A Review Of The Relevant Embryology, Pathohistology, And Anatomy Of The Left Atrial Appendage For The Invasive Cardiac Electrophysiologist.
The three-dimensional morphology of the left atrial appendage provides the substrate for thrombus generation, and is a harbinger for embolic material due to its direct connection to the left-sided circulation. Appreciating the development of the appendage from mesodermal layer to its adult form provides the basis to improve exclusion from the atrial circulation, and thereby can lead to a significant reduction in stroke risk. This process also provides insight into the role of the left atrial appendage as an endocrine organ, its involvement in fluid homeostasis, and its connection to the autonomic nervous system. Knowledge of the surrounding structural arrangement is critical to identify landmarks from both an endocardial and epicardial perspective to improve targeted device placement. Furthermore, correlation of the left atrial appendage body, neck, and ostium to the surrounding anatomy can also improve both procedural efficacy and safety. In addition, a working knowledge of the regional anatomy adds a prudent degree of awareness for procedural complications, and allows for early identification and timely intervention as these situations arise. A detailed understanding of the left atrial appendage embryology, histology, and gross anatomy is imperative to identify the correct device and approach for each individual patient. In addition, this increased awareness can identify areas that are in need of further innovation, and thus provide the ability to adapt and refine existing technologies to overcome pitfalls currently facing catheter-based approaches.


Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B.
It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD.


Association of hip pain with radiographic evidence of hip osteoarthritis: diagnostic test study.
Is there concordance between hip pain and radiographic hip osteoarthritis? In this diagnostic test study, pelvic radiographs were assessed for hip osteoarthritis in two cohorts: the Framingham Osteoarthritis Study (community of Framingham, Massachusetts) and the Osteoarthritis Initiative (a multicenter longitudinal cohort study of osteoarthritis in the United States). Using visual representation of the hip joint, participants reported whether they had hip pain on most days and the location of the pain: anterior, groin, lateral, buttocks, or low back. In the Framingham study, participants with hip pain were also examined for hip pain with internal rotation. The authors analysed the agreement between radiographic hip osteoarthritis and hip pain, and for those with hip pain suggestive of hip osteoarthritis they calculated the sensitivity, specificity, positive predictive value, and negative predictive value of radiographs as the diagnostic test. In the Framingham study (n=946), only 15.6% of hips in patients with frequent hip pain showed radiographic evidence of hip osteoarthritis, and 20.7% of hips with radiographic hip osteoarthritis were frequently painful. The sensitivity of radiographic hip osteoarthritis for hip pain localised to the groin was 36.7%, specificity 90.5%, positive predictive value 6.0%, and negative predictive value 98.9%. Results did not differ much for hip pain at other locations or for painful internal rotation. In the Osteoarthritis Initiative study (n=4366), only 9.1% of hips in patients with frequent pain showed radiographic hip osteoarthritis, and 23.8% of hips with radiographic hip osteoarthritis were frequently painful. The sensitivity of definite radiographic hip osteoarthritis for hip pain localised to the groin was 16.5%, specificity 94.0%, positive predictive value 7.1%, and negative predictive value 97.6%. Results also did not differ much for hip pain at other locations. Hip pain was not present in many hips with radiographic osteoarthritis, and many hips with pain did not show radiographic hip osteoarthritis. Most older participants with a high suspicion for clinical hip osteoarthritis (groin or anterior pain and/or painful internal rotation) did not have radiographic hip osteoarthritis, suggesting that in many cases, hip osteoarthritis might be missed if diagnosticians relied solely on hip radiographs. See the full paper on thebmj.com for funding. The authors have no competing interests. Additional data are available from firstname.lastname@example.com.


Forensic evaluations in psychiatry.
Forensic psychiatry is an important subspecialty of psychiatry. Forensic psychiatrists play an important role in the society in assisting the judiciary in many complicated cases. In India, forensic psychiatry work is undertaken mostly by the general psychiatrists. Forensic psychiatric assessments are often associated with an element of anxiety or fear for a young psychiatrist. The present paper aims at familiarizing the readers with forensic evaluation in various situations so that they are able to carry out the assessments in real-life situations comfortably. Various steps of forensic assessment in different situations are discussed in the background of real-life cases. Assessment areas include criminal responsibility, fitness to plead, issue of guardianship, assessment of mental status, testamentary capacity and others. The paper gives some general guidelines on forensic psychiatric assessment in practical situations in our country. The readers are advised to refer to the standard textbooks and the Indian law for further details.


Slow light based on coherent hole-burning in a Doppler broadened three-level Lambda-type atomic system.
We show theoretically that the propagation of light can be slowed down considerably using the method of coherent hole-burning in a Doppler broadened three-level lambda-type atomic medium without the Doppler-free configurations. The reduction of group velocity of light pulse is achieved by the application of a saturating beam and a strong coupling beam which produce a narrow spectral hole-burning at resonance. We can obtain a larger group index than that using the method of saturation absorption spectroscopy in Doppler-broadened two-level atomic systems.


Interaction kinetic and structural dynamic analysis of ligand binding to acetylcholine-binding protein.
The mechanism of agonist interactions with Cys-loop ligand-gated ion channels has been studied using the acetylcholine-binding protein (AChBP) from Lymnaea stagnalis as a model protein and acetylcholine, nicotine, epibatidine, and a series of substituted quinuclidines as ligands. A biosensor-based assay for direct interaction studies of immobilized AChBP and small molecule ligands was developed. It allowed the characterization of the interaction kinetics of the ligands and the structural dynamics of the protein. The interactions with AChBP were very sensitive to variations in the experimental conditions and showed several types of complexities. These could be resolved into two types of ligand-induced secondary effects with different kinetics, representing fast and slow conformational changes. The data could be rationalized in a mechanistic model, and a structural interpretation of the interaction was obtained by molecular modeling involving induced fit and loop flexibility simulations. The data suggest that AChBP exhibits ligand-induced structural dynamics, as expected for the ligand gating mechanism of Cys-loop receptors. It shows that the formation of the initial encounter complex between AChBP and ligands is very rapid, in accordance with the functional characteristics required of neurotransmission. These developed procedures will enable further exploration of the mechanism of Cys-loop receptor function and the identification of specific ligands suitable for pharmacological use.


Integrating structured biological data by Kernel Maximum Mean Discrepancy.
Many problems in data integration in bioinformatics can be posed as one common question: Are two sets of observations generated by the same distribution? We propose a kernel-based statistical test for this problem, based on the fact that two distributions are different if and only if there exists at least one function having different expectation on the two distributions. Consequently we use the maximum discrepancy between function means as the basis of a test statistic. The Maximum Mean Discrepancy (MMD) can take advantage of the kernel trick, which allows us to apply it not only to vectors, but strings, sequences, graphs, and other common structured data types arising in molecular biology. We study the practical feasibility of an MMD-based test on three central data integration tasks: Testing cross-platform comparability of microarray data, cancer diagnosis, and data-content based schema matching for two different protein function classification schemas. In all of these experiments, including high-dimensional ones, MMD is very accurate in finding samples that were generated from the same distribution, and outperforms its best competitors. We have defined a novel statistical test of whether two samples are from the same distribution, compatible with both multivariate and structured data, that is fast, easy to implement, and works well, as confirmed by our experiments. http://www.dbs.ifi.lmu.de/~borgward/MMD.


Expectation in perceptual decision making: neural and computational mechanisms.
Sensory signals are highly structured in both space and time. These structural regularities in visual information allow expectations to form about future stimulation, thereby facilitating decisions about visual features and objects. Here, we discuss how expectation modulates neural signals and behaviour in humans and other primates. We consider how expectations bias visual activity before a stimulus occurs, and how neural signals elicited by expected and unexpected stimuli differ. We discuss how expectations may influence decision signals at the computational level. Finally, we consider the relationship between visual expectation and related concepts, such as attention and adaptation.


How Internet technology can improve the quality of care for substance use disorders.
By allowing for the efficient delivery of instructional content and the secure collection of self-report data regarding substance use and related problems, the Internet has tremendous potential to improve the effectiveness and accessibility of addiction treatment services. This article discusses some of the ways in which Internet technology can facilitate, complement and support the process of traditional clinician-delivered treatment for individuals with substance use disorders. Internet applications are being used to support a range of activities including (a) the assessment and feedback process that constitutes a central feature of brief motivational interventions, (b) the concurrent monitoring of individual level outcomes among patients who are currently enrolled in addiction treatment programs, (c) the continuing care and ongoing recovery of patients who have completed treatment, and (d) the delivery of clinical training in evidence based practices for addiction treatment providers. This emerging body of literature suggests that addiction counselors and program administrators can enhance the quality of clinician-delivered treatment by incorporating internet applications into existing processes of care. Internet applications provide an unparalleled opportunity to engage patients in the treatment process, incorporate real-time data into treatment planning, prevent relapse, and promote evidence-based treatment approaches.


Estimating sources and sinks of malaria parasites in Madagascar.
In areas where malaria epidemiology is spatially and temporally heterogeneous, human-mediated parasite importation can result in non-locally acquired clinical cases and outbreaks in low-transmission areas. Using mobility estimates derived from the mobile phone data and spatial malaria prevalence data, we identify travel routes relevant to malaria transmission in Madagascar. We find that the primary hubs of parasite importation are in a spatially connected area of the central highlands. Surprisingly, sources of these imported infections are not spatially clustered. We then related these source locations directly to clinical cases in the low-transmission area of the capital. We find that in the capital, a major sink, the primary sources of infection are along the more populated coastal areas, although these sources are seasonally variable. Our results have implications for targeting interventions at source locations to achieve local or national malaria control goals.


