Metabotropic glutamate receptor subtype 1 regulates sodium currents in rat neocortical pyramidal neurons.
Brain sodium channels (NaChs) are regulated by various neurotransmitters such as acetylcholine, serotonin and dopamine. However, it is not known whether NaCh activity is regulated by glutamate, the principal brain neurotransmitter. We show here that activation of metabotropic glutamate receptor (mGluR) subtype 1 regulates fast transient (I(NaT)) and persistent Na(+) currents (I(NaP)) in cortical pyramidal neurons. A selective agonist of group I mGluR, (S)-3,5-dihydroxyphenylglycine (DHPG), reduced action potential amplitude and decreased I(NaT). This reduction was blocked when DHPG was applied in the presence of selective mGluR1 antagonists. The DHPG-induced reduction of the current was accompanied by a shift of both the inactivation curve of I(NaT) and the activation curve of I(NaP). These effects were dependent on the activation of PKC. The respective role of these two regulatory processes on neuronal excitability was determined by simulating transient and persistent Na(+) conductances (G(NaT) and G(NaP)) with fast dynamic-clamp techniques. The facilitated activation of G(NaP) increased excitability near the threshold, but, when combined with the down-regulation of G(NaT), repetitive firing was strongly decreased. Consistent with this finding, the mGluR1 antagonist LY367385 increased neuronal excitability when glutamatergic synaptic activity was stimulated with high external K(+). We conclude that mGluR1-dependent regulation of Na(+) current depresses neuronal excitability, which thus might constitute a novel mechanism of homeostatic regulation acting during intense glutamatergic synaptic activity.


Following Uninsured Patients Through Medicaid Expansion: Ambulatory Care Use and Diagnosed Conditions.
The Patient Protection and Affordable Care Act (ACA) has improved access to health insurance, yet millions remain uninsured. Many patients who remain uninsured access care at community health centers (CHCs); however, little is known about their health conditions and health care use. We assessed ambulatory care use and diagnosed health conditions among a cohort of CHC patients uninsured before enactment of the ACA (pre-ACA: January 1, 2012 to December 31, 2013) and followed them after enactment (post-ACA: January 1, 2014 to December 31, 2015). This retrospective cohort analysis used electronic health record data from CHCs in 11 US states that expanded Medicaid eligibility. We assessed ambulatory care visits and documented health conditions among a cohort of 138,246 patients (aged 19 to 64 years) who were uninsured pre-ACA and either remained uninsured, gained Medicaid, gained other health insurance, or did not have a visit post-ACA. We estimated adjusted predicted probabilities of ambulatory care use using an ordinal logistic mixed-effects regression model. Post-ACA, 20.9% of patients remained uninsured, 15.0% gained Medicaid, 12.4% gained other insurance, and 51.7% did not have a visit. The majority of patients had ≥1 diagnosed health condition. The adjusted proportion of patients with high use (≥6 visits over 2 years) increased from pre-ACA to post-ACA among those who gained Medicaid (pre-ACA: 23%, post-ACA: 34%, P <.001) or gained other insurance (pre-ACA: 29%, post-ACA: 48%, P <.001), whereas the percentage fell slightly for those continuously uninsured. A significant percentage of CHC patients remained uninsured; many who remained uninsured had diagnosed health conditions, and one-half continued to have ≥3 visits to CHCs. CHCs continue to be essential providers for uninsured patients.


Determinants of Participants' Follow-Up and Characterization of Representativeness in Flu Near You, A Participatory Disease Surveillance System.
Flu Near You (FNY) is an Internet-based participatory surveillance system in the United States and Canada that allows volunteers to report influenza-like symptoms using a brief weekly symptom report. Our objective was to evaluate the representativeness of the FNY population compared with the general population of the United States, explore the demographic and behavioral characteristics associated with FNY's high-participation users, and summarize results from a user survey of a cohort of FNY participants. We compared (1) the representativeness of sex and age groups of FNY participants during the 2014-2015 flu season versus the general US population and (2) the distribution of Human Development Index (HDI) scores of FNY participants versus that of the general US population. We analyzed associations between demographic and behavioral factors and the level of participant follow-up (ie, high vs low). Finally, descriptive statistics of responses from FNY's 2015 and 2016 end-of-season user surveys were calculated. During the 2014-2015 influenza season, 47,234 unique participants had at least one FNY symptom report that was either self-reported (users) or submitted on their behalf (household members). The proportion of female FNY participants was significantly higher than that of the general US population (n=28,906, 61.2% vs 51.1%, P<.001). Although each age group was represented in the FNY population, the age distribution was significantly different from that of the US population (P<.001). Compared with the US population, FNY had a greater proportion of individuals with HDI >5.0, signaling that the FNY user distribution was more affluent and educated than the US population baseline. We found that high-participation use (ie, higher participation in follow-up symptom reports) was associated with sex (females were 25% less likely than men to be high-participation users), higher HDI, not reporting an influenza-like illness at the first symptom report, older age, and reporting for household members (all differences between high- and low-participation users P<.001). Approximately 10% of FNY users completed an additional survey at the end of the flu season that assessed detailed user characteristics (3217/33,324 in 2015; 4850/44,313 in 2016). Of these users, most identified as being either retired or employed in the health, education, and social services sectors and indicated that they achieved a bachelor's degree or higher. The representativeness of the FNY population and characteristics of its high-participation users are consistent with what has been observed in other Internet-based influenza surveillance systems. With targeted recruitment of underrepresented populations, FNY may improve as a complementary system to timely tracking of flu activity, especially in populations that do not seek medical attention and in areas with poor official surveillance data.


Disturbed EEG sleep, paranoid cognition and somatic symptoms identify veterans with post-traumatic stress disorder.
Chronic post-traumatic stress disorder (PTSD) behavioural symptoms and medically unexplainable somatic symptoms are reported to occur following the stressful experience of military combatants in war zones. To determine the contribution of disordered EEG sleep physiology in those military combatants who have unexplainable physical symptoms and PTSD behavioural difficulties following war-zone exposure. This case-controlled study compared 59 veterans with chronic sleep disturbance with 39 veterans with DSM-IV and clinician-administered PTSD Scale diagnosed PTSD who were unresponsive to pharmacological and psychological treatments. All had standardised EEG polysomnography, computerised sleep EEG cyclical alternating pattern (CAP) as a measure of sleep stability, self-ratings of combat exposure, paranoid cognition and hostility subscales of Symptom Checklist-90, Beck Depression Inventory and the Wahler Physical Symptom Inventory. Statistical group comparisons employed linear models, logistic regression and chi-square automatic interaction detection (CHAID)-like decision trees. Veterans with PTSD were more likely than those without PTSD to show disturbances in non-rapid eye movement (REM) and REM sleep including delayed sleep onset, less efficient EEG sleep, less stage 4 (deep) non-REM sleep, reduced REM and delayed onset to REM. There were no group differences in the prevalence of obstructive sleep apnoeas/hypopnoeas and periodic leg movements, but sleep-disturbed, non-PTSD military had more EEG CAP sleep instability. Rank order determinants for the diagnosis of PTSD comprise paranoid thinking, onset to REM sleep, combat history and somatic symptoms. Decision-tree analysis showed that a specific military event (combat), delayed onset to REM sleep, paranoid thinking and medically unexplainable somatic pain and fatigue characterise chronic PTSD. More PTSD veterans reported domestic and social misbehaviour. Military combat, disturbed REM/non-REM EEG sleep, paranoid ideation and medically unexplained chronic musculoskeletal pain and fatigue are key factors in determining PTSD disability following war-zone exposure. None. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.


Childhood socioeconomic position and adult leisure-time physical activity: a systematic review protocol.
Participation in leisure-time physical activity benefits health and is thought to be more prevalent in higher socioeconomic groups. Evidence indicates that childhood socioeconomic circumstances may have long-term influences on adult health and behaviour; however, it is unclear if this extends to an influence on adult physical activity. The aim of this review is to examine whether a lower childhood socioeconomic position is associated with lower levels of leisure-time physical activity during adulthood. Keywords will be used to systematically search five online databases and additional studies will be located through a search of reference lists. At least two researchers working independently will screen search results assess the quality of included studies and extract all relevant data. Studies will be included if they are English language publications that test the association between at least one indicator of childhood socioeconomic position and a leisure-time physical activity outcome measured during adulthood. Any disagreements and discrepancies arising during the conduct of the study will be resolved through discussion. This study will address the gap in evidence by systematically reviewing the published literature to establish whether childhood socioeconomic position is related to adult participation in leisure-time physical activity. The findings may be used to inform future research and policy. PROSPERO CRD42014007063.


Addressing the mental health nurse shortage: undergraduate nursing students working as assistants in nursing in inpatient mental health settings.
The population of mental health nurses is ageing and in the next few years we can expect many to retire. This paper makes an argument for the employment of undergraduate nursing students as Assistants in Nursing (AINs) in mental health settings as a strategy to encourage them to consider a career in mental health nursing. Skill mix in nursing has been debated since at least the 1980s. It appears that the use of AINs in general nursing is established and will continue. The research suggests that with the right skill mix, nursing outcomes and safety are not compromised. It seems inevitable that assistants in nursing will increasingly be part of the mental health nursing workforce; it is timely for mental health nurses to lead these changes so nursing care and the future mental health nursing workforce stay in control of nursing.


