusion, the use of electronic compensation for simulating body temperature, atmospheric pressure and saturation with water vapour introduces a bias that affects the accuracy of the estimate of specific airway resistance. Nevertheless, plethysmographic measurements with and without an accompanying adult yielded comparable and equally repeatable estimates of specific airway resistance. The single-step plethysmographic procedure with an accompanying adult is a clinically useful method for evaluating airway function in children too young to perform plethysmographic measurements alone.


Disruption of Protein Complexes from Weighted Complex Networks.
Essential proteins are indispensable units for living organisms. Removing those leads to disruption of protein complexes and causing lethality. Recently, theoretical methods have been presented to detect essential proteins in protein interaction network. In these methods, an essential protein is predicted as a high-degree vertex of protein interaction network. However, interaction data are usually incomplete and an essential protein cannot have high-connection due to data deficiency. Then, it is critical to design informative networks from other biological data sources. In this paper, we defined a minimal set of proteins to disrupt the maximum number of protein complexes. We constructed a weighted graph using a set of given complexes. We proposed a more appropriate method based on betweenness values to diagnose a minimal set of proteins whose removal would generate the disruption of protein complexes. The effectiveness of the proposed method was benchmarked using given dataset of complexes. The results of our method were compared to the results of other methods in terms of the number of disrupted complexes. Also, results indicated significant superiority of the minimal set of proteins in the massive disruption of complexes. Finally, we investigated the performance of our method for yeast and human datasets and analyzed biological properties of the selected proteins. Our algorithm and some example are freely available from http://bs.ipm.ac.ir/softwares/DPC/DPC.zip.


Evidence for Vpr-dependent HIV-1 replication in human CD4+ CEM.NKR T-cells.
Vpr is exclusively expressed in primate lentiviruses and contributes to viral replication and disease progression in vivo. HIV-1 Vpr has two major activities in vitro: arrest of cell cycle in the G2 phase (G2 arrest), and enhancement of viral replication in macrophages. Previously, we reported a potent HIV-1 restriction in the human CD4+ CEM.NKR (NKR) T cells, where wild-type (WT) HIV-1 replication was inhibited by almost 1,000-fold. From the parental NKR cells, we isolated eight clones by limiting dilution. These clones showed three levels of resistance to the WT HIV-1 infection: non-permissive (NP), semi-permissive (SP), and permissive (P). Here, we compared the replication of WT, Vif-defective, Vpr-defective, and Vpu-defective viruses in these cells. Although both WT and Vpu-defective viruses could replicate in the permissive and semi-permissive clones, the replication of Vif-defective and Vpr-defective viruses was completely restricted. The expression of APOBEC3G (A3G) cytidine deaminase in NKR cells explains why Vif, but not Vpr, was required for HIV-1 replication. When the Vpr-defective virus life cycle was compared with the WT virus life cycle in the semi-permissive cells, it was found that the Vpr-defective virus could enter the cell and produce virions containing properly processed Gag and Env proteins, but these virions showed much less efficiency for reverse transcription during the next-round of infection. In addition, although viral replication was restricted in the non-permissive cells, treatment with arsenic trioxide (As2O3) could completely restore WT, but not Vpr-defective virus replication. Moreover, disruption of Vpr binding to its cofactor DCAF1 and/or induction of G2 arrest activity did not disrupt the Vpr activity in enhancing HIV-1 replication in NKR cells. These results demonstrate that HIV-1 replication in NKR cells is Vpr-dependent. Vpr promotes HIV-1 replication from the 2nd cycle likely by overcoming a block at early stage of viral replication; and this activity does not require DCAF1 and G2 arrest. Further studies of this mechanism should provide new understanding of Vpr function in the HIV-1 life cycle.


Neuronal activation for semantically reversible sentences.
Semantically reversible sentences are prone to misinterpretation and take longer for typically developing children and adults to comprehend; they are also particularly problematic for those with language difficulties such as aphasia or Specific Language Impairment. In our study, we used fMRI to compare the processing of semantically reversible and nonreversible sentences in 41 healthy participants to identify how semantic reversibility influences neuronal activation. By including several linguistic and nonlinguistic conditions within our paradigm, we were also able to test whether the processing of semantically reversible sentences places additional load on sentence-specific processing, such as syntactic processing and syntactic-semantic integration, or on phonological working memory. Our results identified increased activation for reversible sentences in a region on the left temporal-parietal boundary, which was also activated when the same group of participants carried out an articulation task which involved saying "one, three" repeatedly. We conclude that the processing of semantically reversible sentences places additional demands on the subarticulation component of phonological working memory.