Looking for avian influenza in remote areas. A case study in Northern Vietnam.
Epidemiological surveys of avian influenza infections rarely focus on backyard poultry systems in remote locations because areas with low levels of poultry production are considered to have little influence on the emergence, re-emergence, persistence or spread of avian influenza viruses. In addition, routine disease investigations in remote areas often are neglected due to the lower availability and relatively high cost of veterinary services there. A bank of avian sera collected in 2005 from ethnic minority households in Ha Giang province (Northern Vietnam), located on the Chinese border, was analysed to estimate the seroprevalence of avian influenza virus (AIV) during a H5N1 epidemic and to identify potential risk factors for infection. The results suggest that the chicken population had been exposed to AIV with a seroprevalence rate of 7.2% [1.45; 10.5]. The H5 and H9 subtypes were identified with a seroprevalence of 3.25% [2.39; 4.11] and 1.12% [0.61; 1.63], respectively. The number of inhabitants in a village and the distance to the main national road were the most influential risk factors of AIV infection, and high-risk clusters were located along the road leading to China. These two results suggest a virus spread through commercial poultry exchanges and a possible introduction of AIV from southern China. Remote areas and small-scale farms may play an under-estimated role in the spread and persistence of AIV.


Antibody responses in primary HIV-1 infection.
HIV-1 establishes persistent infections characterized by high levels of viral replication. This finding is remarkable given the presence of apparently vigorous HIV-specific cellular and humoral immune responses. We review the dynamics of antibody responses and viral escape from these responses during primary HIV-1 infection. Many B cell dysfunctions appear early in HIV-1 infection, and compromise humoral responses to HIV-1 and other pathogens. The rate of viral escape from autologous neutralization varies greatly between individuals with primary HIV-1 infection, and is on average higher than the rate of escape in chronically infected individuals. Mutations, changes in glycosylation and insertions and deletions in the viral envelope may all contribute to viral escape. There may be differences in neutralization sensitivity and evolution of neutralization escape between different HIV-1 subtypes. Although several broadly neutralizing monoclonal antibodies have been identified, the factors that contribute to the development of broad heterologous responses remain unclear. The rapid escape of HIV-1 in response to neutralizing antibodies and the plethora of B cell dysfunctions that occur during HIV infection pose significant obstacles to the design of an effective HIV-1 vaccine. The study of large cohorts of individuals enrolled during primary HIV-1 infection using high-throughput immunoassays, sequencing of the virus and the host, and new statistical tools may help to elucidate the pathways of viral escape, to elicit broadly neutralizing antibody responses, and to suggest means of minimizing the impact of HIV-1 on humoral immunity.


Science of odor as a potential health issue.
Historically, unpleasant odors have been considered warning signs or indicators of potential risks to human health but not necessarily direct triggers of health effects. However, citizen complaints to public health agencies suggest that odors may not simply serve as a warning of potential risks but that odor sensations themselves may cause health symptoms. Mal-odors emitted from large animal production facilities and wastewater treatment plants, for example, elicit complaints of eye, nose, and throat irritation, headache, nausea, diarrhea, hoarseness, sore throat, cough, chest tightness, nasal congestion, palpitations, shortness of breath, stress, drowsiness, and alterations in mood. There are at least three mechanisms by which ambient odors may produce health symptoms. First, symptoms can be induced by exposure to odorants (compounds with odor properties) at levels that also cause irritation or other toxicological effects. That is, irritation--rather than the odor--is the cause of the health symptoms, and odor (the sensation) simply serves as an exposure marker. Second, health symptoms from odorants at non-irritant concentrations can be due to innate (genetically coded) or learned aversions. Third, symptoms may be due to a co-pollutant (such as endotoxin) that is part of an odorant mixture. Objective biomarkers of health symptoms must be obtained, however, to determine if health complaints constitute health effects. One industry that is receiving much attention, worldwide, related to this subject is concentrated animal production agriculture. Sustainability of this industry will likely necessitate the development of new technologies to mitigate odorous aerial emissions. Examples of such "environmentally superior technologies" (EST) developed under the initiative sponsored through agreements between the Attorney General of North Carolina and Smithfield Foods and Premium Standard Farms are described.


Buckminsterfullerane: the inside story.
The stereoisomers of fully reduced buckminsterfullerene C(60)H(60) have been investigated with the molecular mechanics program MM3. Although it might be expected that chemical reduction would deliver all of the hydrogens to the outside, the symmetric structure produced in this way is predicted to be highly strained. Moving just one hydrogen to the inside is predicted to decrease the energy by 53 kilocalories (kcal) per mole. Putting additional hydrogens on the inside further lowers the predicted energy (depending on the steric relations between them). The miniimum energy isomer is predicted to have ten hydrogens inside with C(1) symmetry and to have an energy 400 kcal/mol less than that of the all-outside isomer. These results suggest that a process which could achieve isomerization would produce a mixture of isomers, most of which with ten hydrogens on the inside.


The first prototype of spot-scanning proton arc treatment delivery.
We report the first prototype of spot-scanning arc treatment (SPArc) delivery on a clinical proton beam therapy machine and evaluate its delivery accuracy and efficiency. A new module called Proton Dynamic Arc Delivery (PDAD) was developed to allow simultaneously delivering spot-scanning proton beam treatments while rotating the gantry on an IBA Proteus®One proton machine. A series of measurements was performed to validate the basic beam characteristics. Subsequently, patient specific quality assurance (QA) of a brain SPArc plan was performed. Total SPArc treatment delivery time was also recorded and compared to the clinically delivered intensity modulated proton therapy (IMPT) treatment time. Finally, the log file of the SPArc plan was analyzed and processed to reconstruct the actual delivered dose. All the basic beam characteristics were confirmed in the PDAD mode, similar as those measured using fixed gantry deliveries in clinical mode. The brain SPArc plan with similar or superior plan quality was delivered in 4 mins compared to total 11 mins for the clinical treatment of the three-field IMPT plan. The patient QA result showed a good agreement between the measured and calculated dose distributions with the gamma index of 98.6% (3%/3 mm). The analysis of the log file confirmed the accuracy of the SPArc plan delivery, with the gamma index of 98.3% (1%/1 mm) between reconstructed and the planned doses. The first prototype of dynamic proton arc delivery on a clinical proton therapy system was successfully performed. The measurements and simulations demonstrated the feasibility of SPArc treatment within the clinical requirements.


Condition-dependent expression of pre- and postcopulatory sexual traits in guppies.
Female choice can impose persistent directional selection on male sexually selected traits, yet such traits often exhibit high levels of phenotypic variation. One explanation for this paradox is that if sexually selected traits are costly, only the fittest males are able to acquire and allocate the resources required for their expression. Furthermore, because male condition is dependent on resource allocation, condition dependence in sexual traits is expected to underlie trade-offs between reproduction and other life-history functions. In this study we test these ideas by experimentally manipulating diet quality (carotenoid levels) and quantity in the guppy (Poecilia reticulata), a livebearing freshwater fish that is an important model for understanding relationships between pre- and post-copulatory sexually selected traits. Specifically, we test for condition dependence in the expression of pre- and postcopulatory sexual traits (behavior, ornamentation, sperm traits) and determine whether diet manipulation mediates relationships among these traits. Consistent with prior work we found a significant effect of diet quantity on the expression of both pre- and postcopulatory male traits; diet-restricted males performed fewer sexual behaviors and exhibited significant reductions in color ornamentation, sperm quality, sperm number, and sperm length than those fed ad libitum. However, contrary to our expectations, we found no significant effect of carotenoid manipulation on the expression of any of these traits, and no evidence for a trade-off in resource allocation between pre- and postcopulatory episodes of sexual selection. Our results further underscore the sensitivity of behavioral, ornamental, and ejaculate traits to dietary stress, and highlight the important role of condition dependence in maintaining the high variability in male sexual traits.


Impact of a managed-Medicare physical activity benefit on health care utilization and costs in older adults with diabetes.
The purpose of this article was to determine the effects of a managed-Medicare physical activity benefit on health care utilization and costs among older adults with diabetes. This retrospective cohort study used administrative and claims data for 527 patients from a diabetes registry of a staff model HMO. Participants (n = 163) were enrolled in the HMO for at least 1 year before joining the Enhanced Fitness Program (EFP), a community-based physical activity program for which the HMO pays for each EFP class attended. Control subjects were matched to participants according to the index date of EFP enrollment (n = 364). Multivariate regression models were used to determine 12-month postindex differences in health care use and costs between participants and control subjects while adjusting for age, sex, chronic disease burden, EFP attendance, prevention score, heart registry, and respective baseline use and costs. Participants and control subjects were similar at baseline with respect to age (75 +/- 5.5 years), A1C levels (7.4 +/- 1.4%), chronic disease burden, prevention score, and health care use and costs. After exposure to the program, there was a trend toward lower hospital admissions in EFP participants compared with control subjects (13.5 vs. 20.9%, P = 0.08), whereas total health care costs were not different (P = 0.39). EFP participants who attended > or = 1 exercise session/week on average had approximately 41% less total health care costs compared with those attending <1 session/week (P = 0.03) and with control subjects (P = 0.02). Although elective participation in a community-based physical activity benefit at any level was not associated with lower inpatient or total health care costs, greater participation in the program may lower health care costs. These findings warrant additional investigations to determine whether policies to offer and promote a community-based physical activity benefit in older adults with diabetes can reduce health care costs.


The costs of accessible quality assured syphilis diagnostics: informing quality systems for rapid syphilis tests in a Tanzanian setting.
To determine the costs of Rapid Syphilis Test (RSTs) as compared with rapid plasma reagin (RPR) when implemented in a Tanzanian setting, and to determine the relative impact of a quality assurance (QA) system on the cost of RST implementation. The incremental costs for RPR and RST screening programmes in existing antenatal care settings in Geita District, Tanzania were collected for 9 months in subsequent years from nine health facilities that varied in size, remoteness and scope of antenatal services. The costs per woman tested and treated were estimated for each facility. A sensitivity analysis was constructed to determine the impact of parameter and model uncertainty. In surveyed facilities, a total of 6362 women were tested with RSTs compared with 224 tested with RPR. The range of unit costs was $1.76-$3.13 per woman screened and $12.88-$32.67 per woman treated. Unit costs for the QA system came to $0.51 per woman tested, of which 50% were attributed to salaries and transport for project personnel. Our results suggest that rapid syphilis diagnostics are very inexpensive in this setting and can overcome some critical barriers to ensuring universal access to syphilis testing and treatment. The additional costs for implementation of a quality system were found to be relatively small, and could be reduced through alterations to the programme design. Given the potential for a quality system to improve quality of diagnosis and care, we recommend that QA activities be incorporated into RST roll-out.