Hypertonic saline reverses stiffness in a Sprague-Dawley rat model of acute intestinal edema, leading to improved intestinal function.
Acute edema induced by resuscitation and mesenteric venous hypertension impairs intestinal transit and contractility and reduces intestinal stiffness. Pretreatment with hypertonic saline (HS) can prevent these changes. Changes in tissue stiffness have been shown to trigger signaling cascades via stress fiber formation. We proposed that acute intestinal edema leads to a decrease in intestinal transit that may be mediated by changes in stiffness, leading to stress fiber formation and decreased intestinal transit. Furthermore, HS administration will abolish these detrimental effects of edema. Intestinal edema causes a significant increase in tissue water and a significant decrease in intestinal transit and stiffness compared with sham. HS reversed these changes to sham levels. In addition, tissue edema led to significant stress fiber formation and decreased numbers of focal contacts. HS preserved tissue stiffness, prevented stress fiber formation, and was associated with improved intestinal function. HS eliminates intestinal tissue edema formation and improves intestinal transit. In addition, the action of HS may be mediated through its preservation of tissue stiffness, which leads to prevention of signaling via stress fiber formation, leading to preserved intestinal function. Finally, intestinal edema may provide a novel physiologic model for examining stiffness and stress fiber signaling.


Multi-Scale Deep Reinforcement Learning for Real-Time 3D-Landmark Detection in CT Scans.
Robust and fast detection of anatomical structures is a prerequisite for both diagnostic and interventional medical image analysis. Current solutions for anatomy detection are typically based on machine learning techniques that exploit large annotated image databases in order to learn the appearance of the captured anatomy. These solutions are subject to several limitations, including the use of suboptimal feature engineering techniques and most importantly the use of computationally suboptimal search-schemes for anatomy detection. To address these issues, we propose a method that follows a new paradigm by reformulating the detection problem as a behavior learning task for an artificial agent. We couple the modeling of the anatomy appearance and the object search in a unified behavioral framework, using the capabilities of deep reinforcement learning and multi-scale image analysis. In other words, an artificial agent is trained not only to distinguish the target anatomical object from the rest of the body but also how to find the object by learning and following an optimal navigation path to the target object in the imaged volumetric space. We evaluated our approach on 1487 3D-CT volumes from 532 patients, totaling over 500,000 image slices and show that it significantly outperforms state-of-the-art solutions on detecting several anatomical structures with no failed cases from a clinical acceptance perspective, while also achieving a 20-30 percent higher detection accuracy. Most importantly, we improve the detection-speed of the reference methods by 2-3 orders of magnitude, achieving unmatched real-time performance on large 3D-CT scans.


Reactions of family medicine community preceptors to teaching medical students.
In 1993, the University of California, Los Angeles introduced an interdisciplinary course called ¿Doctoring¿ for all first-year medical students in which students visited family physicians' offices once a month for a total of four visits. The study's objectives were to ascertain preceptors' attitudes about having students in their offices and determine if this experience resulted in professional growth. A survey was mailed to the 101 preceptors recruited to teach in the ¿Doctoring¿ course. Thirty of the respondents were selected randomly for a follow-up telephone interview. In addition, a second survey was mailed to the 31 preceptors who chose not to participate in the course the following year. More than 75% of the preceptors surveyed reported that the medical students had positive effects on their patients' satisfaction with their care. However, interviews with some respondents revealed worries about balancing time with the student vs maintaining a busy practice. Preceptors reported professional growth in the teaching process and greater knowledge and skills in the specific medical content areas of the ¿Doctoring¿ course. Preceptors who did not participate in the course during the subsequent year reported that their decision was based on issues other than satisfaction with the course. Based on the results of the study, preceptors experience professional growth through students' direct presence in their offices. Time management while precepting is the greatest challenge reported by preceptors.


Three-dimensional infrared spectroscopy of isotope-diluted ice Ih.
Using three-dimensional infrared (3D-IR) spectroscopy, we investigate the vibrational dynamics of isotope-diluted ice Ih. By probing the OD stretch mode of HOD in H2O, we observe an extremely rapid decay (≈200 fs) of the population from the second vibrational excited state. Quantum simulations based on a two-dimensional Lippincott-Schroeder potential agree nearly quantitatively with the experimental 3D-IR lineshapes and dynamics. The model suggests that energy dissipation is enhanced due to nonadiabatic effects between vibrational states, which arise from strong mode-mixing between the OD stretch mode with lattice degrees of freedom. Furthermore, we compare the simulation results to ab initio based potentials, in which the hydrogen bond anharmonicity is too small to reproduce the experimental 3D-IR spectra. We thus conclude that the Lippincott-Schroeder potential effectively coalesces many degrees of freedom of the crystal into one intermolecular coordinate.


Coconut fats.
In many areas of Sri Lanka the coconut tree and its products have for centuries been an integral part of life, and it has come to be called the "Tree of life". However, in the last few decades, the relationship between coconut fats and health has been the subject of much debate and misinformation. Coconut fats account for 80% of the fat intake among Sri Lankans. Around 92% of these fats are saturated fats. This has lead to the belief that coconut fats are 'bad for health', particularly in relation to ischaemic heart disease. Yet most of the saturated fats in coconut are medium chain fatty acids whose properties and metabolism are different to those of animal origin. Medium chain fatty acids do not undergo degradation and re-esterification processes and are directly used in the body to produce energy. They are not as 'bad for health' as saturated fats. There is the need to clarify issues relating to intake of coconut fats and health, more particularly for populations that still depend on coconut fats for much of their fat intake. This paper describes the metabolism of coconut fats and its potential benefits, and attempts to highlight its benefits to remove certain misconceptions regarding its use.


Cell wall evolution and diversity.
Plant cell walls display a considerable degree of diversity in their compositions and molecular architectures. In some cases the functional significance of a particular cell wall type appears to be easy to discern: secondary cells walls are often reinforced with lignin that provides durability; the thin cell walls of pollen tubes have particular compositions that enable their tip growth; lupin seed cell walls are characteristically thickened with galactan used as a storage polysaccharide. However, more frequently the evolutionary mechanisms and selection pressures that underpin cell wall diversity and evolution are unclear. For diverse green plants (chlorophytes and streptophytes) the rapidly increasing availability of transcriptome and genome data sets, the development of methods for cell wall analyses which require less material for analysis, and expansion of molecular probe sets, are providing new insights into the diversity and occurrence of cell wall polysaccharides and associated biosynthetic genes. Such research is important for refining our understanding of some of the fundamental processes that enabled plants to colonize land and to subsequently radiate so comprehensively. The study of cell wall structural diversity is also an important aspect of the industrial utilization of global polysaccharide bio-resources.


Defining a core outcome set for adolescent and young adult patients with a spinal deformity.
Background and purpose - Routine outcome measurement has been shown to improve performance in several fields of healthcare. National spine surgery registries have been initiated in 5 Nordic countries. However, there is no agreement on which outcomes are essential to measure for adolescent and young adult patients with a spinal deformity. The aim of this study was to develop a core outcome set (COS) that will facilitate benchmarking within and between the 5 countries of the Nordic Spinal Deformity Society (NSDS) and other registries worldwide. Material and methods - From August 2015 to September 2016, 7 representatives (panelists) of the national spinal surgery registries from each of the NSDS countries participated in a modified Delphi study. With a systematic literature review as a basis and the International Classification of Functioning, Disability and Health framework as guidance, 4 consensus rounds were held. Consensus was defined as agreement between at least 5 of the 7 representatives. Data were analyzed qualitatively and quantitatively. Results - Consensus was reached on the inclusion of 13 core outcome domains: "satisfaction with overall outcome of surgery", "satisfaction with cosmetic result of surgery", "pain interference", physical functioning", "health-related quality of life", "recreation and leisure", "pulmonary fatigue", "change in deformity", "self-image", "pain intensity", "physical function", "complications", and "re-operation". Panelists agreed that the SRS-22r, EQ-5D, and a pulmonary fatigue questionnaire (yet to be developed) are the most appropriate set of patient-reported measurement instruments that cover these outcome domains. Interpretation - We have identified a COS for a large subgroup of spinal deformity patients for implementation and validation in the NSDS countries. This is the first study to further develop a COS in a global perspective.


Effect of supercoiling on formation of protein-mediated DNA loops.
DNA loop formation is one of several mechanisms used by organisms to regulate genes. The free energy of forming a loop is an important factor in determining whether the associated gene is switched on or off. In this paper we use an elastic rod model of DNA to determine the free energy of forming short (50-100 basepair), protein mediated DNA loops. Superhelical stress in the DNA of living cells is a critical factor determining the energetics of loop formation, and we explicitly account for it in our calculations. The repressor protein itself is regarded as a rigid coupler; its geometry enters the problem through the boundary conditions it applies on the DNA. We show that a theory with these ingredients is sufficient to explain certain features observed in modulation of in vivo gene activity as a function of the distance between operator sites for the lac repressor. We also use our theory to make quantitative predictions for the dependence of looping on superhelical stress, which may be testable both in vivo and in single-molecule experiments such as the tethered particle assay and the magnetic bead assay.


Microbial population structures in the deep marine biosphere.
The analytical power of environmental DNA sequences for modeling microbial ecosystems depends on accurate assessments of population structure, including diversity (richness) and relative abundance (evenness). We investigated both aspects of population structure for microbial communities at two neighboring hydrothermal vents by examining the sequences of more than 900,000 microbial small-subunit ribosomal RNA amplicons. The two vent communities have different population structures that reflect local geochemical regimes. Descriptions of archaeal diversity were nearly exhaustive, but despite collecting an unparalleled number of sequences, statistical analyses indicated additional bacterial diversity at every taxonomic level. We predict that hundreds of thousands of sequences will be necessary to capture the vast diversity of microbial communities, and that different patterns of evenness for both high- and low-abundance taxa may be important in defining microbial ecosystem dynamics.


