Credit Default Swaps networks and systemic risk.
Credit Default Swaps (CDS) spreads should reflect default risk of the underlying corporate debt. Actually, it has been recognized that CDS spread time series did not anticipate but only followed the increasing risk of default before the financial crisis. In principle, the network of correlations among CDS spread time series could at least display some form of structural change to be used as an early warning of systemic risk. Here we study a set of 176 CDS time series of financial institutions from 2002 to 2011. Networks are constructed in various ways, some of which display structural change at the onset of the credit crisis of 2008, but never before. By taking these networks as a proxy of interdependencies among financial institutions, we run stress-test based on Group DebtRank. Systemic risk before 2008 increases only when incorporating a macroeconomic indicator reflecting the potential losses of financial assets associated with house prices in the US. This approach indicates a promising way to detect systemic instabilities.


Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage.
Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed "early brain injury," with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as α/δ frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia. Unblinded pilot study testing response to drug intervention. Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41-69 yr]; 11 women). IV sodium nitrite (10 μg/kg/min) for 1 hour. Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to -31%) (p = 0.006, multivariate analysis accounting for major confounds). Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient's susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage.


The mesocortical dopamine projection to anterior cingulate cortex plays no role in guiding effort-related decisions.
Both mesolimbic dopamine (DA) and the anterior cingulate cortex (ACC) have been implicated in enabling animals to expend effort to obtain greater reward. To investigate the role of the DA pathway to ACC in working for reward, the authors tested rats on a cost-benefit T-maze paradigm in which they could either climb a barrier to obtain large reward in 1 arm (high reward [HR]) or select the low-effort alternative containing less reward (low reward [LR]). Surprisingly, ACC DA depletions had no effect on choice performance. Manipulations of barrier and reward sizes demonstrated that lesioned rats were as sensitive to the costs and benefits of the alternatives as controls. These results imply that the DA projection to ACC is not involved in guiding effort-related decisions.


Serological relationship of tumor necrosis factor-inducing exoantigens of Plasmodium falciparum and Plasmodium vivax.
Exoantigens of Plasmodium vivax-parasitized erythrocytes stimulated macrophages to secrete tumor necrosis factor, and antisera raised against the exoantigens inhibited this secretion. The antisera also inhibited the activity of Plasmodium falciparum and Plasmodium yoelii exoantigens, and conversely, antisera against the latter cross-reacted with the exoantigens of P. vivax.


Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis.
While the hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract in combination with lower motor neuron degeneration, the clinical involvement of both compartments is characteristically variable and the site of onset debated. We sought to establish whether there is a consistent signature of cerebral white matter abnormalities in heterogeneous ALS cases. In this observational study, diffusion tensor imaging was applied in a whole-brain analysis of 24 heterogeneous patients with ALS and well-matched healthy controls. Tract-based spatial statistics were used, with optimized voxel-based morphometry of T1 images to determine any associated gray matter involvement. A consistent reduction in fractional anisotropy was demonstrated in the corpus callosum of the ALS group, extending rostrally and bilaterally to the region of the primary motor cortices, independent of the degree of clinical upper motor neuron involvement. Matched regional radial diffusivity increase supported the concept of anterograde degeneration of callosal fibers observed pathologically. Gray matter reductions were observed bilaterally in primary motor and supplementary motor regions, and also in the anterior cingulate and temporal lobe regions. A post hoc group comparison model incorporating significant values for fractional anisotropy, radial diffusivity, and gray matter was 92% sensitive, 88% specific, with an accuracy of 90%. Callosal involvement is a consistent feature of ALS, independent of clinical upper motor neuron involvement, and may reflect independent bilateral cortical involvement or interhemispheric spread of pathology. The predominantly rostral corticospinal tract involvement further supports the concept of independent cortical degeneration even in those patients with ALS with predominantly lower motor neuron involvement clinically.


Statistical models for the deterioration of kidney function in a primary care population: A retrospective database analysis.
Background: Evidence for kidney function monitoring intervals in primary care is weak, and based mainly on expert opinion. In the absence of trials of monitoring strategies, an approach combining a model for the natural history of kidney function over time combined with a cost-effectiveness analysis offers the most feasible approach for comparing the effects of monitoring under a variety of policies. This study aimed to create a model for kidney disease progression using routinely collected measures of kidney function. Methods: This is an open cohort study of patients aged ≥18 years, registered at 643 UK general practices contributing to the Clinical Practice Research Datalink between 1 April 2005 and 31 March 2014. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Hidden Markov models for estimated glomerular filtration rate (eGFR) stage progression were fitted to four patient cohorts defined by baseline albuminuria stage; adjusted for sex, history of heart failure, cancer, hypertension and diabetes, annually updated for age. Results: Of 1,973,068 patients, 1,921,949 had no recorded urine albumin at baseline, 37,947 had normoalbuminuria (<3mg/mmol), 10,248 had microalbuminuria (3-30mg/mmol), and 2,924 had macroalbuminuria (>30mg/mmol). Estimated annual transition probabilities were 0.75-1.3%, 1.5-2.5%, 3.4-5.4% and 3.1-11.9% for each cohort, respectively. Misclassification of eGFR stage was estimated to occur in 12.1% (95%CI: 11.9-12.2%) to 14.7% (95%CI: 14.1-15.3%) of tests. Male gender, cancer, heart failure and age were independently associated with declining renal function, whereas the impact of raised blood pressure and glucose on renal function was entirely predicted by albuminuria. Conclusions: True kidney function deteriorates slowly over time, declining more sharply with elevated urine albumin, increasing age, heart failure, cancer and male gender. Consecutive eGFR measurements should be interpreted with caution as observed improvement or deterioration may be due to misclassification.


Humoral immune responses to adenovirus vectors in the brain.
We have investigated the humoral immune response to E1-deleted adenovirus vectors encoding the lacZ gene introduced into the brains of mice. Injection of these non-replicating vectors into the brain induced systemic antibody production to adenovirus vectors in dose dependent manner. Apparent antibody production to beta-galactosidase, the product of the lacZ gene, was detected later than anti-adenovirus antibody. Neutralizing antibody was not detected. This study demonstrates that E1-deleted adenovirus vectors injected into the brain trigger humoral immune responses to the adenovirus and its gene products, but they are not sufficient to block the infection of cells by adenovirus upon repeat injection.


Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies.
Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.


Results from a round robin test for the ecotoxicological evaluation of construction products using two leaching tests and an aquatic test battery.
A European round robin test according to ISO 5725-2 was conceptually prepared, realised, and evaluated. The aim was to determine the inter-laboratory variability of the overall process for the ecotoxicological characterization of construction products in eluates and bioassays. To this end, two construction products BAM-G1 (granulate) and HSR-2 (roof sealing sheet), both made of EPDM polymers (rubber), were selected. The granular construction product was eluted in a one stage batch test, the planar product in the Dynamic Surface Leaching test (DSLT). A total of 17 laboratories from 5 countries participated in the round robin test: Germany (12), Austria (2), Belgium (1), Czech Republic (1) and France (1). A test battery of four standardised ecotoxicity tests with algae, daphnia, luminescent bacteria and zebrafish eggs was used. As toxicity measures, EC50 and LID values were calculated. All tests, except the fish egg test, were basically able to demonstrate toxic effects and the level of toxicity. The reproducibility of test results depended on the test specimens and the test organisms. Generally, the variability of the EC50 or LID values increased with the overall level of toxicity. For the very toxic BAM-G1 eluate a relative high variability of CV = 73%-110% was observed for EC50 in all biotests, while for the less toxic HSR-2 eluate the reproducibility of EC50 varied with sensitivity: it was very good (CV = 9.3%) for the daphnia test with the lowest sensitivity, followed by the algae test (CV = 36.4%). The luminescent bacteria test, being the most sensitive bioassay for HSR-2 Eluate, showed the highest variability (CV = 74.8%). When considering the complex overall process the reproducibility of bioassays with eluates from construction products was acceptable.


Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy.
Tumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment. Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 microM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry. Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 muM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes. We conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.


Tuberous sclerosis complex-mediated mTORC1 overactivation promotes age-related hearing loss.
The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.