Statistical inference for noisy nonlinear ecological dynamic systems.
Chaotic ecological dynamic systems defy conventional statistical analysis. Systems with near-chaotic dynamics are little better. Such systems are almost invariably driven by endogenous dynamic processes plus demographic and environmental process noise, and are only observable with error. Their sensitivity to history means that minute changes in the driving noise realization, or the system parameters, will cause drastic changes in the system trajectory. This sensitivity is inherited and amplified by the joint probability density of the observable data and the process noise, rendering it useless as the basis for obtaining measures of statistical fit. Because the joint density is the basis for the fit measures used by all conventional statistical methods, this is a major theoretical shortcoming. The inability to make well-founded statistical inferences about biological dynamic models in the chaotic and near-chaotic regimes, other than on an ad hoc basis, leaves dynamic theory without the methods of quantitative validation that are essential tools in the rest of biological science. Here I show that this impasse can be resolved in a simple and general manner, using a method that requires only the ability to simulate the observed data on a system from the dynamic model about which inferences are required. The raw data series are reduced to phase-insensitive summary statistics, quantifying local dynamic structure and the distribution of observations. Simulation is used to obtain the mean and the covariance matrix of the statistics, given model parameters, allowing the construction of a 'synthetic likelihood' that assesses model fit. This likelihood can be explored using a straightforward Markov chain Monte Carlo sampler, but one further post-processing step returns pure likelihood-based inference. I apply the method to establish the dynamic nature of the fluctuations in Nicholson's classic blowfly experiments.


Phytoplankton in the ocean use non-phosphorus lipids in response to phosphorus scarcity.
Phosphorus is an obligate requirement for the growth of all organisms; major biochemical reservoirs of phosphorus in marine plankton include nucleic acids and phospholipids. However, eukaryotic phytoplankton and cyanobacteria (that is, 'phytoplankton' collectively) have the ability to decrease their cellular phosphorus content when phosphorus in their environment is scarce. The biochemical mechanisms that allow phytoplankton to limit their phosphorus demand and still maintain growth are largely unknown. Here we show that phytoplankton, in regions of oligotrophic ocean where phosphate is scarce, reduce their cellular phosphorus requirements by substituting non-phosphorus membrane lipids for phospholipids. In the Sargasso Sea, where phosphate concentrations were less than 10 nmol l-1, we found that only 1.3 +/- 0.6% of phosphate uptake was used for phospholipid synthesis; in contrast, in the South Pacific subtropical gyre, where phosphate was greater than 100 nmol l-1, plankton used 17 6% (ref. 6). Examination of the planktonic membrane lipids at these two locations showed that classes of sulphur- and nitrogen-containing membrane lipids, which are devoid of phosphorus, were more abundant in the Sargasso Sea than in the South Pacific. Furthermore, these non-phosphorus, 'substitute lipids' were dominant in phosphorus-limited cultures of all of the phytoplankton species we examined. In contrast, the marine heterotrophic bacteria we examined contained no substitute lipids and only phospholipids. Thus heterotrophic bacteria, which compete with phytoplankton for nutrients in oligotrophic regions like the Sargasso Sea, appear to have a biochemical phosphorus requirement that phytoplankton avoid by using substitute lipids. Our results suggest that phospholipid substitutions are fundamental biochemical mechanisms that allow phytoplankton to maintain growth in the face of phosphorus limitation.


A probabilistic classifier ensemble weighting scheme based on cross-validated accuracy estimates.
Our hypothesis is that building ensembles of small sets of strong classifiers constructed with different learning algorithms is, on average, the best approach to classification for real-world problems. We propose a simple mechanism for building small heterogeneous ensembles based on exponentially weighting the probability estimates of the base classifiers with an estimate of the accuracy formed through cross-validation on the train data. We demonstrate through extensive experimentation that, given the same small set of base classifiers, this method has measurable benefits over commonly used alternative weighting, selection or meta-classifier approaches to heterogeneous ensembles. We also show how an ensemble of five well-known, fast classifiers can produce an ensemble that is not significantly worse than large homogeneous ensembles and tuned individual classifiers on datasets from the UCI archive. We provide evidence that the performance of the cross-validation accuracy weighted probabilistic ensemble (CAWPE) generalises to a completely separate set of datasets, the UCR time series classification archive, and we also demonstrate that our ensemble technique can significantly improve the state-of-the-art classifier for this problem domain. We investigate the performance in more detail, and find that the improvement is most marked in problems with smaller train sets. We perform a sensitivity analysis and an ablation study to demonstrate the robustness of the ensemble and the significant contribution of each design element of the classifier. We conclude that it is, on average, better to ensemble strong classifiers with a weighting scheme rather than perform extensive tuning and that CAWPE is a sensible starting point for combining classifiers.


Developmental expression of the neurotensin gene in the rat liver.
This study determined whether the neurotensin gene is expressed during early development of the liver. Neurotensin (NT), a gut tridecapeptide localized mainly to the distal small bowel and brain of adults, is an important hormone regulating gut motility, secretion and mucosal growth. Expression of NT peptide and the gene is found in fibrolamellar hepatocarcinomas, a variant of hepatocellular carcinoma, but not in the normal adult liver. Northern and in situ hybridization techniques were used to determine expression of the neurotensin gene (NT/N) in the normal developing liver. NT/N is expressed in the fetal and early postnatal rat liver, but expression is repressed in the liver of the adult. In situ hybridization confirms the authors' Northern data and demonstrates a random distribution of NT/N expression in the fetal and 3-day postnatal liver. The authors conclude from this study that NT/N is expressed during early development of the rat liver with subsequent repression in the adult. NT/N may be reexpressed with malignant transformation of the liver.


Effect of Two Different Types of Olympic Rotation Order on Cardiovascular and Metabolic Variables in Men's Artistic Gymnastics.
The rotation sequence-order differs from a gymnast to another according to the draw at the time of the qualifying competitions in men's artistic gymnastics. Only the six best gymnasts start on the floor exercises, the others could start on any of the other five apparatuses. It has been demonstrated that some gymnastics events are physiologically less taxing than others; hence some gymnasts could experience lower and/or higher levels of cardiovascular and metabolic stress compared to others, depending on the apparatus they start with. In this regard, the objective of this investigation was to compare cardiovascular and metabolic variables between two different types of Olympic rotation-order; one began with the floor exercises and the other began with the pommel horse. Six elite male gymnasts took part in this investigation. Heart rates, synchronized with real-time video acquisition, as well as capillary lactate concentration following each apparatus routine were monitored. Cardiovascular and metabolic stresses were significantly higher when gymnasts started their rotation with the pommel horse in all apparatuses except the pommel horse. The floor exercises' score was significantly affected when gymnasts ended up their competition on this apparatus. As a conclusion, starting gymnastics' competition on the floor exercises implicates less cardiovascular and metabolic stress associated with better performance compared with the other rotation order. As a matter of fact, best gymnasts who start on this apparatus could have a slight advantage compared with the other athletes.


Ethics of research on survivors of trauma.
Essential elements of all research include balance of risks and benefits, unbiased selection of research samples, and assurance of the rights of individual participants. This paper highlights some key ethical issues and summarizes recent evidence relating to participation in, and conduct of, trauma-focused studies with special reference to vulnerable populations (eg, women and children, refugees, survivors of human rights violations, and survivors of trauma in the developing world). A concise ethical framework, rather than rigid guidelines (that may not be applicable to all trauma studies), may be a more useful point of reference for investigators and ethics committees or institutional review boards. Despite the increased empiric data available to inform ethical dilemmas regarding trauma research, more cost-burden analysis research in varying trauma populations and careful investigation of factors that contribute to risk and benefit is required.


The effect of local violence on children's attention and impulse control.
We examined whether the burden of violence in a child's community environment alters the child's behavior and functioning in the classroom setting. To identify the effects of local violence, we exploited variation in the timing of local homicides, based on data from the Chicago Police Department, relative to the timing of interview assessments conducted as part of a randomized controlled trial conducted with preschoolers in Head Start programs from 2004-2006, the Chicago School Readiness Project. We compared children's scores when exposed to recent local violence with scores when no recent violence had occurred to identify causal effects. When children were assessed within a week of a homicide that occurred near their home, they exhibited lower levels of attention and impulse control and lower preacademic skills. The analysis showed strong positive effects of local violence on parental distress, providing suggestive evidence that parental responses may be a likely pathway by which local violence affects young children. Exposure to homicide generates acute psychological distress among caregivers and impairs children's self-regulatory behavior and cognitive functioning.