Population exposure to hazardous air quality due to the 2015 fires in Equatorial Asia.
Vegetation and peatland fires cause poor air quality and thousands of premature deaths across densely populated regions in Equatorial Asia. Strong El-Niño and positive Indian Ocean Dipole conditions are associated with an increase in the frequency and intensity of wildfires in Indonesia and Borneo, enhancing population exposure to hazardous concentrations of smoke and air pollutants. Here we investigate the impact on air quality and population exposure of wildfires in Equatorial Asia during Fall 2015, which were the largest over the past two decades. We performed high-resolution simulations using the Weather Research and Forecasting model with Chemistry based on a new fire emission product. The model captures the spatio-temporal variability of extreme pollution episodes relative to space- and ground-based observations and allows for identification of pollution sources and transport over Equatorial Asia. We calculate that high particulate matter concentrations from fires during Fall 2015 were responsible for persistent exposure of 69 million people to unhealthy air quality conditions. Short-term exposure to this pollution may have caused 11,880 (6,153-17,270) excess mortalities. Results from this research provide decision-relevant information to policy makers regarding the impact of land use changes and human driven deforestation on fire frequency and population exposure to degraded air quality.


Synaptic dynamics in analog VLSI.
Synapses are crucial elements for computation and information transfer in both real and artificial neural systems. Recent experimental findings and theoretical models of pulse-based neural networks suggest that synaptic dynamics can play a crucial role for learning neural codes and encoding spatiotemporal spike patterns. Within the context of hardware implementations of pulse-based neural networks, several analog VLSI circuits modeling synaptic functionality have been proposed. We present an overview of previously proposed circuits and describe a novel analog VLSI synaptic circuit suitable for integration in large VLSI spike-based neural systems. The circuit proposed is based on a computational model that fits the real postsynaptic currents with exponentials. We present experimental data showing how the circuit exhibits realistic dynamics and show how it can be connected to additional modules for implementing a wide range of synaptic properties.


Abortion incidence and access to services in the United States, 2008.
The incidence of abortion has declined nearly every year between 1990 and 2005, but this trend may be ending, or at least leveling off. Access to abortion services is a critical issue, particularly since the number of abortion providers has been falling for the last three decades. In 2009 and 2010, all facilities known or expected to have provided abortion services in 2007 and 2008 were contacted, including hospitals, clinics and physicians' offices. Data on the number of abortions performed were collected and combined with population data to estimate national and state-level abortion rates. Abortion incidence, provision of early medication abortion, gestational limits, charges and antiabortion harassment were assessed by provider type and abortion caseload. In 2008, an estimated 1.21 million abortions were performed in the United States. The abortion rate increased 1% between 2005 and 2008, from 19.4 to 19.6 abortions per 1,000 women aged 15-44; the total number of abortion providers was virtually unchanged. Small changes in national abortion incidence and number of providers masked substantial changes in some states. Accessibility of services changed little: In both years, 35% of women of reproductive age lived in the 87% of counties that lacked a provider. Fifty-seven percent of nonhospital providers experienced antiabortion harassment in 2008; levels of harassment were particularly high in the Midwest (85%) and the South (75%). The long-term decline in abortion incidence has stalled. Higher levels of harassment in some regions suggest the need to enact and enforce laws that prohibit the more intrusive forms of harassment.


An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1.
PAK4 is a metazoan-specific kinase acting downstream of Cdc42. Here we describe the structure of human PAK4 in complex with Inka1, a potent endogenous kinase inhibitor. Using single mammalian cells containing crystals 50 μm in length, we have determined the in cellulo crystal structure at 2.95 Å resolution, which reveals the details of how the PAK4 catalytic domain binds cellular ATP and the Inka1 inhibitor. The crystal lattice consists only of PAK4-PAK4 contacts, which form a hexagonal array with channels of 80 Å in diameter that run the length of the crystal. The crystal accommodates a variety of other proteins when fused to the kinase inhibitor. Inka1-GFP was used to monitor the process crystal formation in living cells. Similar derivatives of Inka1 will allow us to study the effects of PAK4 inhibition in cells and model organisms, to allow better validation of therapeutic agents targeting PAK4.


Co-exposure with fullerene may strengthen health effects of organic industrial chemicals.
In vitro toxicological studies together with atomistic molecular dynamics simulations show that occupational co-exposure with C60 fullerene may strengthen the health effects of organic industrial chemicals. The chemicals studied are acetophenone, benzaldehyde, benzyl alcohol, m-cresol, and toluene which can be used with fullerene as reagents or solvents in industrial processes. Potential co-exposure scenarios include a fullerene dust and organic chemical vapor, or a fullerene solution aerosolized in workplace air. Unfiltered and filtered mixtures of C60 and organic chemicals represent different co-exposure scenarios in in vitro studies where acute cytotoxicity and immunotoxicity of C60 and organic chemicals are tested together and alone by using human THP-1-derived macrophages. Statistically significant co-effects are observed for an unfiltered mixture of benzaldehyde and C60 that is more cytotoxic than benzaldehyde alone, and for a filtered mixture of m-cresol and C60 that is slightly less cytotoxic than m-cresol. Hydrophobicity of chemicals correlates with co-effects when secretion of pro-inflammatory cytokines IL-1β and TNF-α is considered. Complementary atomistic molecular dynamics simulations reveal that C60 co-aggregates with all chemicals in aqueous environment. Stable aggregates have a fullerene-rich core and a chemical-rich surface layer, and while essentially all C60 molecules aggregate together, a portion of organic molecules remains in water.


Microinterventions targeting regulatory focus and regulatory fit selectively reduce dysphoric and anxious mood.
Depression and generalized anxiety, separately and as comorbid states, continue to represent a significant public health challenge. Current cognitive-behavioral treatments are clearly beneficial but there remains a need for continued development of complementary interventions. This manuscript presents two proof-of-concept studies, in analog samples, of "microinterventions" derived from regulatory focus and regulatory fit theories and targeting dysphoric and anxious symptoms. In Study 1, participants with varying levels of dysphoric and/or anxious mood were exposed to a brief intervention either to increase or to reduce engagement in personal goal pursuit, under the hypothesis that dysphoria indicates under-engagement of the promotion system whereas anxiety indicates over-engagement of the prevention system. In Study 2, participants with varying levels of dysphoric and/or anxious mood received brief training in counterfactual thinking, under the hypothesis that inducing individuals in a state of promotion failure to generate subtractive counterfactuals for past failures (a non-fit) will lessen their dejection/depression-related symptoms, whereas inducing individuals in a state of prevention failure to generate additive counterfactuals for past failures (a non-fit) will lessen their agitation/anxiety-related symptoms. In both studies, we observed discriminant patterns of reduction in distress consistent with the hypothesized links between dysfunctional states of the two motivational systems and dysphoric versus anxious symptoms.


Real time 3D visualization of ultrasonic data using a standard PC.
This paper describes a flexible, software-based scan converter capable of rendering 3D volumetric data in real time on a standard PC. The display system is used in the remotely accessible and software-configurable multichannel ultrasound sampling system (RASMUS system) developed at the Center for Fast Ultrasound Imaging. The display system is split into two modules: data transfer and display. These two modules are independent and communicate using shared memory and a predefined set of functions. It is, thus, possible to use the display program with a different data-transfer module which is tailored to another source of data (scanner, database, etc.). The data-transfer module of the RASMUS system is based on a digital signal processor from Analog Devices--ADSP 21060. The beamformer is connected to a PC via the link channels of the ADSP. A direct memory access channel transfers the data from the ADSP to a memory buffer. The display module, which is based on OpenGL, uses this memory buffer as a texture map that is passed to the graphics board. The scan conversion, image interpolation, and logarithmic compression are performed by the graphics board, thus reducing the load on the main processor to a minimum. The scan conversion is done by mapping the ultrasonic data to polygons. The format of the image is determined only by the coordinates of the polygons allowing for any kind of geometry to be displayed on the screen. Data from color flow mapping is added by alpha-blending. The 3D data are displayed either as cross-sectional planes, or as a fully rendered 3D volume displayed as a pyramid. All sides of the pyramid can be changed to reveal B-mode or C-mode scans, and the pyramid can be rotated in all directions in real time.


Generalized periodic epileptiform discharges: etiologies, relationship to status epilepticus, and prognosis.
Generalized periodic epileptiform discharges (GPEDs) are generalized, synchronous electrographic discharges. This study investigates etiologies, relationship to status epilepticus (SE), and the prognosis for patients with GPEDs. All EEGs with GPEDs performed at Duke University Medical Center between January 1994 and October 1995 were identified. Clinical histories and EEGs were reviewed. They were divided into groups depending on the etiology of the GPEDs, whether the patients were in SE or not, and whether they were alive or not at discharge. A comparison of histories and GPED characteristics among groups was undertaken using parametric and nonparametric t tests. Twenty-five patients were enrolled: 7 (28%) had toxic-metabolic encephalopathy, 10 (40%) had anoxia and toxic-metabolic encephalopathy, and 8 (32%) had a primary neurologic process. Eight patients (32%) were in SE. In the SE group, GPED amplitude was higher (110 versus 80 microV, P < 0.05), GPED duration was longer (0.5 versus 0.3 seconds, P < 0.05), and inter-GPED amplitude was higher (34 versus 17 microV, P < 0.05). Nine patients (36%) were alive at discharge; they were more likely to be younger (51 versus 68 years, P < 0.05), have a better mental status at the time of their EEG, and have a higher inter-GPED amplitude (33 versus 18 microV, P < 0.05). A variety of conditions, including SE, can cause GPEDs. Intergroup differences in historic and GPED features exist between those patients in SE and those not in SE and those with good and poor prognoses.