Mitochondrial DNA haplogroups in the Czech population compared to other European countries.
The analysis of mtDNA haplogroup frequency in various populations is a tool for studying human history and population dynamics. The aim of this study is to map the frequency of major mtDNA haplogroups in 300 maternally unrelated individuals representing the Czech population of the central part of the Czech Republic. Eighteen polymorphic sites in the coding region of mtDNA were screened by PCR-RFLP to determine 11 mtDNA haplogroups and 5 subhaplogroups. The most frequent haplogroups were H (41%) and U (21%). Less frequent haplogroups were J and T, each with a frequency of 8%. Frequencies of other haplogroups (V, K, HV, W, preV, X, and I) did not exceed 5%. The results of our study reveal that the frequency of mtDNA haplogroups in the Czech population is similar to the frequencies obtained in other European countries, especially Poland, Germany, and Russia. On the contrary, significant differences in haplogroup frequency were found between the Czech and Finnish populations (haplogroups U, T, W) and populations from Bulgaria and Turkey (haplogroups H).


Helping parents to stop smoking: which interventions are effective?
Parental smoking increases children's risk of respiratory illness. Encouraging parents not to smoke in the home helps, but stopping smoking altogether is more effective in reducing children's exposure. The prevalence of smoking increases with higher levels of social disadvantage and is therefore a major contributor to widening inequalities in health. Randomised trials have shown that adults can be helped to stop with simple advice from health professionals, behavioural support, nicotine replacement and antidepressants.


The Twitter of Babel: mapping world languages through microblogging platforms.
Large scale analysis and statistics of socio-technical systems that just a few short years ago would have required the use of consistent economic and human resources can nowadays be conveniently performed by mining the enormous amount of digital data produced by human activities. Although a characterization of several aspects of our societies is emerging from the data revolution, a number of questions concerning the reliability and the biases inherent to the big data "proxies" of social life are still open. Here, we survey worldwide linguistic indicators and trends through the analysis of a large-scale dataset of microblogging posts. We show that available data allow for the study of language geography at scales ranging from country-level aggregation to specific city neighborhoods. The high resolution and coverage of the data allows us to investigate different indicators such as the linguistic homogeneity of different countries, the touristic seasonal patterns within countries and the geographical distribution of different languages in multilingual regions. This work highlights the potential of geolocalized studies of open data sources to improve current analysis and develop indicators for major social phenomena in specific communities.


The incidence of internal malignancies in pemphigus and bullous pemphigoid in Japan.
To evaluate the significance of the association of malignancy with autoimmune blistering diseases, we studied the incidence of internal malignancies in pemphigus and bullous pemphigoid based upon 496 cases of pemphigus and 1113 cases of bullous pemphigoid in Japan. Results showed that (1) an association between internal malignancies and pemphigus was observed in 25 out of 496 cases (5.0%), while that with bullous pemphigoid was seen in 64 out of 1113 cases (5.8%). Such association ratios were significantly higher than that of the controls aged over 70 years old (0.61%); (2) The average ages of pemphigus/bullous pemphigoid with malignancy were 64.7 and 69.2 years, respectively. The association ratio of malignancy with pemphigus increased by age, while that with pemphigoid was not correlated with aging; (3) Lung cancer was most common in pemphigus and gastric cancer in bullous pemphigoid; (4) There were no significant differences in the titers of circulating antibody, the presence or extent of mucous involvement or annular erythema between bullous pemphigoid patients with malignancy and without malignancy. Our results indicated that detailed examination for internal malignancy is essential for those patients with pemphigus or bullous pemphigoid.


Cholesterol, coronary heart disease and stroke: a review of published evidence from observational studies and randomized controlled trials.
In observational epidemiologic studies, lower blood cholesterol is associated with a reduced risk from coronary heart disease (CHD) throughout the normal range of cholesterol values observed in most Western populations. There is a continuous positive relationship between CHD risk and blood cholesterol down to at least 3 to 4 mmol/l, with no threshold below which a lower cholesterol is not associated with a lower risk. Observational studies suggest that a prolonged difference in total cholesterol of about 1 mmol/l is associated with one-third less CHD deaths in middle age. Evidence from large-scale cholesterol lowering trials in patients at high-risk of CHD have demonstrated that much of the epidemiologically predicted difference in CHD risk associated with differences in cholesterol was achieved within a few years of treatment. Moreover, these trials have demonstrated that such therapy was not associated with increased non-CHD mortality. Total cholesterol is transported in blood as low-density lipoprotein cholesterol or LDL cholesterol (about 70%) and as high density lipoprotein cholesterol or HDL cholesterol (about 30%). Since these two cholesterol fractions have opposing effects on vascular risk, a 1 mmol/l reduction in LDL cholesterol is likely to be associated with 40 to 50% lower CHD risk. The size of the absolute reduction in CHD produced by lowering total and LDL cholesterol is determined by an individual's overall risk rather than their initial cholesterol level. Consequently, the benefits of drug treatment to lower LDL cholesterol are greater in those at higher absolute risk of CHD rather than at high cholesterol levels. Dietary saturated fat is the chief determinant of total and LDL cholesterol levels. Replacing 60% of the intake of saturated fat by other fats and reducing the intake of dietary cholesterol could reduce blood total cholesterol levels by about 0.8 mmol/l (that is by 10 to 15%), with four fifths of this reduction being in LDL cholesterol.


Circulating protein synthesis rates reveal skeletal muscle proteome dynamics.
Here, we have described and validated a strategy for monitoring skeletal muscle protein synthesis rates in rodents and humans over days or weeks from blood samples. We based this approach on label incorporation into proteins that are synthesized specifically in skeletal muscle and escape into the circulation. Heavy water labeling combined with sensitive tandem mass spectrometric analysis allowed integrated synthesis rates of proteins in muscle tissue across the proteome to be measured over several weeks. Fractional synthesis rate (FSR) of plasma creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3) in the blood, more than 90% of which is derived from skeletal muscle, correlated closely with FSR of CK-M, CA-3, and other proteins of various ontologies in skeletal muscle tissue in both rodents and humans. Protein synthesis rates across the muscle proteome generally changed in a coordinate manner in response to a sprint interval exercise training regimen in humans and to denervation or clenbuterol treatment in rodents. FSR of plasma CK-M and CA-3 revealed changes and interindividual differences in muscle tissue proteome dynamics. In human subjects, sprint interval training primarily stimulated synthesis of structural and glycolytic proteins. Together, our results indicate that this approach provides a virtual biopsy, sensitively revealing individualized changes in proteome-wide synthesis rates in skeletal muscle without a muscle biopsy. Accordingly, this approach has potential applications for the diagnosis, management, and treatment of muscle disorders.


Adjusting the neuroimaging statistical inferences for nonstationarity.
In neuroimaging cluster-based inference has generally been found to be more powerful than voxel-wise inference. However standard cluster-based methods assume stationarity (constant smoothness), while under nonstationarity clusters are larger in smooth regions just by chance, making false positive risk spatially variant. Hayasaka et al. proposed a Random Field Theory (RFT) based nonstationarity adjustment for cluster inference and validated the method in terms of controlling the overall family-wise false positive rate. The RFT-based methods, however, have never been directly assessed in terms of homogeneity of local false positive risk. In this work we propose a new cluster size adjustment that accounts for local smoothness, based on local empirical cluster size distributions and a two-pass permutation method. We also propose a new approach to measure homogeneity of local false positive risk, and use this method to compare the RFT-based and our new empirical adjustment methods. We apply these techniques to both cluster-based and a related inference, threshold-free cluster enhancement (TFCE). Using simulated and real data we confirm the expected heterogeneity in false positive risk with unadjusted cluster inference but find that RFT-based adjustment does not fully eliminate heterogeneity; we also observe that our proposed empirical adjustment dramatically increases the homogeneity and TFCE inference is generally quite robust to nonstationarity.