Crystal structure of signal regulatory protein gamma (SIRPγ) in complex with an antibody Fab fragment.
Signal Regulatory Protein γ (SIRPγ) is a member of a closely related family of three cell surface receptors implicated in modulating immune/inflammatory responses. SIRPγ is expressed on T lymphocytes where it appears to be involved in the integrin-independent adhesion of lymphocytes to antigen-presenting cells. Here we describe the first full length structure of the extracellular region of human SIRPγ. We obtained crystals of SIRPγ by making a complex of the protein with the Fab fragment of the anti-SIRP antibody, OX117, which also binds to SIRPα and SIRPβ. We show that the epitope for FabOX117 is formed at the interface of the first and second domains of SIRPγ and comprises residues which are conserved between all three SIRPs. The FabOX117 binding site is distinct from the region in domain 1 which interacts with CD47, the physiological ligand for both SIRPγ and SIRPα but not SIRPβ. Comparison of the three domain structures of SIRPγ and SIRPα showed that these receptors can adopt different overall conformations due to the flexibility of the linker between the first two domains. SIRPγ in complex with FabOX117 forms a dimer in the crystal. Binding to the Fab fixes the position of domain 1 relative to domains 2/3 exposing a surface which favours formation of a homotypic dimer. However, the interaction appears to be relatively weak since only monomers of SIRPγ were observed in sedimentation velocity analytical ultracentrifugation of the protein alone. Studies of complex formation by equilibrium ultracentrifugation showed that only a 1:1 complex of SIRPγ: FabOX117 was formed with a dissociation constant in the low micromolar range (Kd = 1.2 +/- 0.3 μM). The three-domain extracellular regions of SIRPs are structurally conserved but show conformational flexibility in the disposition of the amino terminal ligand-binding Ig domain relative to the two membrane proximal Ig domains. Binding of a cross-reactive anti-SIRP Fab fragment to SIRPγ stabilises a conformation that favours SIRP dimer formation in the crystal structure, though this interaction does not appear sufficiently stable to be observed in solution.


Moving from fact to policy: housing is HIV prevention and health care.
A growing body of empirical evidence shows strong correlations between improved housing status and reduced HIV risk behaviors, improved access to health care for persons living with HIV/AIDS, and better health outcomes. These findings support the provision of housing assistance for low-income persons living with HIV/AIDS: as a basic human right; as a necessary component of systems to enable individuals to manage their HIV/AIDS care and treatment; and as an exciting new tool to end the AIDS crisis in America by reducing the number of new HIV infections. This paper provides a public policy framework for consideration of the research reported in this special issue of AIDS and Behavior, and offers suggestions for using research to move policy and practice towards a true public health response to the housing needs of persons at risk for or living with HIV/AIDS.


Recurrence of Hepatitis B Infection in Liver Transplant Patients Receiving Long-Term Hepatitis B Immunoglobulin Prophylaxis.
BACKGROUND Long-term real-world data are relatively sparse regarding recurrence of chronic hepatitis B virus (HBV) infection after liver transplantation using hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogue (NUC) prophylaxis. MATERIAL AND METHODS Data from 371 adults transplanted for HBV-related disease at 20 European centers and given HBIg for ³12 months ± NUC therapy were analyzed retrospectively. RESULTS HBIg comprised Hepatect® (iv HBIgB; n=299), subcutaneous Zutectra® (sc HBIg, n=236), and other HBIg preparations (n=130); 93.5% received NUC therapy. Mean follow-up was 6.8±3.5 years. The primary efficacy variable, freedom from HBV recurrence, occurred in 95.7% of patients (95% CI [93.1%, 97.5%]). The observed incidence of recurrence was 16/371 (4.3%) (annual rate 0.65%); 5/16 patients with recurrence had discontinued HBIg and 7/16 had anti-HBs <100 IU/l. Excluding these 7 patients, the HBV recurrence rate was 2.4%. The recurrence rate while on HBIg therapy was 1 per 2069 months. In patients who discontinued HBIg, risk of HBV recurrence versus sc HBIg users was increased by 5.2-fold (1 per 1 603 versus 1 per 8379 treatment months). The annual rate of HBV-related hepatocellular carcinoma (HCC) recurrence was 1.7%. CONCLUSIONS These results support the long-term use of HBIg with NUC therapy as an effective management strategy to minimize risk of HBV recurrence and virus-related complications after liver transplantation.


Blood flow in skeletal muscle of tetraplegic man during postural changes.
Relative changes in blood flow and vascular resistance in arm and leg muscle during head-up tilt at 45 degrees were studied in eight patients with complete cervical spinal cord transection and in 13 healthy volunteers. Muscle blood flow was measured by the local 133Xe washout method. In forearm muscle kept at heart level blood flow remained constant in the tetraplegic patients during head-up tilt, in contrast to that seen in the normal subjects, where blood flow decreased by 30%. In the dependent leg muscle, head-up tilt caused a decrease in blood flow of 46% and 40% in the patients and normals, respectively. Abolition of the local veno-arteriolar axon reflex, by inducing local counter-pressure to prevent venous distension in the dependent leg muscle, reduced the decrease in blood flow to 24% and 23%, respectively. Thus, the vascular response to head-up tilt differed significantly in forearm muscle between the two groups, whereas no difference was seen in the leg muscle. The absence of the vasoconstrictor response in forearm muscle indicates that postural sympathetic reflexes to this region depend on sympathetic reflexes integrated in centres located rostrally to the spinal cord. The results further suggest that local veno-arteriolar axon reflexes as well as spinal reflexes contribute to the observed vasoconstriction in the leg muscle.


Proteasome inhibition stabilizes tau inclusions in oligodendroglial cells that occur after treatment with okadaic acid.
Tau-positive inclusions in oligodendrocytes are consistent neuropathological features of corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementias with Parkinsonism linked to chromosome 17. Here we show by immunohistochemistry that tau-positive oligodendroglial inclusion bodies also contain the small heat-shock protein (HSP) alphaB-crystallin but not HSP70. To study the molecular mechanisms underlying inclusion body formation, we engineered an oligodendroglia cell line (OLN-t40) to overexpress the longest human tau isoform. Treatment of OLN-t40 cells with okadaic acid (OA), an inhibitor of protein phosphatase 2A, caused tau hyperphosphorylation and a decrease in the binding of tau to microtubules. Simultaneously, tau-positive aggregates that also stained with the amyloid-binding dye thioflavin-S as well as with antibodies to tau and alphaB-crystallin were detected. However, they were only transiently expressed and were degraded within 24 hr. When the proteasomal apparatus was inhibited by carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG-132) after OA treatment, the aggregates were stabilized and were still detectable after 18 hr in the absence of OA. Incubation with MG-132 alone inhibited tau proteolysis and led to the induction of HSPs, including alphaB-crystallin and to its translocation to the perinuclear region, but did not induce the formation of thioflavin-S-positive aggregates. Hence, although tau hyperphosphorylation induced by protein phosphatase inhibition contributes to pathological aggregate formation, only hyperphosporylation of tau followed by proteasome inhibition leads to stable fibrillary deposits of tau similar to those observed in neurodegenerative diseases.


Some static mechanical properties of the lumbar intervertebral joint, intact and injured.
The in-vitro static load-displacement properties of the intact and the injured human lumbar intervertebral joint have been investigated in a loading apparatus which allows entirely unconstrained relative displacement between the joint members. The spatial relative displacement produced by a given load, alone or in combination with another load (preload), were measured using 14 specimens and emphasizing strict control of the secondary variables which are known to affect the results. An attempt has been made to interpret the results in terms of the relative load-bearing roles of the disk, the facets and the posterior ligaments as a function of the type of load. The results indicate that the disk is the major load-bearing element in lateral and anterior (with respect to fixed superior vertebra) shears, axial compression and flexion, while the facets play a major role in posterior shear and axial torque.


Interpretation of negative results in fine needle aspiration of discrete pulmonary lesions.
A retrospective analysis was carried out on a consecutive series of 181 percutaneous fine needle aspiration biopsies of discrete pulmonary lesions, in which the outcome was established in 95%. In primary bronchial carcinoma the technique had a sensitivity of 86%. There was no relationship between the size, location, or radiological appearance of the lesion and the incidence of false negative results. The principal reason for failure to diagnose malignancy was inadequacy of the material provided for cytological examination. For metastatic neoplasms of non-bronchial origin the procedure had a sensitivity of 42% and a significantly greater false negative rate than for primary bronchial malignancy. For the entire series 72 (40%) of the procedures failed to produce a definite diagnosis, 29 (40%) of these cases subsequently proving to be malignant. A positive diagnosis was established in only 16% of patients with benign conditions. Review of published reports and consideration of the role of this and other biopsy techniques in the investigation of discrete pulmonary lesions lead to the conclusion that needle aspiration biopsy seems particularly appropriate in the investigation of inoperable patients with probable bronchial carcinoma in whom sputum cytology and bronchoscopy do not yield a diagnosis.


Adenylate cyclase toxin is critical for colonization and pertussis toxin is critical for lethal infection by Bordetella pertussis in infant mice.
Proliferation of Bordetella pertussis in the lungs of infant mice challenged by the intranasal route was examined. The bacteria rapidly proliferated in the lungs of mice challenged with a sublethal dose of a wild-type strain (BP338) or a filamentous hemagglutinin mutant (BPM409) from 500 at day 0 to 10(7) at day 15. The infection cleared in about 40 days. Pertussis toxin-deficient mutant BP357 gave a similar profile; however, the number of bacteria recovered was slightly reduced, suggesting that pertussis toxin is not essential for bacterial growth in the lungs. In contrast, adenylate cyclase toxin mutant BP348 was rapidly cleared from the lungs, with no viable bacteria remaining 10 days postchallenge, suggesting that the adenylate cyclase toxin is a colonization factor required for the bacteria to initiate infection.


Genome-wide DNA methylation profiling of CD8+ T cells shows a distinct epigenetic signature to CD4+ T cells in multiple sclerosis patients.
Multiple sclerosis (MS) is thought to be a T cell-mediated autoimmune disorder. MS pathogenesis is likely due to a genetic predisposition triggered by a variety of environmental factors. Epigenetics, particularly DNA methylation, provide a logical interface for environmental factors to influence the genome. In this study we aim to identify DNA methylation changes associated with MS in CD8+ T cells in 30 relapsing remitting MS patients and 28 healthy blood donors using Illumina 450K methylation arrays. Seventy-nine differentially methylated CpGs were associated with MS. The methylation profile of CD8+ T cells was distinctive from our previously published data on CD4+ T cells in the same cohort. Most notably, there was no major CpG effect at the MS risk gene HLA-DRB1 locus in the CD8+ T cells. CD8+ T cells and CD4+ T cells have distinct DNA methylation profiles. This case-control study highlights the importance of distinctive cell subtypes when investigating epigenetic changes in MS and other complex diseases.