Acquisition of Medicaid at the time of injury: An opportunity for sustainable insurance coverage.
Uninsured trauma patients are at higher risk of mortality, limited access to postdischarge resources, and catastrophic health expenditure. Hospital Presumptive Eligibility (HPE), enacted with the 2014 Affordable Care Act, enables uninsured patients to be screened and acquired emergency Medicaid at the time of hospitalization. We sought to identify factors associated with successful acquisition of HPE insurance at the time of injury, hypothesizing that patients with higher Injury Severity Score (ISS) (ISS >15) would be more likely to be approved for HPE. We identified Medicaid and uninsured patients aged 18 to 64 years with a primary trauma diagnosis (International Classification of Diseases, Tenth Revision) in a large level I trauma center between 2015 and 2019. We combined trauma registry data with review of electronic medical records, to determine our primary outcome, HPE acquisition. Descriptive and multivariate analyses were performed. Among 2,320 trauma patients, 1,374 (59%) were already enrolled in Medicaid at the time of hospitalization. Among those uninsured at arrival, 386 (40.8%) acquired HPE before discharge, and 560 (59.2%) remained uninsured. Hospital Presumptive Eligibility patients had higher ISS (ISS >15, 14.8% vs. 5.7%; p < 0.001), longer median length of stay (2 days [interquartile range, 0-5 days] vs. 0 [0-1] days, p < 0.001), were more frequently admitted as inpatients (64.5% vs. 33.6%, p < 0.001), and discharged to postacute services (11.9% vs. 0.9%, p < 0.001). Patient, hospital, and policy factors contributed to HPE nonapproval. In adjusted analyses, Hispanic ethnicity (vs. non-Hispanic Whites: aOR, 1.58; p = 0.02) and increasing ISS (p ≤ 0.001) were associated with increased likelihood of HPE approval. The time of hospitalization due to injury is an underused opportunity for intervention, whereby uninsured patients can acquire sustainable insurance coverage. Opportunities to increase HPE acquisition merit further study nationally across trauma centers. As administrative and trauma registries do not capture information to compare HPE and traditional Medicaid patients, prospective insurance data collection would help to identify targets for intervention. Economic, level IV.


Impact of the 2011 Libyan conflict on road traffic injuries in Benghazi, Libya.
Road traffic injuries (RTIs) are a major public health concern in Libya. In the light of the armed conflict in Libya that broke out on February 2011 and the subsequent instability, the rate and pattern of RTIs was studied. RTI patient data were gathered from Al-Jalaa hospital, the main trauma center in Benghazi, from 2010 to 2011. Various parameters [i.e. age, gender, nationality, method of entry, receiving department, intensive care unit (ICU) admission, duration of stay, method of discharge, and fatalities] were compared with data from the previous year (2010), and statistical analyses were performed (t-test, chi-square, and Poisson regression). During the conflict period, 15.8% (n=2,221) of hospital admissions were RTIs, that is, a rate of 6.08 RTI cases per day, levels not seen for 5 years (t=-5.719, p<0.001). The presence of armed conflict was found to have caused a significant 28% decrease in the trend of RTIs over the previous 10 years (B=-0.327, CI=-0.38--0.28, p<0.001). February and March, the peak period of active combat in Benghazi, witnessed the lowest number of RTIs during the conflict period. The average age of an RTI decreased to 28.35±16.3 years (t=-7.257, p<0.001) with significantly more males (84.1%, n=1,755) being affected (χ(2)=4.595, p=0.032, df=1). There was an increase in the proportion of younger aged patients (from 0 to 29 years) (χ(2)=29.874, p<0.001, df=8). More patients required admission to the ICU (χ(2)=36.808, p<0.001, df=8), and the mortality of an RTI increased to 5.2% (n=116) (χ(2)=48.882, p<0.001, df=6). There were fewer RTIs during the conflict period; however, those that occurred had higher morbidity and mortality. The profile of an RTI victims also changed to an increased prominence of young males and motorcyclists. Further research is required to propose and analyze possible interventions.


Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog.
Hedgehog (HH) signaling proteins mediate inductive events during animal development. Mutation of the only known HH receptor gene, Patched (PTC), has recently been implicated in inherited and sporadic forms of the most common human cancer, basal cell carcinoma (BCC). In Drosophila, HH acts by inactivating PTC function, raising the possibility that overexpression of Sonic Hedgehog (SHH) in human epidermis might have a tumorigenic effect equivalent to loss of PTC function. We used retroviral transduction of normal human keratinocytes to constitutively express SHH. SHH-expressing cells demonstrated increased expression of both the known HH target, BMP-2B, as well as bcl-2, a protein prominently expressed by keratinocytes in BCCs. These keratinocytes were then used to regenerate human skin transgenic for long terminal repeat-driven SHH (LTR-SHH) on immune-deficient mice. LTR-SHH human skin consistently displays the abnormal specific histologic features seen in BCCs, including downgrowth of epithelial buds into the dermis, basal cell palisading and separation of epidermis from the underlying dermis. In addition, LTR-SHH skin displays the gene expression abnormalities previously described for human BCCs, including decreased BP180/BPAG2 and laminin 5 adhesion proteins and expression of basal epidermal keratins. These data indicate that expression of SHH in human skin recapitulates features of human BCC in vivo, suggest that activation of this conserved signaling pathway contributes to the development of epithelial neoplasia and describe a new transgenic human tissue model of neoplasia.


Examining the Influence of Measures of Adiposity on Cognitive Function in Middle Age and Older African Americans.
The objectives of the study were to examine whether measures of total obesity (body mass index [BMI]) and central obesity (waist circumference [WC] and waist-to-hip ratio [WHR]) are associated with cognitive function in African Americans, and whether sex moderates these associations. A sample of 194 African Americans, with a mean age of 58.97 years, completed a battery of cognitive tests and a self-reported health questionnaire. Height, weight, waist and hip circumference, and blood pressure were assessed. Linear regression analyses were run. Results suggested lower performance on measures of verbal fluency and complex attention/cognitive flexibility was accounted for by higher levels of central adiposity. Among men, higher WHR was more strongly related to complex attention/cognitive flexibility performance, but for women, WC was a salient predictor. Higher BMI was associated with poorer verbal memory performance among men, but poorer nonverbal memory performance among women. Findings suggest a need for healthy lifestyle interventions for African Americans to maintain healthy weight and cognitive function.


Small heat shock protein HspB8: its distribution in Alzheimer's disease brains and its inhibition of amyloid-beta protein aggregation and cerebrovascular amyloid-beta toxicity.
Alzheimer's disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-beta precursor protein (APP), the amyloid-beta peptide (Abeta). CAA is also the major pathological lesion in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), caused by a mutation in the gene coding for the Abeta peptide. Several members of the small heat shock protein (sHsp) family, such as alphaB-crystallin, Hsp27, Hsp20 and HspB2, are associated with the pathological lesions of AD, and the direct interaction between sHsps and Abeta has been demonstrated in vitro. HspB8, also named Hsp22 of H11, is a recently discovered member of the sHsp family, which has chaperone activity and is observed in neuronal tissue. Furthermore, HspB8 affects protein aggregation, which has been shown by its ability to prevent formation of mutant huntingtin aggregates. The aim of this study was to investigate whether HspB8 is associated with the pathological lesions of AD and HCHWA-D and whether there are effects of HspB8 on Abeta aggregation and Abeta-mediated cytotoxicity. We observed the expression of HspB8 in classic SPs in AD brains. In addition, HspB8 was found in CAA in HCHWA-D brains, but not in AD brains. Direct interaction of HspB8 with Abeta(1-42), Abeta(1-40) and Abeta(1-40) with the Dutch mutation was demonstrated by surface plasmon resonance. Furthermore, co-incubation of HspB8 with D-Abeta(1-40) resulted in the complete inhibition of D-Abeta(1-40)-mediated death of cerebrovascular cells, likely mediated by a reduction in both the beta-sheet formation of D-Abeta(1-40) and its accumulation at the cell surface. In contrast, however, with Abeta(1-42), HspB8 neither affected beta-sheet formation nor Abeta-mediated cell death. We conclude that HspB8 might play an important role in regulating Abeta aggregation and, therefore, the development of classic SPs in AD and CAA in HCHWA-D.


Does an aggressor's target choice matter? Assessing change in the social network prestige of aggressive youth.
Based on a social dominance approach, aggression is conceptualized as a strategy used to gain position, power, and influence within the peer network. However, aggression may only be beneficial when targeted against particular peers; both victims' social standing and the number of victims targeted may impact aggressors' social standing. The current study examined associations between aggressors' targeting tendencies (victims' social standing and number of victims) and aggressors' own social standing, both concurrently and over time. Analyses were conducted using three analytic samples of seventh and eighth grade aggressors (Ns ranged from 161 to 383, 49% girls; 50% Latina/o). Participants nominated their friends; nominations were used to calculate social network prestige. Peer nominations were used to identify aggressors and their victim(s). For each aggressor, number of victims and victims' social network prestige were assessed. Aggressors with more victims and with highly prestigious victims had higher social network prestige themselves, and they increased more in prestige over time than aggressors with fewer victims and less prestigious victims (though there were some differences across analytic samples). Findings have implications for the need to extend the social dominance approach to better address the links between aggressors and victims. Aggr. Behav. 43:364-374, 2017. © 2017 Wiley Periodicals, Inc.