60 years of advances in neuropsychopharmacology for improving brain health, renewed hope for progress.
Pharmacotherapy is effective in helping many patients suffering from psychiatric and neurological disorders, and both psychotherapeutic and stimulation-based techniques likewise have important roles to play in their treatment. However, therapeutic progress has recently been slow. Future success for improving the control and prevention of brain disorders will depend upon deeper insights into their causes and pathophysiological substrates. It will also necessitate new and more rigorous methods for identifying, validating, developing and clinically deploying new treatments. A field of Research and Development (R and D) that remains critical to this endeavour is Neuropsychopharmacology which transformed the lives of patients by introducing pharmacological treatments for psychiatric disorder some 60 years ago. For about half of this time, the European College of Neuropsychopharmacology (ECNP) has fostered efforts to enhance our understanding of the brain, and to improve the management of psychiatric disorders. Further, together with partners in academia and industry, and in discussions with regulators and patients, the ECNP is implicated in new initiatives to achieve this goal. This is then an opportune moment to survey the field, to analyse what we have learned from the achievements and failures of the past, and to identify major challenges for the future. It is also important to highlight strategies that are being put in place in the quest for more effective treatment of brain disorders: from experimental research and drug discovery to clinical development and collaborative ventures for reinforcing "R and D". The present article sets the scene, then introduces and interlinks the eight articles that comprise this Special Volume of European Neuropsychopharmacology. A broad-based suite of themes is covered embracing: the past, present and future of "R and D" for psychiatric disorders; complementary contributions of genetics and epigenetics; efforts to improve the treatment of depression, neurodevelopmental and neurodegenerative disorders; and advances in the analysis and neuroimaging of cellular and cerebral circuits.


The lagoon at Caroline/Millennium atoll, Republic of Kiribati: natural history of a nearly pristine ecosystem.
A series of surveys were carried out to characterize the physical and biological parameters of the Millennium Atoll lagoon during a research expedition in April of 2009. Millennium is a remote coral atoll in the Central Pacific belonging to the Republic of Kiribati, and a member of the Southern Line Islands chain. The atoll is among the few remaining coral reef ecosystems that are relatively pristine. The lagoon is highly enclosed, and was characterized by reticulate patch and line reefs throughout the center of the lagoon as well as perimeter reefs around the rim of the atoll. The depth reached a maximum of 33.3 m in the central region of the lagoon, and averaged between 8.8 and 13.7 m in most of the pools. The deepest areas were found to harbor large platforms of Favia matthaii, which presumably provided a base upon which the dominant corals (Acropora spp.) grew to form the reticulate reef structure. The benthic algal communities consisted mainly of crustose coralline algae (CCA), microfilamentous turf algae and isolated patches of Halimeda spp. and Caulerpa spp. Fish species richness in the lagoon was half of that observed on the adjacent fore reef. The lagoon is likely an important nursery habitat for a number of important fisheries species including the blacktip reef shark and Napoleon wrasse, which are heavily exploited elsewhere around the world but were common in the lagoon at Millennium. The lagoon also supports an abundance of giant clams (Tridacna maxima). Millennium lagoon provides an excellent reference of a relatively undisturbed coral atoll. As with most coral reefs around the world, the lagoon communities of Millennium may be threatened by climate change and associated warming, acidification and sea level rise, as well as sporadic local resource exploitation which is difficult to monitor and enforce because of the atoll's remote location. While the remote nature of Millennium has allowed it to remain one of the few nearly pristine coral reef ecosystems in the world, it is imperative that this ecosystem receives protection so that it may survive for future generations.


Relationship of height, weight and body mass index to the risk of hip and knee replacements in middle-aged women.
To examine the effect of height, weight and body mass index (BMI) on the risk of hip and knee replacement in middle-aged women. In a prospective cohort study 490 532 women aged 50-69 yrs who were recruited in the UK in 1996-2001 were followed over 2.9 yrs for incident primary hip and knee replacements. Height, weight and BMI were all associated with the risk of hip and knee replacement. Comparing the tallest group (>or=170 cm) with the shortest (<155 cm) the relative risks were 1.90 (95%CI 1.55-2.32) for hip replacement and 1.55 (95%CI 1.19-2.00) for knee replacement. Comparing the heaviest group (>or=75 kg) with the lightest (<60 kg) the relative risks of hip and knee replacement were 2.37 (95%CI 2.04-2.75) and 9.71 (95%CI 7.39-12.77), respectively. Comparing obese women (BMI >or= 30 kg/m(2)) to women with a BMI < 22.5 kg/m(2), the relative risks for hip and knee replacement were 2.47 (95%CI 2.11-2.89) and 10.51 (95%CI 7.85-14.08), respectively. These effects did not vary according to age, education, alcohol and tobacco consumption, or with use of hormonal therapies. Currently, an estimated 27% of hip replacements and 69% of knee replacements in middle-aged women in the UK are attributable to obesity. In middle-aged women, the risk of having a hip or knee replacement increases with both increasing height and increasing BMI. From a clinical perspective, relatively small increases in average BMI among middle-aged women are likely to have a substantial impact on the already increasing rates of joint replacement in the UK.


Experiment-model interaction for analysis of epicardial activation during human ventricular fibrillation with global myocardial ischaemia.
We describe a combined experiment-modelling framework to investigate the effects of ischaemia on the organisation of ventricular fibrillation in the human heart. In a series of experimental studies epicardial activity was recorded from 10 patients undergoing routine cardiac surgery. Ventricular fibrillation was induced by burst pacing, and recording continued during 2.5 min of global cardiac ischaemia followed by 30 s of coronary reflow. Modelling used a 2D description of human ventricular tissue. Global cardiac ischaemia was simulated by (i) decreased intracellular ATP concentration and subsequent activation of an ATP sensitive K⁺ current, (ii) elevated extracellular K⁺ concentration, and (iii) acidosis resulting in reduced magnitude of the L-type Ca²⁺ current I(Ca,L). Simulated ischaemia acted to shorten action potential duration, reduce conduction velocity, increase effective refractory period, and flatten restitution. In the model, these effects resulted in slower re-entrant activity that was qualitatively consistent with our observations in the human heart. However, the flattening of restitution also resulted in the collapse of many re-entrant waves to several stable re-entrant waves, which was different to the overall trend we observed in the experimental data. These findings highlight a potential role for other factors, such as structural or functional heterogeneity in sustaining wavebreak during human ventricular fibrillation with global myocardial ischaemia.


In vitro effects of glutamate and N-methyl-D-aspartate receptor (NMDAR) antagonism on human tendon derived cells.
It is known that extracellular glutamate concentrations are increased in tendinopathy but the effects of glutamate upon human tendon derived cells are unknown. The primary purpose was to investigate the effect of glutamate exposure on human tendon-derived cells in terms of viability, protein, and gene expression. The second purpose was to assess whether NMDAR antagonism would affect the response of tendon-derived cells to glutamate exposure. Human tendon-derived cells were obtained from supraspinatus tendon tissue obtained during rotator cuff repair (tendon tear derived cells) and from healthy hamstring tendon tissue (control cells). The in vitro impact of glutamate exposure and NMDAR antagonism (MK-801) was measured using the Alamar blue cell viability assay, immunocytochemistry, and quantitative real-time PCR. Glutamate reduced cell viability at 24 h in tendon tear derived cells but not in control cells at concentrations of 7.5 mM and above. Cell viability was significantly reduced after 72 h of 1.875 mM glutamate in both cell groups; this deleterious effect was attenuated by NMDAR antagonism with 10 µM MK-801. Both 24 and 72 h of 1.875 mM glutamate exposure reduced Type 1 alpha 1 collagen (COL1A1) and Type 3 alpha 1 collagen (COL3A1) gene expression, but increased Aggrecan gene expression. We propose that these effects of glutamate on tendon derived cells including reduced cell viability and altered matrix gene expression contribute to the pathogenesis of tendinopathy.


Reproducibility of fMRI results across four institutions using a spatial working memory task.
Four U.S. sites formed a consortium to conduct a multisite study of fMRI methods. The primary purpose of this consortium was to examine the reliability and reproducibility of fMRI results. FMRI data were collected on healthy adults during performance of a spatial working memory task at four different institutions. Two sets of data from each institution were made available. First, data from two subjects were made available from each site and were processed and analyzed as a pooled data set. Second, statistical maps from five to eight subjects per site were made available. These images were aligned in stereotactic space and common regions of activation were examined to address the reproducibility of fMRI results when both image acquisition and analysis vary as a function of site. Our grouped and individual data analyses showed reliable patterns of activation in dorsolateral prefrontal cortex and posterior parietal cortex during performance of the working memory task across all four sites. This multisite study, the first of its kind using fMRI data, demonstrates highly consistent findings across sites.