Hepatitis C Nosode: The preparation and homeopathic pathogenetic trial.
A double blind, randomized placebo controlled homeopathic pathogenetic trial (proving) of Hepatitis C (Hep C) nosode was conducted with the aim to introduce the new nosode in homeopathic pharmacopeia. Documentation included approval by Ethics Committee, Informed Consent Form, Laboratory investigations, safety and ethical measures. The volunteers were trained to write data in prescribed diaries and data were analyzed. A fifteen-step method was used in the preparation of Hep C nosode (genotype I and III), allowing future preparation of an identical nosode. 22 volunteers were entered, 15 received Hep C nosode in 30c potency, 7 received placebo, once a week for four weeks. The Hep C nosode was associated with qualitatively and quantitatively distinct symptoms, which can be applied in clinical practice. A significantly higher incidence of pathogenetic effect of homeopathic medicine compared to placebo was observed. Safety was documented. The nosode produced symptoms comparable with Hep C disease. An improved method of nosode preparation was used. A double blind, randomized placebo controlled pathogenetic trial of the Hep C nosode generated guiding symptoms, which may facilitate its prescription in practice. The nosode should be further explored for the treatment of immunologically mediated diseases, infections including Hep C, fibrotic pathology and chronic inflammatory disorders.


Elucidation of ethanol tolerance mechanisms in Saccharomyces cerevisiae by global metabolite profiling.
Ethanol, the major fermentation product of yeast, is a stress factor in yeast. We previously constructed an ethanol-tolerant mutant yeast iETS3 by using the global transcriptional machinery engineering. However, the ethanol-tolerance mechanism has not been systematically investigated. In this study, global metabolite profiling was carried out, mainly by gas chromatography/time-of-flight mass spectrometry (GC/TOF MS), to investigate the mechanisms of ethanol tolerance in iETS3. A total of 108 intracellular metabolites were identified by GC/TOF MS and high performance liquid chromatography, and these metabolites were mostly intermediates of the central carbon metabolism. The metabolite profiles of iETS3 and BY4741, cultured with or without ethanol, were significantly different based on principal component and hierarchical clustering analyses. Our metabolomic analyses identified the compositional changes in cell membranes and the activation of glutamate metabolism and the trehalose synthetic pathway as the possible mechanisms for the ethanol tolerance. These metabolic traits can be considered possible targets for further improvement of ethanol tolerance in the mutant. For example, the KGD1 deletion mutant, with up-regulated glutamate metabolism, showed increased tolerance to ethanol. This study has demonstrated that metabolomics can be a useful tool for strain improvement and phenotypic analysis of microorganisms under stress.


Getting better all the time? Facilitating accurate team self-assessments through simulation.
Our study explores the extent to which teams are accurate assessors of their own performance and teamwork, and how simulation can help this critical skill develop over time. Surgery residents in teams of three completed five daily simulations. After each scenario, each team reviewed their performance and jointly completed a scenario-specific team performance evaluation and a 17-item Communication and Teamwork Skills tool. Videos were rated to obtain discrepancy values. Paired-samples t-tests and mean comparisons were used to examine changes in team self-assessment accuracy and comparisons between high-performing and low-performing teams. Resident (n=30) teams rated team performance higher than faculty across the first 3 days (p<0.01), but provided similar ratings thereafter. Agreement of team performance from day 1 to 5 significantly improved (p<0.001). Teams rated their teamwork higher than faculty across all days (p<0.01). Top performing teams provided more accurate self-assessments for both teamwork (average discrepancy 8% vs 39%) and team performance (average discrepancy 12% vs 23%). Teams that continue to work together over time may become more accurate judges of their own performance, but do not become more accurate assessors of teamwork competencies.


Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity.
Treatment of rats with recombinant human TNF initially causes a marked decrease in food intake, a loss of body weight, and a negative nitrogen balance. These alterations normalize with continued twice daily intraperitoneal injections of the same dose. Rats tolerized to TNF in this manner are refractory to a lethal dose of TNF. Also, TNF-pretreated and -tolerized rats have prolonged survival and reversed histopathologic changes after injection of a lethal dose of endotoxin compared with control animals. The TNF-tolerant state is dependent on the dose of TNF used and the length of TNF pretreatment. TNF-induced tolerance is relatively short lived, being present 2-4 d after TNF pretreatment and dissipating by 2 wk. Rats made tolerant to endotoxin are also tolerant to a lethal dose of TNF. A bidirectional crossreacting tolerance exists between TNF and endotoxin. The mechanism of TNF tolerance is unclear, but it does not appear to be due to a humoral immune response or a perturbation of the uptake and clearance of injected TNF.


Trichotillomania: a perspective synthesised from neuroscience and lived experience.
Trichotillomania, or hair-pulling disorder, is one of a family of disorders called body-focused repetitive behaviours (BFRBs), which also include disordered skin-picking (dermotillomania) and nail-biting (onychophagia). The disorders affect 1%-2% of the population, cause high levels of distress and have high levels of comorbidity with other psychiatric diagnoses. The key facts and figures are briefly reviewed and some important points are further explored: (1) BFRBs are associated with psychological distress, but are distinct from other diagnoses, (2) The pathological behaviours mirror excessive self-grooming behaviours in other species, and may relate to immune-system mediated feedback loops, and (3) The resulting behaviours are stigmatised and cause intense shame and isolation for those who suffer, which might in itself maintain the feedback loop. These observations lead to the hypothesis that the core disorder is one of pathological grooming, which may have a basis in an immune response, with shame being both a consequence and a maintainer of the disorder. The major barrier to testing the hypotheses and potential interventions remains the stigma that keeps these disorders, and those who suffer from them, in the shadows.