Neonatal repetitive pain in rats leads to impaired spatial learning and dysregulated hypothalamic-pituitary-adrenal axis function in later life.
Preterm birth is a major health issue. As part of their life-saving care, most preterm infants require hospitalization and are inevitably exposed to repetitive skin-breaking procedures. The long-term effects of neonatal repetitive pain on cognitive and emotional behaviors involving hypothalamic-pituitary-adrenal (HPA) axis function in young and adult rats are unknown. From P8 to P85, mechanical hypersensitivity of the bilateral hindpaws was observed in the Needle group (P < 0.001). Compared with the Tactile group, the Needle group took longer to find the platform on P30 than on P29 (P = 0.03), with a decreased number of original platform site crossings during the probe trial of the Morris water maze test (P = 0.026). Moreover, the Needle group spent more time and took longer distances in the central area than the Tactile group in the Open-field test, both in prepubertal and adult rats (P < 0.05). The HPA axis function in the Needle group differed from the Tactile group (P < 0.05), with decreased stress responsiveness in prepuberty and puberty (P < 0.05) and increased stress responsiveness in adulthood (P < 0.05). This study indicates that repetitive pain that occurs during a critical period may cause severe consequences, with behavioral and neuroendocrine disturbances developing through prepuberty to adult life.


Significantly high levels of anti-dsDNA immunoglobulin E in sera and the ability of dsDNA to induce the degranulation of basophils from chronic urticaria patients.
Chronic urticaria (CU) appears to be of autoimmune origin in about half of all patients, since several autoreactive immunoglobulin Gs (IgGs), such as anti-FcεRIα and anti-IgE, are detected in the sera of such patients. However, whether autoreactive IgE is associated with CU remains unclear. In this study, we attempted to identify autoreactive IgE antibodies in sera from patients with CU. Sera were collected from 67 normal subjects, 85 patients with CU and 28 patients with atopic dermatitis (AD). An autologous serum skin test (ASST) was performed on 27 of the CU patients. Autoreactive IgE and IgG levels against self-antigens were measured using enzyme-linked immunosorbent assays. The basophils were activated with dsDNA, and the CD63 expression level was examined using a fluorescence-activated cell sorter. The anti-dsDNA IgE levels were significantly higher in patients with CU and AD than in normal subjects, but no differences in the anti-dsDNA IgG levels were seen. The levels of thioredoxin-, peroxiredoxin- and thyroglobulin-reactive IgE and IgG were not significantly higher in the CU patients than in the other 2 groups. There was no significant difference in the levels of anti-dsDNA IgE between ASST-positive and ASST-negative patients. The basophils from 2 out of 9 CU patients exhibited degranulation in response to dsDNA. Our data suggest that anti-dsDNA IgE is involved in the pathogenesis of some cases of CU.


Carotid plaque and intima-media thickness assessed by b-mode ultrasonography in subjects ranging from young adults to centenarians.
BACKGROUND AND PURPOSE-To investigate relationships among plaque formation, increasing intima-media thickness, and age, we examined ultrasonographically carotid arteries of subjects who had no major atherosclerotic risk factors and who ranged in age from young adults to centenarians. We studied 319 healthy subjects (154 men, 165 women; age range, 21 to 105 years) with no history of hypertension, diabetes mellitus, or atherosclerotic disease. Mean intima-media wall thickness (IMT) of common carotid arteries at plaque-free sites and prevalence of plaques were evaluated by B-mode ultrasound. Mean common carotid IMT increased in a linear manner with age for all decades of life, including centenarians [IMT=(0.009xAge)+0.116] (r=0.83). In centenarians (n=30), intima-media complexes were diffusely thickened (mean IMT, 1.01 mm). Plaque prevalence increased up to the tenth decade of life (83.3%, n=30) but decreased in centenarians (60.0%). IMT and plaque prevalence were closely associated in the seventh and eighth decades of life but not at older ages. The present study indicates that increased IMT is a physiological effect of aging that corresponds to diffuse intimal thickening, especially in very elderly persons, and that IMT is distinct from pathological plaque formation.


Spontaneous structural transition in phospholipid-inspired aromatic phosphopeptide nanostructures.
Phospholipid membranes could be considered a prime example of the ability of nature to produce complex yet ordered structures, by spontaneous and efficient self-assembly. Inspired by the unique properties and architecture of phospholipids, we designed simple amphiphilic decapeptides, intended to fold in the center of the peptide sequence, with a phosphorylated serine "head" located within a central turn segment, and two hydrophobic "tails". The molecular design also included the integration of the diphenylalanine motif, previously shown to facilitate self-assembly and increase nanostructure stability. Secondary structure analysis of the peptides indeed indicated the presence of stabilized conformations in solution, with a central turn connecting two hydrophobic "tails", and interactions between the hydrophobic strands. The mechanisms of assembly into supramolecular structures involved structural transitions between different morphologies, which occurred over several hours, leading to the formation of distinctive nanostructures, including half-elliptical nanosheets and curved tapes. The phosphopeptide building blocks appear to self-assemble via a particular combination of aromatic, hydrophobic and ionic interactions, as well as hydrogen bonding, as demonstrated by proposed constructed simulated models of the peptides and self-assembled nanostructures. Molecular dynamics simulations also gave insight into mechanisms of structural transitions of the nanostructures at a molecular level. Because of the biocompatibility of peptides, the phosphopeptide assemblies allow for expansion of the library of biomolecular nanostructures available for future design and application of biomedical devices.


Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production.
Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.


Shape allophiles improve entropic assembly.
We investigate a class of "shape allophiles" that fit together like puzzle pieces as a method to access and stabilize desired structures by controlling directional entropic forces. Squares are cut into rectangular halves, which are shaped in an allophilic manner with the goal of re-assembling the squares while self-assembling the square lattice. We examine the assembly characteristics of this system via the potential of mean force and torque, and the fraction of particles that entropically bind. We generalize our findings and apply them to self-assemble triangles into a square lattice via allophilic shaping. Through these studies we show how shape allophiles can be useful for assembling and stabilizing desired phases with appropriate allophilic design.


The effect of ibuprofen on ethanol concentration and elimination rate.
Pursuant to a recent driving under the influence (DUI) case, a medical study of six subjects was cited reporting that ibuprofen causes a decrease in the maximum rate of elimination of ethanol. Such a drug interaction is of significant forensic science interest and warrants further examination. This study investigates the effect of ibuprofen on ethanol elimination rate and ethanol concentration in nineteen volunteers. Volunteer subjects were randomly assigned to two groups administered either a placebo followed by ethanol or ibuprofen followed by ethanol. Subjects served as their own control. Blood ethanol concentrations were monitored every 30 to 60 min for up to 4 h with Intoximeter 3000 instruments. A blood sample was drawn at the final Intoximeter test and analyzed for ethanol and ibuprofen by gas chromatography and mass spectrometry, respectively. The mean elimination rate (+/- SD) as calculated using Widmark's elimination factor was 0.018 +/- 0.006 g/dL for ethanol and 0.017 +/- 0.007 g/dL/h for ethanol with ibuprofen. Mean ethanol concentrations (g/dL +/- SD) were: 0.095 +/- 0.026 (ethanol) and 0.095 +/- 0.033 (ethanol and ibuprofen) at 30 min; 0.077 +/- 0.026 (ethanol) and 0.075 +/- 0.031 (ethanol and ibuprofen) at 150 min; and 0.089 +/- 0.025 (ethanol) and 0.087 +/- 0.030 (ethanol and ibuprofen) overall. There was no statistically significant affect of ibuprofen on either the peak blood ethanol concentration or the ethanol elimination rate (p less than or equal to 0.001). These results reveal no evidence of a significant ethanol-ibuprofen interaction.


3D gradient echo snapshot CEST MRI with low power saturation for human studies at 3T.
For clinical implementation, a chemical exchange saturation transfer (CEST) imaging sequence must be fast, with high signal-to-noise ratio (SNR), 3D coverage, and produce robust contrast. However, spectrally selective CEST contrast requires dense sampling of the Z-spectrum, which increases scan duration. This article proposes a compromise: using a 3D snapshot gradient echo (GRE) readout with optimized CEST presaturation, sampling, and postprocessing, highly resolved Z-spectroscopy at 3T is made possible with 3D coverage at almost no extra time cost. A 3D snapshot CEST sequence was optimized for low-power CEST MRI at 3T. Pulsed saturation was optimized for saturation power and saturation duration. Spectral sampling and postprocessing (B0 correction, denoising) was optimized for spectrally selective Lorentzian CEST effect extraction. Reproducibility was demonstrated in 3 healthy volunteers and feasibility was shown in 1 tumor patient. Low-power saturation was achieved by a train of 80 pulses of duration tp = 20 ms (total saturation time tsat = 3.2 seconds at 50% duty cycle) with B1 = 0.6 μT at 54 irradiation frequency offsets. With the 3D snapshot CEST sequence, a 180 × 220 × 54 mm field of view was acquired in 7 seconds per offset. Spectrally selective CEST effects at +3.5 and -3.5 ppm were quantified using multi-Lorentzian fitting. Reproducibility was high with an intersubject coefficient of variation below 10% in CEST contrasts. Amide and nuclear overhauser effect CEST effects showed similar correlations in tumor and necrosis as show in previous ultra-high field work. A sophisticated CEST tool ready for clinical application was developed and tested for feasibility.