Mind the Gap: Information Sharing Between Health, Mental Health and Social Care Services.
Information sharing is key to integrated, collaborative, and continuous care. People with a lived experience of mental illness may access several services across the health, mental health and social care sectors, which creates challenges for information sharing. The health informatics community has traditionally not prioritised social care informatics. However, with the growing role of social care in the lives of people with complex health conditions, now is the time when we must consider the articulation between health informatics and social care informatics in Australia. This paper reports the results of a qualitative study to understand the current context of information sharing between health, mental health and social care services. Interviews and focus groups with nine clinicians, caseworkers and support workers were undertaken. Thematic analysis supported the development of several themes. These include the growing role of social care services, the importance of trust and the challenge created by the complexity of conditions people can present with when accessing social care services. To ensure the growing range of social care services do not get left behind with the increasing digitisation of the Australian health system, the health informatics community should prioritise the inclusion of social care informatics in its scope of practice.


[Observation on therapeutic effect of chronic fatigue syndrome treated with coiling dragon needling and moving cupping on back].
To compare the differences of therapeutic effect of chronic fatigue syndrome treated with the combined therapy of coiling dragon needling and cupping on back and the western medicine therapy with Prednisone. Seventy-two cases were randomly divided into an acupuncture and cupping group (37 cases) and a Prednisone group (35 cases). In acupuncture and cupping group, Jiaji (EX-B 2) points of T1--L5 were applied with coiling dragon needling (once a day), combined with moving cupping on back (once every two days); in Prednisone group, Prednisone tablets were orally taken for 10 mg at 8:00 am. Seven days made one course, and 2 courses were carried on totally. FS-14 scale and BELL's chronic fatigue syndrome integral table were applied to evaluate the fatigue degree of patients before and after treatment, and the therapeutic effects of both groups were compared. After one course of treatment, the BELL's scores of both groups were obviously improved (both P < 0.01), but there was no significant difference between groups (P > 0.05); after two courses of treatment, the BELL's score in acupuncture and cupping group improved more obviously than that in Prednisone group, and the total effective rate of 91.9% (34/37) in acupuncture and cupping group was superior to that of 71.4% (25/35) in Prednisone group (P < 0.05). The therapeutic effect of chronic fatigue syndrome treated with coiling dragon needling and moving cupping on back is positive, superior to that of Prednisone with oral administration.


Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas.
Microsurgical excision is an established treatment for vestibular schwannoma (VS). In 1992 the authors used a patient questionnaire to evaluate the functional outcome and quality of life in a series of 224 consecutive patients. In addition, starting with gamma knife surgery (GKS) in 1992, the authors decided to use the same methodology to evaluate prospectively the results of this modality to compare the two alternatives. Among the 500 patients who were included prospectively, the authors only evaluated patients in whom GKS was the primary treatment for unilateral VS. Four years of follow up was available for the first 104 consecutive patients. Statistical analysis of the GKS and microsurgery populations has shown that only a comparison of Stage II and III (according to the Koos classification) was meaningful in terms of group size and preoperative risk factor distribution. Objective results and questionnaire answers from the first 97 consecutive patients were compared with the 110 patients in the microsurgery group who fulfilled the inclusion criteria. Questionnaire answers indicated that 100% of patients who underwent GKS compared with 63% of patients who underwent microsurgery had no new facial motor disturbance. Forty-nine percent of patients who underwent GKS (17% in the microsurgery study) had no ocular symptoms, and 91% of patients treated with GKS (61% in the microsurgery study) had no functional deterioration after treatment. The mean hospitalization stay was 3 days after GKS and 23 days after microsurgery. All the patients who underwent GKS who had been employed, except one, had kept the same professional activity (56% in the microsurgery study). The mean time away from work was 7 days for GKS (130 days in the microsurgery study). Among patients whose preoperative hearing level was Class 1 according to the Gardner and Robertson scale, 70% preserved functional hearing after GKS (Class 1 or 2) compared with only 37.5% in the microsurgery group. Functional side effects happen during the first 2 years after radiosurgery. Findings after 4 years of follow up indicated that GKS provided better functional outcomes than microsurgery in this patient series.


Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease: A Randomized Clinical Trial.
There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate. To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD. Participants were recruited into a double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, with 24 months of treatment and follow-up. This multicenter study in England and Scotland involved 32 National Health Service memory clinics within secondary specialist services for people with dementia. From 886 screened patients, 554 patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination [sMMSE] score ≥24) were randomized. Participants were randomly allocated 1:1:1 in a semifactorial design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months. Primary outcome measures were decrease in sMMSE score and Bristol Activities of Daily Living Scale (BADLS), analyzed by intention-to-treat repeated-measures regression. Of 544 eligible participants (241 women and 303 men), the mean (SD) age was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% [114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for the placebo group. Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The combined minocycline group had mean sMMSE scores 0.1 points higher than the placebo group (95% CI, -1.1 to 1.2; P = .90). The decrease in mean sMMSE scores was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs placebo = -0.53; 95% CI, -2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline = -0.31; 95% CI, -0.2 to 1.8; P = .77). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population. isrctn.org Identifier: ISRCTN16105064.


Impact of age and retinal degeneration on the light input to circadian brain structures.
Aging causes anatomical and functional changes in visual and circadian systems. In wild type mice rods, cones, and photosensitive retinal ganglion cells (pRGCs) decline with age. In rd/rd cl mice, the early loss of rods and cones is followed by protracted transneuronal loss of inner retinal neurons as well as the pRGCs. Here we use Fos induction to study the light input pathway to the suprachiasmatic nuclei (SCN), the intergeniculate leaflets (IGL) and ventral lateral geniculate nuclei (vLGN) of old (∼700 days) and young (∼150 days) wild type and rd/rd cl mice. Cholera toxin tracing was used in parallel to study the anatomy of this pathway. We find that aging rather than retinal degeneration is a more important factor in reducing light input to the SCN, causing both a reduction in Fos expression and retinal afferents. Furthermore, we show light-induced Fos within the vLGN and IGL is predominantly subserved by rods and cones, and once again aging reduces the amplitude of this response.


Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line.
The neurodegenerative process in Parkinson's disease (PD) is accompanied by the presence of a neuroinflammatory response, which has been suggested as one of the principal components involved in PD progression. In this report we assessed the inflammatory potential of alpha-synuclein, a protein central to PD pathogenesis, released by neurons on the mouse microglia cell line BV-2. BV-2 cells were treated with conditioned medium isolated from normal SH-SY5Y cells and clones that over-express WT or mutant A53T alpha-synuclein. Conditioned medium isolated from over-expressing clones induced the transcription and release of pro-inflammatory cytokines. Treatment of SH-SY5Y alpha-synuclein over-expressing cells with MPP+, the active metabolite of the neurotoxin MPTP, increased the inflammatory response in BV-2 cells. In contrast, the direct exposure of BV-2 cells to MPP+ failed to induce an inflammatory response. These results support the hypothesis that WT and A53T alpha-synuclein has an important role in the initiation and maintenance of inflammation in PD, through the activation of a pro-inflammatory response in microglial cells.


Antithrombotic therapy in patients with any form of intracranial haemorrhage: a systematic review of the available controlled studies.
Patients with intracranial haemorrhage may sometimes require antithrombotic drugs or be inadvertently given antithrombotic therapy. We systematically reviewed all published trials comparing any antithrombotic agent with control among patients with any form of intracranial haemorrhage. We extracted data on deaths, recurrent intracranial haemorrhage and functional outcome. There were 9 randomised trials of 5 different antithrombotic agents versus control in patients with subarachnoid haemorrhage (6 trials, n = 1,224) or with acute intracerebral haemorrhage (3 trials, n = 819). The overall odds ratio (OR) for death among patients with any intracranial haemorrhage given an antiplatelet agent (8 trials, 1,997 patients) was 0.85 (95% confidence interval, CI, 0.63-1.15), and for recurrent intracranial haemorrhage it was 1.00 (95% CI 0.73-1.37). The corresponding ORs for patients with intraparenchymal cerebral haemorrhage were 0.96 (0.62-1.5) and 1.02 (0.5-1.8), respectively, but 65% of these patients received only a few doses of antithrombotic treatment. The overall OR for death in patients with any intraparenchymal cerebral haemorrhage given heparin compared with control (3 trials, 819 patients, subcutaneous heparin) was 0.96 (95% CI 0.38-2.40), and for recurrent intracranial haemorrhage it was 2.00 (95% CI 0.86-4.70). There were no reliable data on the effects of antithrombotic agents on functional outcome. These scant data do not support reliable conclusions about the safety or otherwise of antithrombotic agents in patients with acute intracranial haemorrhage. Antithrombotic agents should be avoided where possible in patients with acute intracerebral haemorrhage.


Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials.
Long-term follow-up of randomised trials of aspirin in prevention of vascular events showed that daily aspirin reduced the incidence of colorectal cancer and several other cancers and reduced metastasis. However, statistical power was inadequate to establish effects on less common cancers and on cancers in women. Observational studies could provide this information if results can be shown to be reliable. We therefore compared effects of aspirin on risk and outcome of cancer in observational studies versus randomised trials. For this systematic review, we searched for case-control and cohort studies published from 1950 to 2011 that reported associations between aspirin use and risk or outcome of cancer. Associations were pooled across studies by meta-analysis and stratified by duration, dose, and frequency of aspirin use and by stage of cancer. We compared associations from observational studies with the effect of aspirin on 20-year risk of cancer death and on metastasis in the recent reports of randomised trials. In case-control studies, regular use of aspirin was associated with reduced risk of colorectal cancer (pooled odds ratio [OR] 0·62, 95% CI 0·58-0·67, p(sig)<0·0001, 17 studies), with little heterogeneity (p(het)=0·13) in effect between studies, and good agreement with the effect of daily aspirin use on 20-year risk of death due to colorectal cancer from the randomised trials (OR 0·58, 95% CI 0·44-0·78, p(sig)=0·0002, p(het)=0·45). Similarly consistent reductions were seen in risks of oesophageal, gastric, biliary, and breast cancer. Overall, estimates of effect of aspirin on individual cancers in case-control studies were highly correlated with those in randomised trials (r(2)=0·71, p=0·0006), with largest effects on risk of gastrointestinal cancers (case-control studies, OR 0·62, 95% CI 0·55-0·70, p<0·0001, 41 studies; randomised trials, OR 0·54, 95% CI 0·42-0·70, p<0·0001). Estimates of effects in cohort studies were similar when analyses were stratified by frequency and duration of aspirin use, were based on updated assessments of use during follow-up, and were appropriately adjusted for baseline characteristics. Although fewer observational studies stratified analyses by the stage of cancer at diagnosis, regular use of aspirin was associated with a reduced proportion of cancers with distant metastasis (OR 0·69, 95% CI 0·57-0·83, p(sig)<0·0001, p(het)=0·89, five studies), but not with any reduction in regional spread (OR 0·98, 95% CI 0·88-1·09, p(sig)=0·71, p(het)=0·88, seven studies), consistent again with the findings in randomised trials. Observational studies show that regular use of aspirin reduces the long-term risk of several cancers and the risk of distant metastasis. Results of methodologically rigorous studies are consistent with those obtained from randomised controlled trials, but sensitivity is particularly dependent on appropriately detailed recording and analysis of aspirin use. None.


Assessing white matter ischemic damage in dementia patients by measurement of myelin proteins.
White matter ischemia is difficult to quantify histologically. Myelin-associated glycoprotein (MAG) is highly susceptible to ischemia, being expressed only adaxonally, far from the oligodendrocyte cell body. Myelin-basic protein (MBP) and proteolipid protein (PLP) are expressed throughout the myelin sheath. We compared MAG, MBP, and PLP levels in parietal white matter homogenates from 17 vascular dementia (VaD), 49 Alzheimer's disease (AD), and 33 control brains, after assessing the post-mortem stability of these proteins. Small vessel disease (SVD) and cerebral amyloid angiopathy (CAA) severity had been assessed in paraffin sections. The concentration of MAG remained stable post-mortem, declined with increasing SVD, and was significantly lower in VaD than controls. The concentration of MBP fell progressively post-mortem, limiting its diagnostic utility in this context. Proteolipid protein was stable post-mortem and increased significantly with SVD severity. The MAG/PLP ratio declined significantly with SVD and CAA severity. The MAG and PLP levels and MAG/PLP did not differ significantly between AD and control brains. We validated the utility of MAG and MAG/PLP measurements on analysis of 74 frontal white matter samples from an Oxford cohort in which SVD had previously been scored. MAG concentration and the MAG/PLP ratio are useful post-mortem measures of ante-mortem white matter ischemia.


A genetic investigation of Korean mummies from the Joseon Dynasty.
Two Korean mummies (Danwoong-mirra and Yoon-mirra) found in medieval tombs in the central region of the Korean peninsula were genetically investigated by analysis of mitochondrial DNA (mtDNA), Y-chromosomal short tandem repeat (Y-STR) and the ABO gene. Danwoong-mirra is a male child mummy and Yoon-mirra is a pregnant female mummy, dating back about 550 and 450 years, respectively. DNA was extracted from soft tissues or bones. mtDNA, Y-STR and the ABO gene were amplified using a small size amplicon strategy and were analyzed according to the criteria of ancient DNA analysis to ensure that authentic DNA typing results were obtained from these ancient samples. Analysis of mtDNA hypervariable region sequence and coding region single nucleotide polymorphism (SNP) information revealed that Danwoong-mirra and Yoon-mirra belong to the East Asian mtDNA haplogroups D4 and M7c, respectively. The Y-STRs were analyzed in the male child mummy (Danwoong-mirra) using the AmpFlSTR® Yfiler PCR Amplification Kit and an in-house Y-miniplex plus system, and could be characterized in 4 loci with small amplicon size. The analysis of ABO gene SNPs using multiplex single base extension methods revealed that the ABO blood types of Danwoong-mirra and Yoon-mirra are AO01 and AB, respectively. The small size amplicon strategy and the authentication process in the present study will be effectively applicable to future genetic analyses of various forensic and ancient samples.


Russian Old Believers: genetic consequences of their persecution and exile, as shown by mitochondrial DNA evidence.
In 1653, the Patriarch Nikon modified liturgical practices to bring the Russian Orthodox Church in line with those of the Eastern (Greek) Orthodox Church, from which it had split 200 years earlier. The Old Believers (staroveri) rejected these changes and continued to worship using the earlier practices. These actions resulted in their persecution by the Russian Orthodox Church, which forced them into exile across Siberia. Given their history, we investigate whether populations of Old Believers have diverged genetically from other Slavic populations as a result of their isolation. We also examine whether the three Old Believer populations analyzed in this study are part of a single gene pool (founder population) or are instead derived from heterogeneous sources. As part of this analysis, we survey the mitochondrial DNAs (mtDNAs) of 189 Russian Old Believer individuals from three populations in Siberia and 201 ethnic Russians from different parts of Siberia for phylogenetically informative mutations in the coding and noncoding regions. Our results indicate that the Old Believers have not significantly diverged genetically from other Slavic populations over the 200-300 years of their isolation in Siberia. However, they do show some unique patterns of mtDNA variation relative to other Slavic groups, such as a high frequency of subhaplogroup U4, a surprisingly low frequency of haplogroup H, and low frequencies of the rare East Eurasian subhaplogroup D5.


Telephone-delivered cognitive-behavioral therapy for pain management among older military veterans: a randomized trial.
This study investigated the effectiveness of telephone-delivered cognitive-behavioral therapy (T-CBT) in the management of chronic pain with older military veterans enrolled in VA primary-care clinics. We conducted a randomized clinical trial comparing T-CBT with telephone-delivered pain education (T-EDU). A total of 98 military veterans with chronic pain were enrolled in the study and randomized into one of two treatment conditions. Study participants were recruited from primary-care clinics at an urban VA medical center and affiliated VA community-based outpatient clinics (CBOCs). Pain management outcomes were measured at midtreatment (10 weeks), posttreatment (20 weeks), 3-month follow-up (32 weeks), and 6-month follow-up (46 weeks). No significant differences were found between the two treatment groups on any of the outcome measures. Both treatment groups reported small but significant increases in level of physical and mental health, and reductions in pain and depressive symptoms. Improvements in all primary outcome measures were mediated by reductions in catastrophizing. Telephone-delivered CBT and EDU warrant further study as easily accessible interventions for rural-living older individuals with chronic pain.