The Arabidopsis SENESCENCE-ASSOCIATED GENE 13 Regulates Dark-Induced Senescence and Plays Contrasting Roles in Defense Against Bacterial and Fungal Pathogens.
SENESCENCE-ASSOCIATED GENE 13 (SAG13) of Arabidopsis is a widely conserved gene of unknown function that has been extensively used as a marker of plant senescence. SAG13 induction occurs during plant cell death processes, including senescence and hypersensitive response, a type of programmed cell death that occurs in response to pathogens. This implies that SAG13 expression is regulated through at least two different signaling pathways affecting these two different processes. Our work highlights a contrasting role for SAG13 in regulating resistance against disease-causing biotrophic bacterial and necrotrophic fungal pathogens with contrasting infection strategies. We provide further evidence that SAG13 is not only induced during oxidative stress but also plays a role in protecting the plant against other stresses. SAG13 is also required for normal seed germination, seedling growth, and anthocyanin accumulation. The work presented here provides evidence for the role of SAG13 in regulating multiple plant processes including senescence, defense, seed germination, and abiotic stress responses. SAG13 is a valuable molecular marker for these processes and is conserved in multiple plant species, and this knowledge has important implications for crop improvement.


Two-particle anomalous diffusion: probability density functions and self-similar stochastic processes.
Two-particle dispersion is investigated in the context of anomalous diffusion. Two different modelling approaches related to time subordination are considered and unified in the framework of self-similar stochastic processes. By assuming a single-particle fractional Brownian motion and that the two-particle correlation function decreases in time with a power law, the particle relative separation density is computed for the cases with time sub-ordination directed by a unilateral M-Wright density and by an extremal Lévy stable density. Looking for advisable mathematical properties (for instance, the stationarity of the increments), the corresponding self-similar stochastic processes are represented in terms of fractional Brownian motions with stochastic variance, whose profile is modelled by using the M-Wright density or the Lévy stable density.


Low back pain.
Low back pain is a common reason for physician visits and is associated with enormous costs to health care and industry. Radiographic abnormalities of the lumbar spine, including disk protrusion, are common in asymptomatic subjects and only loosely associated with symptoms and neurologic examination. Therefore, highly selective evaluation is required to avoid subjecting patients with back pain to unnecessary tests and surgical procedures. Reassurance about the favorable prognosis of low back pain is an important component of therapy. Most patients with simple back pain recover with symptomatic treatment. Plain radiographs are indicated for evaluation of patients with radiculopathy and those with risk factors for underlying medical conditions. The majority of patients with back pain, even those with radiculopathy, improve with conservative management and surgery is unnecessary. Surgical consultation and CT or MR imaging scans are indicated for patients with persistent or progressive neurologic deficits or persistent sciatica with nerve root tension signs. Acute radiculopathy with bilateral neurologic deficits, saddle anesthesia, or urinary symptoms is suggestive of cord compression or cauda equina syndrome and requires urgent surgical referral.


Head impact velocities in FIS World Cup snowboarders and freestyle skiers: Do real-life impacts exceed helmet testing standards?
Prior to the 2013-2014 season, the International Ski Federation (FIS) increased the helmet testing speed from a minimum requirement of 5.4 to 6.8 m/s for alpine downhill, super-G and giant slalom and for freestyle ski cross, but not for the other freestyle disciplines or snowboarding. Whether this increased testing speed reflects impact velocities in real head injury situations on snow is unclear. We therefore investigated the injury mechanisms and gross head impact biomechanics in four real head injury situations among World Cup (WC) snowboard and freestyle athletes and compared these with helmet homologation laboratory test requirements. The helmets in the four cases complied with at least European Standards (EN) 1077 (Class B) or American Society for Testing and Materials (ASTM) F2040. We analysed four head injury videos from the FIS Injury Surveillance System throughout eight WC seasons (2006-2014) in detail. We used motion analysis software to digitize the helmet's trajectory and estimated the head's kinematics in two dimensions, including directly preimpact and postimpact. All four impacts were to the occiput. In the four cases, the normal-to-slope preimpact velocity ranged from 7.0(±SD 0.2) m/s to 10.5±0.5 m/s and the normal-to-slope velocity change ranged from 8.4±0.6 m/s to 11.7±0.7 m/s. The sagittal plane helmet angular velocity estimates indicated a large change in angular velocity (25.0±2.9 rad/s to 49.1±0.3 rad/s). The estimated normal-to-slope preimpact velocity was higher than the current strictest helmet testing rule of 6.8 m/s in all four cases.


Mechanism of H2 Production by Models for the [NiFe]-Hydrogenases: Role of Reduced Hydrides.
The intermediacy of a reduced nickel-iron hydride in hydrogen evolution catalyzed by Ni-Fe complexes was verified experimentally and computationally. In addition to catalyzing hydrogen evolution, the highly basic and bulky (dppv)Ni(μ-pdt)Fe(CO)(dppv) ([1](0); dppv = cis-C2H2(PPh2)2) and its hydride derivatives have yielded to detailed characterization in terms of spectroscopy, bonding, and reactivity. The protonation of [1](0) initially produces unsym-[H1](+), which converts by a first-order pathway to sym-[H1](+). These species have C1 (unsym) and Cs (sym) symmetries, respectively, depending on the stereochemistry of the octahedral Fe site. Both experimental and computational studies show that [H1](+) protonates at sulfur. The S = 1/2 hydride [H1](0) was generated by reduction of [H1](+) with Cp*2Co. Density functional theory (DFT) calculations indicate that [H1](0) is best described as a Ni(I)-Fe(II) derivative with significant spin density on Ni and some delocalization on S and Fe. EPR spectroscopy reveals both kinetic and thermodynamic isomers of [H1](0). Whereas [H1](+) does not evolve H2 upon protonation, treatment of [H1](0) with acids gives H2. The redox state of the "remote" metal (Ni) modulates the hydridic character of the Fe(II)-H center. As supported by DFT calculations, H2 evolution proceeds either directly from [H1](0) and external acid or from protonation of the Fe-H bond in [H1](0) to give a labile dihydrogen complex. Stoichiometric tests indicate that protonation-induced hydrogen evolution from [H1](0) initially produces [1](+), which is reduced by [H1](0). Our results reconcile the required reductive activation of a metal hydride and the resistance of metal hydrides toward reduction. This dichotomy is resolved by reduction of the remote (non-hydride) metal of the bimetallic unit.


Biological activity, lipoprotein-binding behavior, and in vivo disposition of extracted and native forms of Salmonella typhimurium lipopolysaccharides.
Although phenol-extracted gram-negative bacterial lipopolysaccharides (LPS) have been used to study the properties of endotoxins for many years, nothing is known about the behavior of native (unextracted) LPS in vivo. Accordingly, we have compared extracted and native forms of LPS with regard to their biological activity, their ability to bind to plasma high density lipoproteins (HDL), and their fate after intravenous injection into rats. The LPS of Salmonella typhimurium G-30 were labeled with [(3)H]galactose, and whole bacteria, bacterial outer membranes, outer membrane fragments (harvested from the bacterial culture supernatant), and phenol extracts of the bacteria were prepared. After defining the LPS, phospholipid, and protein composition of these preparations, we compared the activity of the LPS in phenol extracts and membrane fragments in two assays. In both the limulus lysate assay and the rabbit pyrogen test, the LPS in phenol extracts were slightly more potent than the LPS in membrane fragments. We next studied the ability of the LPS in each preparation to bind to rat lipoproteins in vitro, and each preparation was then injected intravenously into rats for measurements of LPS-HDL binding and tissue uptake in vivo. Two patterns of lipoprotein binding were observed. Less than 25% of the LPS in both outer membranes and whole bacteria bound to HDL in vitro. When the outer membranes and whole bacteria were injected into rats, their LPS again bound poorly to HDL and they were rapidly removed from plasma into the liver and spleen. In contrast, >50% of the LPS in both culture supernatant membrane fragments and phenol-water extracts bound to HDL in vitro. When these preparations were injected into rats, approximately 50% of the LPS in the membrane fragments and phenol-water extracts bound to HDL and remained in the plasma over the 10-min study period. Moreover, the LPS in these preparations accumulated in the ovary and the adrenal gland, two tissues that use HDL-cholesterol for hormone synthesis. Binding to HDL thus greatly influenced the plasma half-life and tissue uptake of both extracted and native LPS. We conclude that extraction of S. typhimurium LPS with phenol does not significantly alter the biological activity or the lipoprotein binding behavior of the LPS and that the in vivo fates of phenol-extracted and membrane fragment LPS are essentially identical. The results thus provide important support for many previous studies that have used phenol-extracted LPS to mimic the activities of native LPS in vivo. However, the only native LPS that resembled the behavior of extracted LPS were the LPS that had been shed from the bacteria in fragments of membrane that had reduced amounts of protein and phospholipid. Removal of LPS from other outer membrane constituents, whether by chemical extraction or by a natural process of surface shedding, thus alters the behavior of the LPS; the most important feature of this alteration appears to be the ability of these LPS to bind readily to HDL.