Loss of pin fixation in displaced supracondylar humeral fractures in children: causes and prevention.
Although the results are generally good following pin fixation of supracondylar humeral fractures in children, occasionally there is postoperative displacement. The purposes of the present study were to identify the causes leading to loss of fixation after pin fixation and to present methods for prevention. We evaluated 322 displaced supracondylar humeral fractures that had been treated with percutaneous pin fixation. We examined fracture classification, pin configuration, intraoperative alignment after fixation, change in alignment after fixation, details of additional procedures, and final radiographic and clinical outcomes. Adequate radiographs were available for 279 of the 322 fractures. Eight (2.9%) of the 279 fractures were associated with postoperative loss of fixation; all eight were Gartland type-III fractures. Seven of these eight fractures initially had been treated with two lateral-entry pins, and one had been treated with two crossed pins. In patients with Gartland type-III fractures, loss of fixation was successfully avoided more often when three pins were used (with fixation being maintained in thirty-seven of thirty-seven patients) as opposed to when two lateral-entry pins were used (with fixation being maintained in thirty-five of forty-two patients) (p = 0.01). In all cases, loss of fixation was due to technical errors that were identifiable on the intraoperative fluoroscopic images and that could have been prevented with proper technique. We identified three types of pin-fixation errors: (1) failure to engage both fragments with two pins or more, (2) failure to achieve bicortical fixation with two pins or more, and (3) failure to achieve adequate pin separation (>2 mm) at the fracture site. Postoperative displacement following pin fixation of supracondylar humeral fractures in children is uncommon. In the present series, loss of fixation was most likely to occur when Gartland type-III fractures were treated with two lateral-entry pins. There were no failures when three pins were used. In all cases of failure, there were identifiable technical errors in pin placement. Therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.


Automated Detection of Postictal Generalized EEG Suppression.
Although there is no strict consensus, some studies have reported that Postictal generalized EEG suppression (PGES) is a potential electroencephalographic (EEG) biomarker for risk of sudden unexpected death in epilepsy (SUDEP). PGES is an epoch of EEG inactivity after a seizure, and the detection of PGES in clinical data is extremely difficult due to artifacts from breathing, movement and muscle activity that can adversely affect the quality of the recorded EEG data. Even clinical experts visually interpreting the EEG will have diverse opinions on the start and end of PGES for a given patient. The development of an automated EEG suppression detection tool can assist clinical personnel in the review and annotation of seizure files, and can also provide a standard for quantifying PGES in large patient cohorts, possibly leading to further clarification of the role of PGES as a biomarker of SUDEP risk. In this paper, we develop an automated system that can detect the start and end of PGES using frequency domain features in combination with boosting classification algorithms. The average power for different frequency ranges of EEG signals are extracted from the prefiltered recorded signal using the fast fourier transform and are used as the feature set for the classification algorithm. The underlying classifiers for the boosting algorithm are linear classifiers using a logistic regression model. The tool is developed using 12 seizures annotated by an expert then tested and evaluated on another 20 seizures that were annotated by 11 experts.


Evaluation of whole genome amplification and bioinformatic methods for the characterization of Leishmania genomes at a single cell level.
Here, we report a pilot study paving the way for further single cell genomics studies in Leishmania. First, the performances of two commercially available kits for Whole Genome Amplification (WGA), PicoPLEX and RepliG were compared on small amounts of Leishmania donovani DNA, testing their ability to preserve specific genetic variations, including aneuploidy levels and SNPs. We show here that the choice of WGA method should be determined by the planned downstream genetic analysis, PicoPLEX and RepliG performing better for aneuploidy and SNP calling, respectively. This comparison allowed us to evaluate and optimize corresponding bio-informatic methods. As PicoPLEX was shown to be the preferred method for studying single cell aneuploidy, this method was applied in a second step, on single cells of L. braziliensis, which were sorted by fluorescence activated cell sorting (FACS). Even sequencing depth was achieved in 28 single cells, allowing accurate somy estimation. A dominant karyotype with three aneuploid chromosomes was observed in 25 cells, while two different minor karyotypes were observed in the other cells. Our method thus allowed the detection of aneuploidy mosaicism, and provides a solid basis which can be further refined to concur with higher-throughput single cell genomic methods.


Serum cytokine and glucose levels as predictors of poststroke fatigue in acute ischemic stroke patients.
Fatigue is a common but often overlooked symptom after stroke. This study investigated whether stroke type, infarct volume, and laterality, as well as the levels of various cytokines and other blood components in the acute phase of acute ischemic stroke (AIS), can predict the level of fatigue at 6, 12, and 18 months after its onset. In 45 patients with acute stroke, serum levels of C-reactive protein, hemoglobin, glucose, and 13 cytokines were measured within 72 h of stroke onset. The cytokine measurements were performed using BioPlex XMap technology (Luminex). The acute serum levels of interleukin (IL)-1β and glucose were positively correlated with the score on the Fatigue Severity Scale (FSS) at 6 months after the stroke (r = 0.37, p = 0.015, and r = 0.37, p = 0.017, respectively). The acute serum levels of IL-ra and IL-9 were negatively correlated with FSS score at 12 months after the stroke (r = -0.38, p = 0.013, and r = -0.36, p = 0.019, respectively). The FSS score at 12 months after stroke was significantly lower in patients with radiologically confirmed infarction than in those without such confirmation (p = 0.048). The FSS score at 18 months was not correlated with any of the measured variables. High acute serum levels of glucose and IL-1β, and low IL1-ra and IL-9 may predict fatigue after AIS, indicating that the development of poststroke fatigue can be accounted for by the proinflammatory response associated with AIS. These novel findings support a new cytokine theory of fatigue after stroke. However, more research is needed to validate the results of this study.


Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.
Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2-/- mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2-/- mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1β, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11b+F4/80+ARG1+ cells with no alteration in CD11b+F4/80+NOS2+ cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2-/- mice. In bone marrow chimeras between Slc7a2-/- and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.


A cytokine study in children and adolescents with Tourette's disorder.
While immune system dysregulation has been postulated to play a role in Tourette's disorder (TD), most research has focused on the hypothesis of an autoimmune process similar to rheumatic fever. This study examined the potential role of cytokines, modulators of the immune system. We hypothesized that children with TD would have increased levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1 beta and IL-6, and decreased IL-2. We also explored whether comorbid obsessive compulsive disorder (OCD) had an effect on the cytokine profile of TD patients. Thirty-two children and adolescents with TD (27 males, ages 7-18 years), 17 with comorbid OCD (14 males), and 16 healthy comparison subjects (7 males, ages 9-19), were enrolled. Plasma cytokines were examined using an enzyme-linked immunosorbent assay. The Mann-Whitney and binary logistic regression tests were used to compare the groups. Only patients with comorbid OCD (TD+OCD; n=17) had significantly elevated IL-12 plasma levels compared to controls (2.73+/-5.12 pg/ml vs. 0.55+/-0.88 pg/ml, rank statistic=222.5; p<0.04). IL-2 was significantly higher in the TD+OCD subgroup compared to the non-OCD TD subgroup (0.74+/-0.29 pg/ml vs. 0.49+/-0.24 pg/ml, rank statistics=108.5; p<0.03). There were no other significant cytokine differences between groups. Findings suggest a role for IL-12 and IL-2 in TD, and that the TD+OCD subgroup may involve different neuroimmunological functions than the TD-OCD subgroup. Larger studies with medication-free patients should follow.


Rapid Response of Nitrogen Cycling Gene Transcription to Labile Carbon Amendments in a Soil Microbial Community.
Episodic inputs of labile carbon (C) to soil can rapidly stimulate nitrogen (N) immobilization by soil microorganisms. However, the transcriptional patterns that underlie this process remain unclear. In order to better understand the regulation of N cycling in soil microbial communities, we conducted a 48-h laboratory incubation with agricultural soil where we stimulated the uptake of inorganic N by amending the soil with glucose. We analyzed the metagenome and metatranscriptome of the microbial communities at four time points that corresponded with changes in N availability. The relative abundances of genes remained largely unchanged throughout the incubation. In contrast, glucose addition rapidly increased the transcription of genes encoding ammonium and nitrate transporters, enzymes responsible for N assimilation into biomass, and genes associated with the N regulatory network. This upregulation coincided with an increase in transcripts associated with glucose breakdown and oxoglutarate production, demonstrating a connection between C and N metabolism. When concentrations of ammonium were low, we observed a transient upregulation of genes associated with the nitrogen-fixing enzyme nitrogenase. Transcripts for nitrification and denitrification were downregulated throughout the incubation, suggesting that dissimilatory transformations of N may be suppressed in response to labile C inputs in these soils. These results demonstrate that soil microbial communities can respond rapidly to changes in C availability by drastically altering the transcription of N cycling genes.IMPORTANCE A large portion of activity in soil microbial communities occurs in short time frames in response to an increase in C availability, affecting the biogeochemical cycling of nitrogen. These changes are of particular importance as nitrogen represents both a limiting nutrient for terrestrial plants as well as a potential pollutant. However, we lack a full understanding of the short-term effects of labile carbon inputs on the metabolism of microbes living in soil. Here, we found that soil microbial communities responded to labile carbon addition by rapidly transcribing genes encoding proteins and enzymes responsible for inorganic nitrogen acquisition, including nitrogen fixation. This work demonstrates that soil microbial communities respond within hours to carbon inputs through altered gene expression. These insights are essential for an improved understanding of the microbial processes governing soil organic matter production, decomposition, and nutrient cycling in natural and agricultural ecosystems.


The impact of targeted molecular therapies on the level of renal cell carcinoma vena caval tumor thrombus.
Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.


Prescribing generic drugs using a generic name: Are we teaching it right?
The Indian Medical Council (Professional conduct, Etiquette and Ethics) Regulations, 2002, state that "Every physician should, as far as possible, prescribe drugs with generic names and he/she shall ensure that there is a rational prescription and use of drugs.". Undergraduate medical students are introduced to drug nomenclature early on during their pharmacology course. They are told that generic name or, more appropriately, non-proprietary name (usually international non-proprietary name INN), is to be used while writing prescriptions.