Emotional content of true and false memories.
Many people believe that emotional memories (including those that arise in therapy) are particularly likely to represent true events because of their emotional content. But is emotional content a reliable indicator of memory accuracy? The current research assessed the emotional content of participants' pre-existing (true) and manipulated (false) memories for childhood events. False memories for one of three emotional childhood events were planted using a suggestive manipulation and then compared, along several subjective dimensions, with other participants' true memories. On most emotional dimensions (e.g., how emotional was this event for you?), true and false memories were indistinguishable. On a few measures (e.g., intensity of feelings at the time of the event), true memories were more emotional than false memories in the aggregate, yet true and false memories were equally likely to be rated as uniformly emotional. These results suggest that even substantial emotional content may not reliably indicate memory accuracy.


A Satellite-Based Imaging Instrumentation Concept for Hyperspectral Thermal Remote Sensing.
This paper describes the concept of the hyperspectral Earth-observing thermal infrared (TIR) satellite mission HiTeSEM (High-resolution Temperature and Spectral Emissivity Mapping). The scientific goal is to measure specific key variables from the biosphere, hydrosphere, pedosphere, and geosphere related to two global problems of significant societal relevance: food security and human health. The key variables comprise land and sea surface radiation temperature and emissivity, surface moisture, thermal inertia, evapotranspiration, soil minerals and grain size components, soil organic carbon, plant physiological variables, and heat fluxes. The retrieval of this information requires a TIR imaging system with adequate spatial and spectral resolutions and with day-night following observation capability. Another challenge is the monitoring of temporally high dynamic features like energy fluxes, which require adequate revisit time. The suggested solution is a sensor pointing concept to allow high revisit times for selected target regions (1-5 days at off-nadir). At the same time, global observations in the nadir direction are guaranteed with a lower temporal repeat cycle (>1 month). To account for the demand of a high spatial resolution for complex targets, it is suggested to combine in one optic (1) a hyperspectral TIR system with ~75 bands at 7.2-12.5 µm (instrument NEDT 0.05 K-0.1 K) and a ground sampling distance (GSD) of 60 m, and (2) a panchromatic high-resolution TIR-imager with two channels (8.0-10.25 µm and 10.25-12.5 µm) and a GSD of 20 m. The identified science case requires a good correlation of the instrument orbit with Sentinel-2 (maximum delay of 1-3 days) to combine data from the visible and near infrared (VNIR), the shortwave infrared (SWIR) and TIR spectral regions and to refine parameter retrieval.


13C-direct detected NMR experiments for the sequential J-based resonance assignment of RNA oligonucleotides.
We present here a set of (13)C-direct detected NMR experiments to facilitate the resonance assignment of RNA oligonucleotides. Three experiments have been developed: (1) the (H)CC-TOCSY-experiment utilizing a virtual decoupling scheme to assign the intraresidual ribose (13)C-spins, (2) the (H)CPC-experiment that correlates each phosphorus with the C4' nuclei of adjacent nucleotides via J(C,P) couplings and (3) the (H)CPC-CCH-TOCSY-experiment that correlates the phosphorus nuclei with the respective C1',H1' ribose signals. The experiments were applied to two RNA hairpin structures. The current set of (13)C-direct detected experiments allows direct and unambiguous assignment of the majority of the hetero nuclei and the identification of the individual ribose moieties following their sequential assignment. Thus, (13)C-direct detected NMR methods constitute useful complements to the conventional (1)H-detected approach for the resonance assignment of oligonucleotides that is often hindered by the limited chemical shift dispersion. The developed methods can also be applied to large deuterated RNAs.


Amygdala volume and nonverbal social impairment in adolescent and adult males with autism.
Autism is a syndrome of unknown cause, marked by abnormal development of social behavior. Attempts to link pathological features of the amygdala, which plays a key role in emotional processing, to autism have shown little consensus. To evaluate amygdala volume in individuals with autism spectrum disorders and its relationship to laboratory measures of social behavior to examine whether variations in amygdala structure relate to symptom severity. We conducted 2 cross-sectional studies of amygdala volume, measured blind to diagnosis on high-resolution, anatomical magnetic resonance images. Participants were 54 males aged 8 to 25 years, including 23 with autism and 5 with Asperger syndrome or pervasive developmental disorder not otherwise specified, recruited and evaluated at an academic center for developmental disabilities and 26 age- and sex-matched community volunteers. The Autism Diagnostic Interview-Revised was used to confirm diagnoses and to validate relationships with laboratory measures of social function. Amygdala volume, judgment of facial expressions, and eye tracking. In study 1, individuals with autism who had small amygdalae were slowest to distinguish emotional from neutral expressions (P=.02) and showed least fixation of eye regions (P=.04). These same individuals were most socially impaired in early childhood, as reported on the Autism Diagnostic Interview-Revised (P<.04). Study 2 showed smaller amygdalae in individuals with autism than in control subjects (P=.03) and group differences in the relation between amygdala volume and age. Study 2 also replicated findings of more gaze avoidance and childhood impairment in participants with autism with the smallest amygdalae. Across the combined sample, severity of social deficits interacted with age to predict different patterns of amygdala development in autism (P=.047). These findings best support a model of amygdala hyperactivity that could explain most volumetric findings in autism. Further psychophysiological and histopathological studies are indicated to confirm these findings.


Structural basis for the activity of a cytoplasmic RNA terminal uridylyl transferase.
Cytoplasmic terminal uridylyl transferases comprise a conserved family of enzymes that negatively regulate the stability or biological activity of a variety of eukaryotic RNAs, including mRNAs and tumor-suppressor let-7 microRNAs. Here we describe crystal structures of the Schizosaccharomyces pombe cytoplasmic terminal uridylyl transferase Cid1 in two apo conformers and bound to UTP. We demonstrate that a single histidine residue, conserved in mammalian Cid1 orthologs, is responsible for discrimination between UTP and ATP. We also describe a new high-affinity RNA substrate-binding mechanism of Cid1, which is essential for enzymatic activity and is mediated by three basic patches across the surface of the enzyme. Overall, our structures provide a basis for understanding the activity of Cid1 and a mechanism of UTP selectivity conserved in its human orthologs, suggesting potential implications for anticancer drug design.


Impact of alcohol advertising and media exposure on adolescent alcohol use: a systematic review of longitudinal studies.
To assess the impact of alcohol advertising and media exposure on future adolescent alcohol use. We searched MEDLINE, the Cochrane Library, Sociological Abstracts, and PsycLIT, from 1990 to September 2008, supplemented with searches of Google scholar, hand searches of key journals and reference lists of identified papers and key publications for more recent publications. We selected longitudinal studies that assessed individuals' exposure to commercial communications and media and alcohol drinking behaviour at baseline, and assessed alcohol drinking behaviour at follow-up. Participants were adolescents aged 18 years or younger or below the legal drinking age of the country of origin of the study, whichever was the higher. Thirteen longitudinal studies that followed up a total of over 38,000 young people met inclusion criteria. The studies measured exposure to advertising and promotion in a variety of ways, including estimates of the volume of media and advertising exposure, ownership of branded merchandise, recall and receptivity, and one study on expenditure on advertisements. Follow-up ranged from 8 to 96 months. One study reported outcomes at multiple time-points, 3, 5, and 8 years. Seven studies provided data on initiation of alcohol use amongst non-drinkers, three studies on maintenance and frequency of drinking amongst baseline drinkers, and seven studies on alcohol use of the total sample of non-drinkers and drinkers at baseline. Twelve of the thirteen studies concluded an impact of exposure on subsequent alcohol use, including initiation of drinking and heavier drinking amongst existing drinkers, with a dose response relationship in all studies that reported such exposure and analysis. There was variation in the strength of association, and the degree to which potential confounders were controlled for. The thirteenth study, which tested the impact of outdoor advertising placed near schools failed to detect an impact on alcohol use, but found an impact on intentions to use. Longitudinal studies consistently suggest that exposure to media and commercial communications on alcohol is associated with the likelihood that adolescents will start to drink alcohol, and with increased drinking amongst baseline drinkers. Based on the strength of this association, the consistency of findings across numerous observational studies, temporality of exposure and drinking behaviours observed, dose-response relationships, as well as the theoretical plausibility regarding the impact of media exposure and commercial communications, we conclude that alcohol advertising and promotion increases the likelihood that adolescents will start to use alcohol, and to drink more if they are already using alcohol.