Acute Sport Concussion Assessment Optimization: A Prospective Assessment from the CARE Consortium.
Numerous medical organizations recommend a multifaceted approach to the assessment of concussion occurring during sporting events. A number of tools are available to clinicians, with a wide breadth of sensitivity and specificity; however, little work has been done to evaluate the combined efficiency of these tools in concussed male and female athletes from a broad array of collegiate sports and with variable time from the pre-season baseline evaluation. The aim of this study was to optimize the concussion assessment battery for application within the first 72 h of injury, and to identify the necessary baseline retesting frequency. Between 2014 and 2017, a total of 1458 National Collegiate Athletic Association (NCAA) athletes sustaining 1640 diagnosed concussions completed a baseline assessment each year of the investigation and were evaluated up to three times within the first 72 h of injury using a standardized assessment protocol. Classification and regression tree analyses were implemented to identify the most efficient multifaceted assessment pathway to quantify concussion-related outcomes. Results were optimized for assessments occurring within 1 h post-injury, 1-24 h post-injury, and 24-72 h post-injury when using the raw post-injury assessment performance, difference scores from baseline evaluations occurring in the same year, and difference scores from baseline evaluations occurring the year prior. At each of the assessment time points, the analyses indicated that alone or in combination, a symptom evaluation, Balance Error Scoring System (BESS) scores collected on the firm surface, and Standardized Assessment of Concussion (SAC) total score offered the best overall performance when compared with pre-morbid performance captured in the same season. Optimized sensitivity of the multifaceted approach was 61% within 1 h of injury, 67% at the 1-24 h interval, and 55% at the 24-72 h interval when difference scores from the same-season baseline were available. This investigation identified key concussion assessments in quantifying post-concussion performance among student athletes, that were maximized when same-season pre-morbid evaluations were available. Consistent with clinical recommendations, medical professionals should continue to focus on symptom reporting, postural control, and neurocognitive screening to support the clinical examination when making a concussion diagnosis.


The Mayo Dysphagia Questionnaire-30: documentation of reliability and validity of a tool for interventional trials in adults with esophageal disease.
The aim of this study was to develop the Mayo Dysphagia Questionnaire-30 Day (MDQ-30), a tool to measure esophageal dysphagia, by adapting items from validated instruments for use in clinical trials, and assess its feasibility, reproducibility, and concurrent validity. Outpatients referred to endoscopy for dysphagia or seen in a specialty clinic were recruited. Feasibility testing was done to identify problematic items. Reproducibility was measured by test-retest format. Concurrent validity reflects agreement between information gathered in a structured interview versus the patients' written responses. The MDQ-30, a 28-item instrument, took 10 min (range = 5-30 min) to complete. Four hundred thirty-one outpatients [210 (49%) men; mean age = 61 years] participated. Overall, most concurrent validity kappa values for dysphagia were very good to excellent with a median of 0.78 (min 0.28, max 0.95). The majority of reproducibility kappa values for dysphagia were moderate to excellent with a median kappa value of 0.66 (min 0.07, max 1.0). Overall, concurrent validity and reproducibility kappa values for gastroesophageal reflux disease (GERD) symptoms were 0.81 (95% CI = 0.72, 0.91) and 0.66 (95% CI = 0.55, 0.77), respectively. Individual item percent agreement was generally very good to excellent. Internal consistency was excellent. We conclude that the MDQ-30 is an easy-to-complete tool to evaluate reliably dysphagia symptoms over the last 30 days.


Evidence-based criteria in the nutritional context.
During the last decade, approaches to evidence-based medicine, with its heavy reliance on the randomized clinical trial (RCT), have been adapted to nutrition science and policy. However, there are distinct differences between the evidence that can be obtained for the testing of drugs using RCTs and those needed for the development of nutrient requirements or dietary guidelines. Although RCTs present one approach toward understanding the efficacy of nutrient interventions, the innate complexities of nutrient actions and interactions cannot always be adequately addressed through any single research design. Because of the limitations inherent in RCTs, particularly of nutrients, it is suggested that nutrient policy decisions will have to be made using the totality of the available evidence. This may mean action at a level of certainty that is different from what would be needed in the evaluation of drug efficacy. Similarly, it is judged that the level of confidence needed in defining nutrient requirements or dietary recommendations to prevent disease can be different from that needed to make recommendations to treat disease. In brief, advancing evidence-based nutrition will depend upon research approaches that include RCTs but go beyond them. Also necessary to this advance is the assessing, in future human studies, of covariates such as biomarkers of exposure and response, and the archiving of samples for future evaluation by emerging technologies.