Diabetes resolution and hyperinsulinaemia after metabolic Roux-en-Y gastric bypass.
The global prevalence of type 2 diabetes mellitus and impaired glucose metabolism continues to rise in conjunction with the pandemic of obesity. The metabolic Roux-en-Y gastric bypass operation offers the successful resolution of diabetes in addition to sustained weight loss and excellent long-term outcomes in morbidly obese individuals. The procedure consists of the physiological BRAVE effects: (i) Bile flow alteration; (ii) Reduction of gastric size; (iii) Anatomical gut rearrangement and altered flow of nutrients; (iv) Vagal manipulation and (v) Enteric gut hormone modulation. This operation provides anti-diabetic effects through decreasing insulin resistance and increasing the efficiency of insulin secretion. These metabolic outcomes are achieved through weight-independent and weight-dependent mechanisms. These include the foregut, midgut and hindgut mechanisms, decreased inflammation, fat, adipokine and bile metabolism, metabolic modulation, shifts in gut microbial composition and intestinal gluconeogenesis. In a small minority of patients, gastric bypass results in hyperinsulinaemic hypoglycaemia that may lead to nesidioblastosis (pancreatic beta-cell hypertrophy with islet hyperplasia). Elucidating the precise metabolic mechanisms of diabetes resolution and hyperinsulinaemia after surgery can lead to improved operations and disease-specific procedures including 'diabetes surgery'. It can also improve our understanding of diabetes pathogenesis that may provide novel strategies for the management of metabolic syndrome and impaired glucose metabolism.


Effect of prenatal gamma irradiation during the late fetal period on the postnatal development of the mouse.
Pregnant Swiss albino mice were exposed to 0.3, 0.5, 1.0, or 1.5 Gy of gamma radiation on day 17 of gestation. Sham-exposed controls were examined for comparison. Exposed mice as well as controls were left to complete gestation and parturition. Pups were observed up to age 6 weeks; appearance of physiological markers (pinna detachment, eye opening, fur development, vaginal opening, and testes descent), postnatal mortality, body weight, body length, head length, head width, and tail length were recorded. A significant delay in fur development was observed at 0.3 Gy and in other physiological markers at doses above 0.3 Gy, while a significant increase in mortality and growth retardation occurred only at 1.0 and 1.5 Gy. Although congenital anomalies such as syndactyly and bent tail were observed at doses of 0.5-1.5 Gy, only syndactyly showed a statistically significant increase in frequency. A statistically significant lower body weight was observed during the first week of postnatal life, but body weights increased to normal levels by the second week in animals exposed to doses less than 1.0 Gy. At higher doses, low body weight persisted throughout the postnatal period. Head length and tail length showed a significant decrease from controls at 0.5-1.5 Gy, and the effect was evident from birth to age 6 weeks. But a similar effect on body length and head width was noticed only at 1.0 and 1.5 Gy. These studies indicate that even in the absence of any major morphological changes, normal development of physiological landmarks and postnatal growth can be impaired by fetal irradiation at 17 days p.c. (post coitus). Morphological changes appear to have a threshold between 0.3-0.5 Gy, while physiological marker effects may occur with a lower threshold.


Nanowire-based multifunctional antireflection coatings for solar cells.
Organic (P3HT/PCBM) solar cells are coated with ZnO nanowires as antireflection coatings and show up to 36% enhancement in efficiency. The improvement is ascribed to an effective refractive index which results in Fabry-Perot absorption bands which match the polymer band-gap. The effect is particularly pronounced at high light incidence angles. Simultaneously, the coating is used as a UV-barrier, demonstrating a 50% reduction in the rate of degradation of the polymers under accelerated lifetime testing. The coating also allows the surface of the solar cell to self-clean via two distinct routes. On one hand, photocatalytic degradation of organic material on ZnO is enhanced by the high surface area of the nanowires and quantified by dye degradation measurements. On the other, the surface of the nanowires can be functionalized to tune the water contact angle from superhydrophilic (16°) to superhydrophobic (152°), resulting in self-cleaning via the Lotus effect. The multifunctional ZnO nanowires are grown by a low cost, low temperature hydrothermal method, compatible with process limitations of organic solar cells.


Management and outcome of vein of Galen malformation.
To describe our experience of treating children with vein of Galen aneurysmal malformation (VGM) in a single UK centre between 2003 and 2008. Retrospective review of case notes and neuroimaging. 33 children were seen (26 neonates, seven infants), of whom 28 underwent endovascular treatment. Four were not offered treatment as they had evidence of severe diffuse brain injury at presentation; treatment was deferred in another who subsequently died. Seven children died (two of whom had endovascular treatment). Of the survivors (all treated), 13 (39%) are neurodevelopmentally intact, seven (21%) have mild neurodevelopmental impairment and the remaining six (18%) have significant neurological impairment. The authors were not able to identify clinical or radiological parameters which strongly predicted outcome. Of note, two children with initially low Bicêtre scores were neurologically intact after successful embolisation. The outlook for children with VGM is significantly better since the advent of endovascular treatment. Decisions about the appropriateness and timing of treatment should be taken by an experienced multidisciplinary team.


The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts.
In this study, we investigated apoptosis induced in human trisomic and diabetic fibroblasts by daunorubicin (DNR) and its derivative, idarubicin (IDA). The cells were incubated with DNR or IDA for 2 h and then cultured in a drug-free medium for a further 2-48 h. The apoptosis in the cultured cell lines was assessed by biochemical analysis. We found that both drugs induced a time dependent loss of mitochondrial membrane potential, and a significant increase in intracellular calcium and caspase-3 activity. Mitochondrial polarization and changes in the level of intracellular calcium were observed during the first 2-6 h after drug treatment. Caspase-3 activation occurred in the late stages of the apoptotic pathway. Our findings also demonstrated that idarubicin was more cytotoxic and more effective than daunorubicin in inducing apoptosis in trisomic and diabetic fibroblasts.


Paclitaxel (Taxol(R)) inhibits motility of paclitaxel-resistant human ovarian carcinoma cells.
The effect of paclitaxel on the adhesive and motility properties of human ovarian carcinoma cell lines was investigated. Paclitaxel significantly inhibited the motility of OVCAR 5, SK-OV-3, and HOC-1OTC ovarian carcinoma cell lines (IC50 = 2.1 x 10(-8), 2 x 10(-9), and 1.9 x 10(-8) m, respectively) but did not affect the adhesion of these cells to the subendothelial matrix. The association between inhibition of motility and cytotoxic activity was investigated using an A2780 subclone (1A9) and three paclitaxel-resistant variants (designated 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18). Although paclitaxel did not significantly affect the adhesion to subendothelial matrix of the sublines, it completely inhibited their migration. Inhibition of migration was similar in 1A9 cells and the resistant sublines, with an IC50 of 1 x 10(-8) for 1A9 cells and 5.4 x 10(-9), 1.1 x 10(-8), and 5.2 x 10(-9) m for 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively. Paclitaxel inhibited motility induced by soluble attractant (chemotaxis) and immobilized attractant (haptotaxis). Inhibition of cell motility occurred in the absence of an antiproliferative effect, because higher concentrations of paclitaxel were required to inhibit tumor cell proliferation (IC50 = 1.9 x 10(-7) and 4.6 x 10(-6), 1 x 10(-5), and 3.1 x 10(-6) m for 1A9 and 1A9/PTX22, 1A9/PTX10, and 1A9/PTX18, respectively). These data show that paclitaxel is a potent inhibitor of ovarian carcinoma cell motility and that this activity is independent of its cytotoxic activity.


The Listeria monocytogenes protein InlB is an agonist of mammalian phosphoinositide 3-kinase.
The Gram-positive pathogen Listeria monocytogenes induces its own internalization into some non-phagocytic mammalian cells by stimulating host tyrosine phosphorylation, phosphoinositide (PI) 3-kinase activity, and rearrangements in the actin cytoskeleton. Entry into many cultured cell lines is mediated by the bacterial protein InlB. Here we investigate the role of InlB in regulating mammalian signal transduction and cytoskeletal structure. Treatment of Vero cells with purified InlB caused rapid and transient increases in the lipid products of the PI 3-kinase p85-p110, tyrosine phosphorylation of the mammalian adaptor proteins Gab1, Cbl, and Shc, and association of these proteins with p85. InlB also stimulated large scale changes in the actin cytoskeleton (membrane ruffling), which were PI 3-kinase-dependent. These results identify InlB as the first reported non-mammalian agonist of PI 3-kinase and demonstrate similarities in the signal transduction events elicited by this bacterial protein and known agonists such as epidermal growth factor.


Identification of Chinese medicine syndromes in persistent insomnia associated with major depressive disorder: a latent tree analysis.
Chinese medicine (CM) syndrome (zheng) differentiation is based on the co-occurrence of CM manifestation profiles, such as signs and symptoms, and pulse and tongue features. Insomnia is a symptom that frequently occurs in major depressive disorder despite adequate antidepressant treatment. This study aims to identify co-occurrence patterns in participants with persistent insomnia and major depressive disorder from clinical feature data using latent tree analysis, and to compare the latent variables with relevant CM syndromes. One hundred and forty-two participants with persistent insomnia and a history of major depressive disorder completed a standardized checklist (the Chinese Medicine Insomnia Symptom Checklist) specially developed for CM syndrome classification of insomnia. The checklist covers symptoms and signs, including tongue and pulse features. The clinical features assessed by the checklist were analyzed using Lantern software. CM practitioners with relevant experience compared the clinical feature variables under each latent variable with reference to relevant CM syndromes, based on a previous review of CM syndromes. The symptom data were analyzed to build the latent tree model and the model with the highest Bayes information criterion score was regarded as the best model. This model contained 18 latent variables, each of which divided participants into two clusters. Six clusters represented more than 50 % of the sample. The clinical feature co-occurrence patterns of these six clusters were interpreted as the CM syndromes Liver qi stagnation transforming into fire, Liver fire flaming upward, Stomach disharmony, Hyperactivity of fire due to yin deficiency, Heart-kidney noninteraction, and Qi deficiency of the heart and gallbladder. The clinical feature variables that contributed significant cumulative information coverage (at least 95 %) were identified. Latent tree model analysis on a sample of depressed participants with insomnia revealed 13 clinical feature co-occurrence patterns, four mutual-exclusion patterns, and one pattern with a single clinical feature variable.