The updated ESTRO core curricula 2011 for clinicians, medical physicists and RTTs in radiotherapy/radiation oncology.
In 2007 ESTRO proposed a revision and harmonisation of the core curricula for radiation oncologists, medical physicists and RTTs to encourage harmonised education programmes for the professional disciplines, to facilitate mobility between EU member states, to reflect the rapid development of the professions and to secure the best evidence-based education across Europe. Working parties for each core curriculum were established and included a broad representation with geographic spread and different experience with education from the ESTRO Educational Committee, local representatives appointed by the National Societies and support from ESTRO staff. The revised curricula have been presented for the ESTRO community and endorsement is ongoing. All three curricula have been changed to competency based education and training, teaching methodology and assessment and include the recent introduction of the new dose planning and delivery techniques and the integration of drugs and radiation. The curricula can be downloaded at http://www.estro-education.org/europeantraining/Pages/EuropeanCurricula.aspx. The main objective of the ESTRO core curricula is to update and harmonise training of the radiation oncologists, medical physicists and RTTs in Europe. It is recommended that the authorities in charge of the respective training programmes throughout Europe harmonise their own curricula according to the common framework.


Perioperative management of anticoagulation during device implantation-the UK perspective.
Increasing numbers of patients taking oral anticoagulation are presenting for device implantation. Cessation of anticoagulation in the perioperative period may expose patients to increased risk of thromboembolic events, while continuing anticoagulation may increase the risk of bleeding. There are few guidelines or randomized controlled trials to guide perioperative management. We carried out a questionnaire-based study of all cardiologists implanting devices in the United Kingdom to establish if there was consensus on management of anticoagulation in patients undergoing pacemaker implantation. There is significant variation in management of these patients. Eighty-nine percent of doctors stop oral anticoagulation a mean 3.7 days prior to pacemaker implantation in patients with a mechanical mitral valve, with 94% using heparin to provide preoperative anticoagulation: 58% unfractionated heparin, 40% low molecular weight heparin. The maximum accepted international normalized ratio for implantation ranged from 1.4 to 3 (median 1.8). Postoperatively, 86% restart heparin after a mean 8.5 hours. Only 11% continue oral anticoagulation throughout the implantation period. There is a hierarchy of perceived embolic risk with doctors using progressively less anticoagulation in patients with prosthetic aortic valve, high-risk, and low-risk atrial fibrillation. In contrast, only 7% of implanters stop theinopyridines prior to device implantation in patients with a 2-month-old drug eluting stent. Perioperative anticoagulation management of patients undergoing device procedures is currently performed with little consensus. This emphasizes the need for careful national and international audit of periprocedural anticoagulation management and its associated complications with a view to developing international consensus guidelines. (PACE 2010; 389-393).


Is the pro-adhesive activity of plasma von Willebrand factor counteracted by a physiological inhibitor of platelet adhesiveness?
1. Abnormal plasma levels of von Willebrand factor are accompanied by abnormal platelet function in some disease states. 2. Platelet retention in glass bead columns, platelet aggregation in vitro, beta-thromboglobulin and 6-oxo-prostaglandin F1 alpha were monitored in six normal male volunteers before and after an acute rise of von Willebrand factor, as induced by the intravenous administration of 1-deamino 8-D-arginine vasopressin (DDAVP). 3. After DDAVP a steady twofold rise of von Willebrand factor occurred. Platelet retention increased by 74% immediately after DDAVP but returned to baseline values within 60-120 min. No consistent changes of the other variables were observed. 4. These results suggest that as yet unidentified mechanism(s) inhibits the pro-adhesive activity of von Willebrand factor.


A "clearcut" case? Brown bear selection of coarse woody debris and carpenter ants on clearcuts.
Forest management alters habitat characteristics, resulting in various effects among and within species. It is crucial to understand how habitat alteration through forest management (e.g. clearcutting) affects animal populations, particularly with unknown future conditions (e.g. climate change). In Sweden, brown bears (Ursus arctos) forage on carpenter ants (Camponotus herculeanus) during summer, and may select for this food source within clearcuts. To assess carpenter ant occurrence and brown bear selection of carpenter ants, we sampled 6999 coarse woody debris (CWD) items within 1019 plots, of which 902 were within clearcuts (forests ⩽30 years of age) and 117 plots outside clearcuts (forests >30 years of age). We related various CWD and site characteristics to the presence or absence of carpenter ant galleries (nests) and bear foraging sign at three spatial scales: the CWD, plot, and clearcut scale. We tested whether both absolute and relative counts (the latter controlling for the number of CWD items) of galleries and bear sign in plots were higher inside or outside clearcuts. Absolute counts were higher inside than outside clearcuts for galleries (mean counts; inside: 1.8, outside: 0.8). CWD was also higher inside (mean: 6.8) than outside clearcuts (mean: 4.0). However, even after controlling for more CWD inside clearcuts, relative counts were higher inside than outside clearcuts for both galleries (mean counts; inside: 0.3, outside: 0.2) and bear sign (mean counts; inside: 0.03, outside: 0.01). Variables at the CWD scale best explained gallery and bear sign presence than variables at the plot or clearcut level, but bear selection was influenced by clearcut age. CWD circumference was important for both carpenter ant and bear sign presence. CWD hardness was most important for carpenter ant selection. However, the most important predictor for bear sign was the presence or absence of carpenter ant galleries. Bears had a high foraging "success" rate (⩾88%) in foraging CWD where galleries also occurred, which was assessed by summing CWD items with the concurrence of bear sign and galleries, divided by the sum of all CWD with bear sign. Clearcuts appeared to increase the occurrence of a relatively important summer food item, the carpenter ant, on Swedish managed forests for the brown bear. However, the potential benefit of this increase can only be determined from a better understanding of the seasonal and interannual variation of the availability and use of other important brown bear food items, berries (e.g. Vaccinium myrtillus and Empetrum spp.), as well as other primary needs for bears (e.g. secure habitat and denning habitat), within the landscape mosaic of managed forests.


Advanced temperature compensation for piezoresistive sensors based on crystallographic orientation.
We describe a highly effective method of reducing thermal sensitivity in piezoresistive sensors, in particular silicon cantilevers, by taking advantage of the dependence of the piezoresistive coefficient of silicon on crystallographic orientation. Two similar strain-sensing elements are used, positioned at 45 degrees to each other: One is set along a crystalline axis associated with a maximum piezoresistive coefficient to produce the displacement signal, while the other is set along an axis of the vanishing coefficient to produce the reference signal. Unlike other approaches, both sensing elements are coupled to the same cantilever body, maximizing thermal equilibration. Measurements show at least one order of magnitude improvement in thermal disturbance rejection over conventional approaches using uncoupled resistors.


Murder, minors, selective serotonin reuptake inhibitors, and the involuntary intoxication defense.
This article examines the clinical and legal aspects of the involuntary intoxication defense, primarily as it relates to violent acts perpetrated by minor and adult patients who have been prescribed selective serotonin reuptake inhibitors (SSRIs) and related psychoactive medications in a therapeutic context. The Model Penal Code recognizes the involuntary intoxication defense and its potential applicability to cases in which the defendant's criminal behavior is believed to be associated with prescription medication use. Two case reports of juvenile murderers who attributed their violent behavior to SSRI treatment are presented. Selected pertinent case law is reviewed. Currently there is a lack of convincing scientific evidence that clearly confirms or negates the postulated relationship between antidepressant agents and violent behavior. However, the use of the involuntary intoxication defense will likely continue to increase due to the growing number of novel psychotropic medications being developed and marketed along with advances in the scientific understanding of their actions and side effects.


Security implications and governance of cognitive neuroscience.
In recent years, significant efforts have been made toward elucidating the potential of the human brain. Spanning fields as disparate as psychology, biomedicine, computer science, mathematics, electrical engineering, and chemistry, research venturing into the growing domains of cognitive neuroscience and brain research has become fundamentally interdisciplinary. Among the most interesting and consequential applications to international security are the military and defense community's interests in the potential of cognitive neuroscience findings and technologies. In the United States, multiple governmental agencies are actively pursuing such endeavors, including the Department of Defense, which has invested over $3 billion in the last decade to conduct research on defense-related innovations. This study explores governance and security issues surrounding cognitive neuroscience research with regard to potential security-related applications and reports scientists' views on the role of researchers in these areas through a survey of over 200 active cognitive neuroscientists.


Thrombospondin-2 influences the proportion of cartilage and bone during fracture healing.
Thrombospondin-2 (TSP2) is a matricellular protein with increased expression during growth and regeneration. TSP2-null mice show accelerated dermal wound healing and enhanced bone formation. We hypothesized that bone regeneration would be enhanced in the absence of TSP2. Closed, semistabilized transverse fractures were created in the tibias of wildtype (WT) and TSP2-null mice. The fractures were examined 5, 10, and 20 days after fracture using microCT, histology, immunohistochemistry, quantitative RT-PCR, and torsional mechanical testing. Ten days after fracture, TSP2-null mice showed 30% more bone by microCT and 40% less cartilage by histology. Twenty days after fracture, TSP2-null mice showed reduced bone volume fraction and BMD. Mice were examined 5 days after fracture during the stage of neovascularization and mesenchymal cell influx to determine a cellular explanation for the phenotype. TSP2-null mice showed increased cell proliferation with no difference in apoptosis in the highly cellular fracture callus. Although mature bone and cartilage is minimal 5 days after fracture, TSP2-null mice had reduced expression of collagen IIa and Sox9 (chondrocyte differentiation markers) but increased expression of osteocalcin and osterix (osteoblast differentiation markers). Importantly, TSP2-null mice had a 2-fold increase in vessel density that corresponded with a reduction in vascular endothelial growth factor (VEGF) and Glut-1 (markers of hypoxia inducible factor [HIF]-regulated transcription). Finally, by expressing TSP2 using adenovirus starting 3 days after fracture, chondrogenesis was restored in TSP2-null mice. We hypothesize that TSP2 expressed by cells in the fracture mesenchyme regulates callus vascularization. The increase in vascularity increases tissue oxemia and decreases HIF; thus, undifferentiated cells in the callus develop into osteoblasts rather than chondrocytes. This leads to an alternative strategy for achieving fracture healing with reduced endochondral ossification and enhanced appositional bone formation. Controlling the ratio of cartilage to bone during fracture healing has important implications for expediting healing or promoting regeneration in nonunions.