Increased functional connectivity with puberty in the mentalising network involved in social emotion processing.
This article is part of a Special Issue "Puberty and Adolescence". There is increasing evidence that puberty plays an important role in the structural and functional brain development seen in adolescence, but little is known of the pubertal influence on changes in functional connectivity. We explored how pubertal indicators (salivary concentrations of testosterone, oestradiol and DHEA; pubertal stage; menarcheal status) relate to functional connectivity between components of a mentalising network identified to be engaged in social emotion processing by our prior work, using psychophysiological interaction (PPI) analysis. Female adolescents aged 11 to 13years were scanned whilst silently reading scenarios designed to evoke either social emotions (guilt and embarrassment) or basic emotions (disgust and fear), of which only social compared to basic emotions require the representation of another person's mental states. Pubertal stage and menarcheal status were used to assign participants to pre/early or mid/late puberty groups. We found increased functional connectivity between the dorsomedial prefrontal cortex (DMPFC) and the right posterior superior temporal sulcus (pSTS) and right temporo-parietal junction (TPJ) during social relative to basic emotion processing. Moreover, increasing oestradiol concentrations were associated with increased functional connectivity between the DMPFC and the right TPJ during social relative to basic emotion processing, independent of age. Our analysis of the PPI data by phenotypic pubertal status showed that more advanced puberty stage was associated with enhanced functional connectivity between the DMPFC and the left anterior temporal cortex (ATC) during social relative to basic emotion processing, also independent of age. Our results suggest increased functional maturation of the social brain network with the advancement of puberty in girls.


Ginger (Zingiber officinale) reduces muscle pain caused by eccentric exercise.
Ginger has been shown to exert anti-inflammatory effects in rodents, but its effect on human muscle pain is uncertain. Heat treatment of ginger has been suggested to enhance its hypoalgesic effects. The purpose of this study was to examine the effects of 11 days of raw (study 1) and heat-treated (study 2) ginger supplementation on muscle pain. Study 1 and 2 were identical double-blind, placebo controlled, randomized experiments with 34 and 40 volunteers, respectively. Participants consumed 2 grams of either raw (study 1) or heated (study 2) ginger or placebo for 11 consecutive days. Participants performed 18 eccentric actions of the elbow flexors to induce pain and inflammation. Pain intensity, perceived effort, plasma prostaglandin E(2), arm volume, range-of-motion and isometric strength were assessed prior to and for 3 days after exercise. Results Raw (25%, -.78 SD, P = .041) and heat-treated (23%, -.57 SD, P = .049) ginger resulted in similar pain reductions 24 hours after eccentric exercise compared to placebo. Smaller effects were noted between both types of ginger and placebo on other measures. Daily supplementation with ginger reduced muscle pain caused by eccentric exercise, and this effect was not enhanced by heat treating the ginger. This study demonstrates that daily consumption of raw and heat-treated ginger resulted in moderate-to-large reductions in muscle pain following exercise-induced muscle injury. Our findings agree with those showing hypoalgesic effects of ginger in osteoarthritis patients and further demonstrate ginger's effectiveness as a pain reliever.


Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This article about currently available antiplatelet drugs is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). It describes the mechanism of action, pharmacokinetics, and pharmacodynamics of aspirin, reversible cyclooxygenase inhibitors, thienopyridines, and integrin alphaIIbbeta3 receptor antagonists. The relationships among dose, efficacy, and safety are thoroughly discussed, with a mechanistic overview of randomized clinical trials. The article does not provide specific management recommendations; however, it does highlight important practical aspects related to antiplatelet therapy, including the optimal dose of aspirin, the variable balance of benefits and hazards in different clinical settings, and the issue of interindividual variability in response to antiplatelet drugs.


Variation in responses of fishes across multiple reserves within a network of marine protected areas in temperate waters.
Meta-analyses of field studies have shown that biomass, density, species richness, and size of organisms protected by no-take marine reserves generally increase over time. The magnitude and timing of changes in these response variables, however, vary greatly and depend upon the taxonomic groups protected, size and type of reserve, oceanographic regime, and time since the reserve was implemented. We conducted collaborative, fishery-independent surveys of fishes for seven years in and near newly created marine protected areas (MPAs) in central California, USA. Results showed that initially most MPAs contained more and larger fishes than associated reference sites, likely due to differences in habitat quality. The differences between MPAs and reference sites did not greatly change over the seven years of our study, indicating that reserve benefits will be slow to accumulate in California's temperate eastern boundary current. Fishes in an older reserve that has been closed to fishing since 1973, however, were significantly more abundant and larger than those in associated reference sites. This indicates that reserve benefits are likely to accrue in the California Current ecosystem, but that 20 years or more may be needed to detect significant changes in response variables that are due to MPA implementation. Because of the high spatial and temporal variability of fish recruitment patterns, long-term monitoring is needed to identify positive responses of fishes to protection in the diverse set of habitats in a dynamic eastern boundary current. Qualitative estimates of response variables, such as would be obtained from an expert opinion process, are unlikely to provide an accurate description of MPA performance. Similarly, using one species or one MPA as an indicator is unlikely to provide sufficient resolution to accurately describe the performance of multiple MPAs.


Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.
The endocannabinoid system (ECS) regulates multiple physiological processes, including cutaneous cell growth and differentiation. Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, (-)-cannabidiol (CBD), on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Activation of TRPV4 interfered with the prolipogenic ERK1/2 MAPK pathway and resulted in the downregulation of nuclear receptor interacting protein-1 (NRIP1), which influences glucose and lipid metabolism, thereby inhibiting sebocyte lipogenesis. CBD also exerted complex antiinflammatory actions that were coupled to A2a adenosine receptor-dependent upregulation of tribbles homolog 3 (TRIB3) and inhibition of the NF-κB signaling. Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.


The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas.
New drugs are constantly sought after to improve the survival of patients with malignant gliomas. The ideal substance would selectively target tumor cells without eliciting toxic side effects. Here, we report on the anti-proliferative, anti-migratory, and anti-invasive properties of the natural, nontoxic compound Curcumin observed in five human glioblastoma (GBM) cell lines in vitro. We used monolayer wound healing assays, modified Boyden chamber trans-well assays, and cell growth assays to quantify cell migration, invasion, and proliferation in the absence or presence of Curcumin at various concentrations. Levels of the transcription factor phospho-STAT3, a potential target of Curcumin, were determined by sandwich-ELISA. Subsequent effects on transcription of genes regulating the cell cycle were analyzed by quantitative real-time PCR. Effects on apoptosis were determined by caspase assays. Curcumin potently inhibited GBM cell proliferation as well as migration and invasion in all cell lines contingent on dose. Simultaneously, levels of the biologically active phospho-STAT3 were decreased and correlated with reduced transcription of the cell cycle regulating gene c-Myc and proliferation marking Ki-67, pointing to a potential mechanism by which Curcumin slows tumor growth. Curcumin is part of the diet of millions of people every day and is without known toxic side effects. Our data show that Curcumin bears anti-proliferative, anti-migratory, and anti-invasive properties against GBM cells in vitro. These results warrant further in vivo analyses and indicate a potential role of Curcumin in the treatment of malignant gliomas.


Bile duct basement membrane thickening in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is characterized histologically by portal inflammation, bile duct injury and regeneration and concentric periductal fibrosis. Although seen commonly in our experience, the significance of histological thickening of the bile duct basement membrane on periodic acid Schiff (PAS)-positive, diastase-resistant (DPAS) staining has never been analysed formally. In this paper we provide an evidence-based assessment of basement membrane thickening (BMT) reproducibility and diagnostic accuracy. A total of 128 archived medical liver core biopsies were retrieved and blinded for review by two independent histopathologists. BMT was assessed and designated as absent or present with a grade (G) of G1-G3. The sensitivity of any BMT for PSC was good at 77%, with moderate specificity at 61%. When only G3 BMT was considered positive, the specificity was high at 95% but the sensitivity was poor at 16%. The interobserver agreement (0.69) and consistency (0.72) were good. Basement membrane thickening is a reproducible predictor for PSC with good sensitivity and specificity. The presence of G2 and especially G3 BMT showed high specificity and could be regarded as highly predictive of PSC. The presence of more than G1 BMT should be reported and the possibility of PSC should be raised in the differential diagnosis.