Analysis of macular OCT images using deformable registration.
Optical coherence tomography (OCT) of the macula has become increasingly important in the investigation of retinal pathology. However, deformable image registration, which is used for aligning subjects for pairwise comparisons, population averaging, and atlas label transfer, has not been well-developed and demonstrated on OCT images. In this paper, we present a deformable image registration approach designed specifically for macular OCT images. The approach begins with an initial translation to align the fovea of each subject, followed by a linear rescaling to align the top and bottom retinal boundaries. Finally, the layers within the retina are aligned by a deformable registration using one-dimensional radial basis functions. The algorithm was validated using manual delineations of retinal layers in OCT images from a cohort consisting of healthy controls and patients diagnosed with multiple sclerosis (MS). We show that the algorithm overcomes the shortcomings of existing generic registration methods, which cannot be readily applied to OCT images. A successful deformable image registration algorithm for macular OCT opens up a variety of population based analysis techniques that are regularly used in other imaging modalities, such as spatial normalization, statistical atlas creation, and voxel based morphometry. Examples of these applications are provided to demonstrate the potential benefits such techniques can have on our understanding of retinal disease. In particular, included is a pilot study of localized volumetric changes between healthy controls and MS patients using the proposed registration algorithm.


Principal component analysis to assess the composition and fate of impurities in a large river-embedded reservoir: Qingcaosha Reservoir.
Qingcaosha Reservoir (QR) is the largest river-embedded reservoir in east China, which receives its source water from the Yangtze River (YR). The temporal and spatial variations in dissolved organic matter (DOM), chromophoric DOM (CDOM), nitrogen, phosphorus and phytoplankton biomass were investigated from June to September in 2012 and were integrated by principal component analysis (PCA). Three PCA factors were identified: (1) phytoplankton related factor 1, (2) total DOM related factor 2, and (3) eutrophication related factor 3. Factor 1 was a lake-type parameter which correlated with chlorophyll-a and protein-like CDOM (r = 0.793 and r = 0.831, respectively). Factor 2 was a river-type parameter which correlated with total DOC and humic-like CDOM (r = 0.668 and r = 0.726, respectively). Factor 3 correlated with total nitrogen and phosphorus (r = 0.864 and r = 0.621, respectively). The low flow speed, self-sedimentation and nutrient accumulation in QR resulted in increases in PCA factor 1 scores (phytoplankton biomass and derived CDOM) in the spatial scale, indicating a change of river-type water (YR) to lake-type water (QR). In summer, the water temperature variation induced a growth-bloom-decay process of phytoplankton combined with the increase of PCA factor 2 (humic-like CDOM) in the QR, which was absent in the YR.


Effect of defibrotide on platelet function.
Defibrotide, a polydeoxyribonucleotide, has been found to modulate endothelial cell function, causing an increase in tissue plasminogen activator (t-PA) levels, a decrease in plasminogen activator inhibitor (PAI) levels, and an increase in prostaglandin I2 (PGI2) formation in humans. Defibrotide has no direct anticoagulant effect but has a synergistic action with heparin. A strong antithrombotic effect has been observed in animal models. Thus, defibrotide has a beneficial effect in cases of deep venous thrombosis (DVT), peripheral obliterative vascular disorder (POVD), stroke, vasculitis, and thromboembolism. Defibrotide also inhibits platelet function and activation. A significant decrease in platelet aggregate formation on the suture line in microarterial anastomosis in rats is one way defibrotide can inhibit platelet function and activation. In humans, a slight prolongation' of the lag period in collagen-induced aggregation has been observed. In addition, a slight decrease in the maximum amplitude of the secondary wave of ADP and adrenalin-induced aggregations was also found. Platelet adhesion is diminished, the platelet differential count on formvar membrane is altered, and platelet aggregate formation is significantly inhibited. With an increase in platelet cyclic AMP (cAMP) content and a decrease in malonyl dialdehyde (MDA) and thromboxane B2 (TXB2) formation, the levels of platelet secretion products such as PF-4 and beta-thromboglobulin (beta-TG) in plasma decreased progressively. It was also demonstrated that the 14C-glucose transport defect of the platelet membrane of atherosclerotic patients was partially corrected with defibrotide treatment.


Detection methods for neural autoantibodies.
Antibodies are part of the adaptive immune response that provides protection against microorganisms. In rare instances individuals can develop antibodies that bind to normal central nervous system structures. These antibodies have been classified into two groups depending on the subcellular location of their target antigens. Biomarker antibodies bind to cytosolic or nuclear targets. They do not impact on the normal function of the cell, but are most often paraneoplastic biomarkers that may suggest screening for different cancers. The second, more recently discovered group of antibodies recognize the three-dimensional structure of native proteins that are accessible on the cell surface. Understanding of this important difference is reflected in the nature of assays used to detect antibodies in these two groups. Western blots and, more recently, line blots, both of which use linear, denatured targets, are used to detect antibodies to intracellular targets. Newer assays have been developed that maintain the native structure of protein targets to permit detection of antibodies that recognize extracellular targets. In this chapter we describe the methods used to detect both antibody types, and discuss assay cut-offs, sample handling, and which biologic fluid to test.


The effect of Medicare Part D on drug and medical spending.
It is not known what effect the increased use of prescription drugs by enrollees in Medicare Part D has had on spending for other medical care. We compared spending for prescription drugs and other medical care 2 years before the implementation of Part D in January 2006 with such expenditures 2 years after the program's implementation in four groups of elderly beneficiaries: Medicare Advantage enrollees with stable, uncapped, employer-based drug coverage throughout the study period (no-cap group), those who had no previous drug coverage, and those who had previous limited benefits (with either a $150 or a $350 quarterly cap) before they were covered by Part D in 2006. Between December 2005 and December 2007, as compared with the increase in the no-cap group, the increase in total monthly drug spending was $41 higher (95% confidence interval [CI], $33 to $50) (74%) among enrollees with no previous drug coverage, $27 higher (95% CI, $20 to $34) (27%) among those with a previous $150 quarterly cap, and $13 higher (95% CI, $8 to $18) (11%) among those with a previous $350 cap. The use of both lipid-lowering and antidiabetic medications rose in the groups with no or minimal previous drug coverage. As compared with expenditures in the no-cap group, monthly medical expenditures (excluding drugs) were $33 lower (95% CI, $29 to $37) in the group with no previous coverage and $46 lower (95% CI, $29 to $63) in the group with a previous $150 quarterly cap, whereas medical spending was $30 higher (95% CI, $25 to $36) in the group with a previous $350 cap. Enrollment in Medicare Part D was associated with increased spending on prescription drugs. Groups that had no or minimal drug coverage before the implementation of Part D had reductions in other medical spending that approximately offset the increased spending on drugs, but medical spending increased in the group that had more generous previous coverage.


Spontaneous chordoma: a case report on a female UM-HET3 mouse from the SLAM study.
A female UM-HET3 mouse from the Study of Longitudinal Aging in Mice (SLAM) was euthanized at 164 weeks of age due to hind limb weakness. Necropsy and histological analysis revealed that the most probable cause of the clinical finding was the compression of the thoracolumbar segment of the spinal cord by herniated intervertebral disks. In addition, a spontaneous chordoma was incidentally found in the coccygeal bones. Given the rarity of this type of tumor, bio-clinical annotations acquired throughout lifespan, detailed histopathological assessment, and comparative clinical-pathological correlations for this mouse are presented and discussed.


Mutational analysis of the repeated open reading frames, ORFs 63 and 70 and ORFs 64 and 69, of varicella-zoster virus.
Varicella-zoster virus (VZV) open reading frame 63 (ORF63), located between nucleotides 110581 and 111417 in the internal repeat region, encodes a nuclear phosphoprotein which is homologous to herpes simplex virus type 1 (HSV-1) ICP22 and is duplicated in the terminal repeat region as ORF70 (nucleotides 118480 to 119316). We evaluated the role of ORFs 63 and 70 in VZV replication, using recombinant VZV cosmids and PCR-based mutagenesis to make single and dual deletions of these ORFs. VZV was recovered within 8 to 10 days when cosmids with single deletions were transfected into melanoma cells along with the three intact VZV cosmids. In contrast, VZV was not detected in transfections carried out with a dual deletion cosmid. Infectious virus was recovered when ORF63 was cloned into a nonnative AvrII site in this cosmid, confirming that failure to generate virus was due to the dual ORF63/70 deletion and that replication required at least one gene copy. This requirement may be related to our observation that ORF63 interacts directly with ORF62, the major immediate-early transactivating protein of VZV. ORF64 is located within the inverted repeat region between nucleotides 111565 and 112107; it has some homology to the HSV-1 Us10 gene and is duplicated as ORF69 (nucleotides 117790 to 118332). ORF64 and ORF69 were deleted individually or simultaneously using the VZV cosmid system. Single deletions of ORF64 or ORF69 yielded viral plaques with the same kinetics and morphology as viruses generated with the parental cosmids. The dual deletion of ORF64 and ORF69 was associated with an abnormal plaque phenotype characterized by very large, multinucleated syncytia. Finally, all of the deletion mutants that yielded recombinants retained infectivity for human T cells in vitro and replicated efficiently in human skin in the SCIDhu mouse model of VZV pathogenesis.