Dietary products consumption in relation to serum 25-hydroxyvitamin D and selenium level in Saudi children and adults.
Vitamin D deficiency is a global health threat that has been associated with several chronic diseases. Selenium is an essential trace element because of role in major metabolic processes, immune function, thyroid hormone metabolism, male infertility, neoplasms and cardiovascular disease. We aimed to investigate for the first time in the Saudi population the association between vitamin D and selenium status with various dietary products consumption. A total of 259 children and 95 adults were included in this cross-sectional study. We estimated the consumption frequencies of various dietary food products using a qualitative food frequency questionnaire (FFQ) and also measured serum levels of 25-hydroxyvitamin D and selenium. Associations between variables of interest were assessed. Vitamin D deficiency and insufficiency were observed in 80% of the boys, 90% of the girls, 64% of men and 50% of women. Modest associations were found between mean serum 25 (OH) D concentration and consumption frequencies of fresh milk in children (r=0.11; P<0.05), more specifically in girls (r=0.12; P<0.05), and to the overall consumption of dairy products in women (r=0.12; P<0.05). Vitamin D status was also inversely associated with selenium in adults (r=-0.43; P<0.05). There was a significant correlation between delta changes of serum selenium, triglycerides and HDL levels (P-values <0.05). Vitamin D and selenium levels are modestly associated with dietary products consumption. Changes in selenium levels were associated with increased serum triglyceride levels, indicating a potential biomarker for cardiovascular risk and dyslipidemia. The widespread vitamin D deficiency observed in the present study highlight the need for adequate fortification of dairy products.


Prevalence and correlates of domain-specific sedentary time of adults in the Netherlands: findings from the 2006 Dutch time use survey.
Relatively little is known about how total sedentary time is accumulated in different domains and if correlates of sedentary time differ across domains. Time use surveys present a unique opportunity to study sedentary time in more detail. This study aimed to use the 2006 Dutch time use survey to 1) describe the (sedentary) time use of Dutch adults, and 2) explore socio-demographic and health-related correlates of total (non-occupational) and domain-specific sedentary time. The Dutch time use survey randomly selected participants from a population-representative research sample of Dutch households. Participants reported daily activities on seven consecutive days using a time use diary and socio-demographic and health-related characteristics during telephone interviews. All reported activities were coded for activity domain (i.e. education; household; leisure; occupation; sleep; transport; voluntary work) and activity intensity (i.e. sedentary; light intensity physical activity; moderate-to-vigorous intensity physical activity). As occupational activities were not specified in sufficient detail, the intensity of these activities was unknown. We described the time spent in different domains and intensities, and assessed the socio-demographic and health-related correlates of high levels of total (non-occupational), household, leisure, and transport sedentary time using logistic regression analyses. The final dataset consisted of 1614 adult (18+) participants. On average, participants spent 8.0 h (61.1%) of their daily waking non-occupational time on sedentary activities. More than 87% of leisure time was spent sedentary. Men, participants aged 18-34 and 65+ years, full-time employed participants and obese participants had higher levels of total non-occupational sedentary time. The correlates of household, leisure and transport sedentary time differed by domain. This study reports high levels of total non-occupational sitting time of Dutch adults. The large proportion of sedentary leisure activities might indicate the potential of strategies aiming to reduce leisure sedentary time. The difference in correlates across sedentary behaviour domains demonstrates the importance of targeting these domains differently in interventions and policies.


Central norepinephrine metabolism in affective illness: MHPG in the cerebrospinal fluid.
Concentrations of the norepinephrine metabolite 3-methoxy-4-hydroxyphenyl glycol in cerebrospinal fluid were measured by a gas chromatographic method in 34 patients with affective illness and in 44 controls. Concentrations of this metabolite in spinal fluid were significantly lower in depressed patients than in controls or manic patients. These low values may occur secondary to depressive phenomena such as reduced psychomotor activity, or they may reflect a primary change in norepinephrine metabolism in depressive illness.


Disentangling the impacts of outcome valence and outcome frequency on the post-error slowing.
Post-error slowing (PES) reflects efficient outcome monitoring, manifested as slower reaction time after errors. Cognitive control account assumes that PES depends on error information, whereas orienting account posits that it depends on error frequency. This raises the question how the outcome valence and outcome frequency separably influence the generation of PES. To address this issue, we varied the probability of observation errors (50/50 and 20/80, correct/error) the "partner" committed by employing an observation-execution task and investigated the corresponding behavioral and neural effects. On each trial, participants first viewed the outcome of a flanker-run that was supposedly performed by a 'partner', and then performed a flanker-run themselves afterwards. We observed PES in the two error rate conditions. However, electroencephalographic data suggested error-related potentials (oERN and oPe) and rhythmic oscillation associated with attentional process (alpha band) were respectively sensitive to outcome valence and outcome frequency. Importantly, oERN amplitude was positively correlated with PES. Taken together, these findings support the assumption of the cognitive control account, suggesting that outcome valence and outcome frequency are both involved in PES. Moreover, the generation of PES is indexed by oERN, whereas the modulation of PES size could be reflected on the alpha band.


CNS tumor 22 years after spinal neuroblastoma IV: diagnostic dilemma between recurrence and secondary malignancy.
We present the very unusual case of a young woman suffering from a brain tumor 22 years after a stage IV spinal neuroblastoma as an infant, demonstrating the difficulties of differentiating late neuroblastoma relapse from secondary supratentorial primitive neuroectodermal tumor (sPNET). Lacking specific immunohistochemical features, the first cerebral tumor at the age of 21 was regarded as sPNET, and we pursued a therapeutic approach consisting of neurosurgical resection as well as irradiation and high-dose alkylator-based chemotherapy according to the HIT2000 protocol. Two years later the patient suffered from a diffusely infiltrating local recurrence, changing its imaging appearance as well as its immunohistochemical characteristics, now revealing disseminated positivity for neuron-specific enolase and neural cell adhesion molecule. Moreover, the lack of PNET-specific translocations (EWS/FLI1 gene fusion) in both brain tumors as well as the development of hepatic metastases was more compatible with the diagnosis of a very late relapse 22 years after initial stage IV spinal neuroblastoma.


HIV-1 infection impairs regulatory T-cell suppressive capacity on a per-cell basis.
The impact of CD4+ regulatory T cells (Tregs) on human immunodeficiency virus type 1 (HIV-1) pathogenesis remains incompletely understood. Although it has been shown that Tregs can be infected with HIV-1, the consequences of infection on a per-cell basis are still unknown. In vitro HIV-GFP infected and noninfected Tregs were isolated by flow-based cell-sorting to investigate Treg suppressive capacity and gene expression profiles. Our data show that HIV-1-infected Tregs were significantly less suppressive than noninfected Tregs and demonstrated down-regulation of genes critical to Treg function. This impaired function may have detrimental consequences for the control of generalized immune activation and accelerate HIV disease progression.


Oculomotor Responses to Dynamic Stimuli in a 44-Channel Suprachoroidal Retinal Prosthesis.
To investigate oculomotor behavior in response to dynamic stimuli in retinal implant recipients. Three suprachoroidal retinal implant recipients performed a four-alternative forced-choice motion discrimination task over six sessions longitudinally. Stimuli were a single white bar ("moving bar") or a series of white bars ("moving grating") sweeping left, right, up, or down across a 42″ monitor. Performance was compared with normal video processing and scrambled video processing (randomized image-to-electrode mapping to disrupt spatiotemporal structure). Eye and head movement was monitored throughout the task. Two subjects had diminished performance with scrambling, suggesting retinotopic discrimination was used in the normal condition and made smooth pursuit eye movements congruent to the moving bar stimulus direction. These two subjects also made stimulus-related eye movements resembling optokinetic reflex (OKR) for moving grating stimuli, but the movement was incongruent with stimulus direction. The third subject was less adept at the task, appeared primarily reliant on head position cues (head movements were congruent to stimulus direction), and did not exhibit retinotopic discrimination and associated eye movements. Our observation of smooth pursuit indicates residual functionality of cortical direction-selective circuits and implies a more naturalistic perception of motion than expected. A distorted OKR implies improper functionality of retinal direction-selective circuits, possibly due to retinal remodeling or the non-selective nature of the electrical stimulation. Retinal implant users can make naturalistic eye movements in response to moving stimuli, highlighting the potential for eye tracker feedback to improve perceptual localization and image stabilization in camera-based visual prostheses.


Sensitivity to geometric shape regularity in humans and baboons: A putative signature of human singularity.
Among primates, humans are special in their ability to create and manipulate highly elaborate structures of language, mathematics, and music. Here we show that this sensitivity to abstract structure is already present in a much simpler domain: the visual perception of regular geometric shapes such as squares, rectangles, and parallelograms. We asked human subjects to detect an intruder shape among six quadrilaterals. Although the intruder was always defined by an identical amount of displacement of a single vertex, the results revealed a geometric regularity effect: detection was considerably easier when either the base shape or the intruder was a regular figure comprising right angles, parallelism, or symmetry rather than a more irregular shape. This effect was replicated in several tasks and in all human populations tested, including uneducated Himba adults and French kindergartners. Baboons, however, showed no such geometric regularity effect, even after extensive training. Baboon behavior was captured by convolutional neural networks (CNNs), but neither CNNs nor a variational autoencoder captured the human geometric regularity effect. However, a symbolic model, based on exact properties of Euclidean geometry, closely fitted human behavior. Our results indicate that the human propensity for symbolic abstraction permeates even elementary shape perception. They suggest a putative signature of human singularity and provide a challenge for nonsymbolic models of human shape perception.


Understanding how dogs encourage and motivate walking: cross-sectional findings from RESIDE.
Many people live with dogs but not all walk with them regularly. This study examines the demographic and behavioural factors that contribute towards owners reporting having a strong sense of encouragement and motivation to walk provided by their dogs, which we call 'the Lassie effect'. Data was collected from 629 dog owners participating in the RESIDE cross-sectional survey in Perth, Western Australia. Multivariable logistic regression analyses of factors associated with two separate outcome survey items 'Dog encouragement to walk' (how often dog encouraged me to go walking in last month) and 'Dog motivation to walk' (Having a dog makes me walk more). Owning a larger dog; having an increased level of attachment to dog; knowing dog enjoys going for a walk; believing walking keeps dog healthy; and having high social support from family to go walking, were positively associated with both outcomes 'dog encouragement to walk' and 'dog motivation to walk'. Conversely, reporting the presence of children at home; that the child is the main person who walks with the dog; and perceiving dog-specific barriers to walking with dog daily; were negatively associated with both outcomes. In addition, 'Dog motivation to walk' only was positively associated with a belief walking reduces barking, and negatively with owning a dog that is overweight or a dog that is too old/sick. Reporting that the spouse/partner is main person who walks with the dog was also negatively associated with 'dog motivation to walk', as was increased perceived access to public open spaces with dog-supportive features. There are both dog and owner factors that are associated with an owner's sense of encouragement, and motivation to walk the dog, which in turn has been found to be associated with dog waking behaviour. These factors may be targeted in future interventions to increase and maintain physical activity levels of both people and pets.


[Suicide among the Tikúna on the Upper Solimões River: an expression of conflicts].
This study focuses on suicide among the Tikúna Indians on the Upper Solimões River in the Brazilian Amazonia. The very nature of the object requires an interdisciplinary approach. The ethnography is concerned with capturing links among suicides occurring over the last decade, in the process of confrontation between different factions or groups that express, in the present, an older historical context, the mechanisms of conflict characterizing the ancient malocas, or indigenous lodges. At the very base of such confrontations lies the abandonment inflicted on this population, especially the bankruptcy of the health care model proposed for the Upper Solimões area.


Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase.
Non-centrosomal microtubule bundles play important roles in cellular organization and function. Although many diverse proteins are known that can bundle microtubules, biochemical mechanisms by which cells could locally control the nucleation and formation of microtubule bundles are understudied. Here, we demonstrate that the concentration of tubulin into a condensed, liquid-like compartment composed of the unstructured neuronal protein tau is sufficient to nucleate microtubule bundles. We show that, under conditions of macro-molecular crowding, tau forms liquid-like drops. Tubulin partitions into these drops, efficiently increasing tubulin concentration and driving the nucleation of microtubules. These growing microtubules form bundles, which deform the drops while remaining enclosed by diffusible tau molecules exhibiting a liquid-like behavior. Our data suggest that condensed compartments of microtubule bundling proteins could promote the local formation of microtubule bundles in neurons by acting as non-centrosomal microtubule nucleation centers and that liquid-like tau encapsulation could provide both stability and plasticity to long axonal microtubule bundles.


Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway.
Arsenic is present in the environment and has become a worldwide health concern due to its toxicity and carcinogenicity. However, the specific mechanism(s) by which arsenic elicits its toxic effects has yet to be fully elucidated. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been recognized as the master regulator of a cellular defense mechanism against toxic insults. This review highlights studies demonstrating that arsenic activates the Nrf2-Keap1 antioxidant pathway by a distinct mechanism from that of natural compounds such as sulforaphane (SF) found in broccoli sprouts or tert-butylhyrdoquinone (tBHQ), a natural antioxidant commonly used as a food preservative. Evidence also suggests that arsenic prolongs Nrf2 activation and may mimic constitutive activation of Nrf2, which has been found in several human cancers due to disruption of the Nrf2-Keap1 axis. The current literature strongly suggests that activation of Nrf2 by arsenic potentially contributes to, rather than protects against, arsenic toxicity and carcinogenicity. The mechanism(s) by which known Nrf2 activators, such as the natural chemopreventive compounds SF and lipoic acid, protect against the deleterious effects caused by arsenic will also be discussed. These findings will provide insight to further understand how arsenic promotes a prolonged Nrf2 response, which will lead to the identification of novel molecular markers and development of rational therapies for the prevention or intervention of arsenic-induced diseases. The National Institute of Environmental Health Science (NIEHS) Outstanding New Environmental Scientist (ONES) award has provided the opportunity to review the progress both in the fields of arsenic toxicology and Nrf2 biology. Much of the funding has led to (1) the novel discovery that arsenic activates the Nrf2 pathway by a mechanism different to that of other Nrf2 activators, such as sulforaphane and tert-butylhydroquinone, (2) activation of Nrf2 by chemopreventive compounds protects against arsenic toxicity and carcinogenicity both in vitro and in vivo, (3) constitutive activation of Nrf2 by disrupting Keap1-mediated negative regulation contributes to cancer and chemoresistance, (4) p62-mediated sequestration of Keap1 activates the Nrf2 pathway, and (5) arsenic-mediated Nrf2 activation may be through a p62-dependent mechanism. All of these findings have been published and are discussed in this review. This award has laid the foundation for my laboratory to further investigate the molecular mechanism(s) that regulate the Nrf2 pathway and how it may play an integral role in arsenic toxicity. Moreover, understanding the biology behind arsenic toxicity and carcinogenicity will help in the discovery of potential strategies to prevent or control arsenic-mediated adverse effects.


Intermediate monocytes lead to enhanced myocardial remodelling in STEMI patients with diabetes.
This study aimed to evaluate the potential associations of intermediate monocytes (CD14(++)CD16(+)) with myocardial remodelling in ST segment elevation myocardial infarction (STEMI) patients with diabetes.A total of 67 STEMI patients with diabetes were enrolled. The control group consisted of 65 STEMI patients without diabetes. All patients received emergency medical services for reperfusion therapy in less than 12 hours after onset of AMI. Blinded to patient clinical characteristics, monocyte subset analysis was performed using flow cytometry immediately after admission. mRNA of Chemokine Decoy Receptor D6 in each subset of monocytes was validated by Q-PCR. Expression of CCL2 in patient plasma was determined with an Elisa kit. Infarct size and left ventricular ejection fraction (LVEF) were measured using 3-dimensional echocardiography 3 days and 6 months after AMI. The incidences of recurrent cardiovascular events and death in each group were measured using the Kaplan-Meier estimator in follow-up during the next 24 months. Cox proportional-hazard models were further used to analyze the relationship of monocyte cell counts and event-free survival after adjusting for confounding factors.The number of circulating intermediate monocytes was significantly correlated with LVEF% and infarct size (r = -0.32; P = 0.008; r = 0.57, P < 0.001) in STEMI patients with diabetes compared with those without diabetes 6 months after AMI. Chemokine Decoy Receptor D6 transcript levels were lower in intermediate monocytes of STEMI patients with diabetes compared to the subsets in STEMI patients without diabetes (P < 0.001). Higher levels of CCL2 (pg/mL) were observed in STEMI patients with diabetes compared to STEMI patients without diabetes (P < 0.001). During a mean follow-up period of 24 ± 1 month, recurrent cardiovascular events or death occurred in 23 patients belonging to the STEMI with diabetes group and 10 belonging to the control group. Univariate Kaplan-Meier analysis revealed that counts of the intermediate monocytes according to median showed statistical significance in STEMI patients with diabetes (P = 0.010). After full adjustment for confounding factors, the cells were found to remain independently related to recurrent cardiovascular events or death in this group (P = 0.004, 95% CI: 1.62-12.49).Intermediate monocytes were associated with LV remodelling in STEMI patients with diabetes. The cells were predictive for recurrent cardiovascular events or death in these patients. A low level of D6 mRNA in the intermediate monocytes of STEMI patients with diabetes and high level of CCL2 in these patients may partially explain the causality.


Tiagabine in the maintenance treatment of bipolar disorders.
Tiagabine, an anticonvulsant, has been reported to have efficacy in prophylactic treatment of bipolar disorder in case reports and in case series. To review the efficacy and acceptability of tiagabine, relative to placebo, and other agents in the prevention and/or attenuation of episodes of bipolar affective disorder. The efficacy and acceptability of tiagabine were considered in terms of mood symptoms, mortality, general health, social functioning, adverse effects and overall acceptability to patients. The following databases were searched on 13-10-2005. The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Registers (CCDANCTR-Studies and CCDANCTR-References),The Cochrane Controlled Clinical Trials Register (CCCTR),EMBASE,MEDLINE,LILACS,PsycLIT andPsyndex. Reference lists of relevant papers and major textbooks of affective disorder were examined.Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials. Specialist journals and conference proceedings were handsearched. Randomised controlled trials which compare tiagabine with placebo, alternative mood stabilisers or antipsychotics, where the stated intent of intervention was the maintenance treatment of bipolar affective disorder, were sought. Bipolar patients, male and female, of all ages were to be included. Data were to be extracted from the original reports if they met our inclusion criteria. The main outcomes to be assessed were:(1) The efficacy of tiagabine treatment in preventing or attenuating further episodes of bipolar affective disorder, including its efficacy in rapid cycling disorder.(2) The acceptability of tiagabine treatment to patients.(3) The prevalence of side effects.(4) Mortality, if any, on tiagabine treatment.Outcomes concerning relapse or recurrence were to be analysed excluding data from studies using discontinuation protocols, which were to be analysed separately. Sub-group analyses were to be performed to examine the effects of tiagabine treatment in rapid cycling bipolar disorder and previous mood stabiliser non-responders. Data were to be analysed using Review Manager version 4.2.8. No randomised controlled trials of tiagabine in the maintenance treatment of bipolar disorder were found. There is an insufficient methodologically rigorous evidence base to provide guidance on the use of tiagabine in the maintenance treatment of bipolar disorder. There is a need for randomised controlled trials examining the therapeutic potential of this agent in bipolar disorder, after the nature of reported episodes of syncope or seizure in tiagabine-treated bipolar patients has been established.