Nanolesions induced by heavy ions in human tissues: Experimental and theoretical studies.
The biological effects of energetic heavy ions are attracting increasing interest for their applications in cancer therapy and protection against space radiation. The cascade of events leading to cell death or late effects starts from stochastic energy deposition on the nanometer scale and the corresponding lesions in biological molecules, primarily DNA. We have developed experimental techniques to visualize DNA nanolesions induced by heavy ions. Nanolesions appear in cells as "streaks" which can be visualized by using different DNA repair markers. We have studied the kinetics of repair of these "streaks" also with respect to the chromatin conformation. Initial steps in the modeling of the energy deposition patterns at the micrometer and nanometer scale were made with MCHIT and TRAX models, respectively.


Clinical cerebral microdialysis: a methodological study.
Clinical microdialysis enables monitoring of the cerebral extracellular chemistry of neurosurgical patients. Introduction of the technique into different hospitals' neurosurgical units has resulted in variations in the method of application. There are several variables to be considered, including length of the catheter membrane, type of perfusion fluid, flow rate of perfusion fluid, and on-line compared with delayed analysis of samples. The objects of this study were as follows: 1) to determine the effects of varying catheter characteristics on substance concentration; 2) to determine the relative recovery and true extracellular concentration by varying the flow rate and extrapolating to zero flow; and 3) to compare substance concentration obtained using a bedside enzyme analyzer with that of off-line high-performance liquid chromatography (HPLC). A specially designed bolt was used to conduct two adjacent microdialysis catheters into the frontal cortex of patients with head injury or poor-grade subarachnoid hemorrhage who were receiving ventilation. One reference catheter (10-mm membrane, perfused with Ringer's solution at 0.3 microl/minute) was constant for all studies. The other catheter was varied in terms of membrane length (10 mm or 30 mm), perfusion fluid (Ringer's solution or normal saline), and flow rate (0.1-1.5 microl/minute). The effect of freezing the samples on substance concentration was established by on-line analysis and then repeated analysis after storage at -70 degrees C for 3 months. Samples assayed with the bedside enzyme analyzer were reassessed using HPLC for the determination of glutamate concentrations. Two adjacent microdialysis catheters that were identical in membrane length, perfusion fluid, and flow rate showed equivalent results. Variations in perfusion fluid and freezing and thawing of samples did not result in differences in substance concentration. Catheter length had a significant impact on substance recovery. Variations in flow rate enabled the relative recovery to be calculated using a modification of the extrapolation-to-zero-flow method. The recovery was approximately 70% at 0.3 microl/minute and 30% at 1 microl/minute (10-mm membrane) for all analytes. Glutamate results obtained with the enzyme analyzer showed good correlation with those from HPLC.


Pediatric ALL relapses after allo-SCT show high individuality, clonal dynamics, selective pressure, and druggable targets.
Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post-allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post-allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients' first relapses, which disappeared in the post-allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children's post-allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post-allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.


An optimized design to reduce eddy current sensitivity in velocity-selective arterial spin labeling using symmetric BIR-8 pulses.
Velocity-selective arterial spin labeling (VSASL) tags arterial blood on a velocity-selective (VS) basis and eliminates the tagging/imaging gap and associated transit delay sensitivity observed in other ASL tagging methods. However, the flow-weighting gradient pulses in VS tag preparation can generate eddy currents (ECs), which may erroneously tag the static tissue and create artificial perfusion signal, compromising the accuracy of perfusion quantification. A novel VS preparation design is presented using an eight-segment B1 insensitive rotation with symmetric radio frequency and gradient layouts (sym-BIR-8), combined with delays after gradient pulses to optimally reduce ECs of a wide range of time constants while maintaining B0 and B1 insensitivity. Bloch simulation, phantom, and in vivo experiments were carried out to determine robustness of the new and existing pulse designs to ECs, B0 , and B1 inhomogeneity. VSASL with reduced EC sensitivity across a wide range of EC time constants was achieved with the proposed sym-BIR-8 design, and the accuracy of cerebral blood flow measurement was improved. The sym-BIR-8 design performed the most robustly among the existing VS tagging designs, and should benefit studies using VS preparation with improved accuracy and reliability.


A large-scale, consortium-based genomewide association study of asthma.
Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)


Optimal vaccination strategies for 2009 pandemic H1N1 and seasonal influenza vaccines in humans.
A randomized clinical trial was conducted to assess whether the immunogenicity of seasonal and pandemic (H1N1/09) influenza vaccines is affected by the order of vaccine administration. 151 healthy adult volunteers were randomized into three groups. All groups received one dose (15 μg haemagglutinin) each of a pandemic H1N1 vaccine and a seasonal trivalent vaccine. Group 1 received the pandemic H1N1 vaccine first, followed by the seasonal vaccine 21 days later. Group 2 received vaccinations in vice versa and Group 3 received both vaccines simultaneously. Post-vaccination blood samples were collected to determine the immunogenicity by hemagglutination-inhibition (HI), microneutralization (MN), and B cell ELISPOT assays. All three vaccination strategies were well-tolerated and generated specific immune responses. However, we found a significant difference in magnitude of antibody responses to pandemic H1N1 between the three groups. Pre- or co-vaccination with the seasonal flu vaccine led to a significant reduction by 50% in HI titre to pandemic H1N1 virus after pandemic vaccination. Pre- or co-vaccination of pandemic H1N1 vaccine had no effect on seasonal flu vaccination. MN and ELISPOT assays showed a similar effect. Vaccination with pandemic H1N1 vaccine first is recommended to avoid an associated inhibitory effect by the seasonal trivalent flu vaccine.


HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi.
Understanding how individuals with a high degree of HIV exposure avoid persistent infection is paramount to HIV vaccine design. Evidence suggests that mucosal immunity, particularly virus-specific CTL, could be critically important in protection against sexually acquired HIV infection. Therefore, we have looked for the presence of HIV-specific CD8+ T cells in cervical mononuclear cells from a subgroup of highly HIV-exposed but persistently seronegative female sex workers in Nairobi. An enzyme-linked immunospot assay was used to measure IFN-gamma release in response to known class I HLA-restricted CTL epitope peptides using effector cells from the blood and cervix of HIV-1-resistant and -infected sex workers and from lower-risk uninfected controls. Eleven of 16 resistant sex workers had HIV-specific CD8+ T cells in the cervix, and a similar number had detectable responses in blood. Where both blood and cervical responses were detected in the same individual, the specificity of the responses was similar. Neither cervical nor blood responses were detected in lower-risk control donors. HIV-specific CD8+ T cell frequencies in the cervix of HIV-resistant sex workers were slightly higher than in blood, while in HIV-infected donor cervical response frequencies were markedly lower than blood, so that there was relative enrichment of cervical responses in HIV-resistant compared with HIV-infected donors. HIV-specific CD8+ T cell responses in the absence of detectable HIV infection in the genital mucosa of HIV-1-resistant sex workers may be playing an important part in protective immunity against heterosexual HIV-1 transmission.


A gene regulatory network orchestrates neural crest formation.
The neural crest is a multipotent, migratory cell population that is unique to vertebrate embryos and gives rise to many derivatives, ranging from the peripheral nervous system to the craniofacial skeleton and pigment cells. A multimodule gene regulatory network mediates the complex process of neural crest formation, which involves the early induction and maintenance of the precursor pool, emigration of the neural crest progenitors from the neural tube via an epithelial to mesenchymal transition, migration of progenitor cells along distinct pathways and overt differentiation into diverse cell types. Here, we review our current understanding of these processes and discuss the molecular players that are involved in the neural crest gene regulatory network.


Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial.
Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke or other cardiovascular events. We compared the selective thromboxane-prostaglandin receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event. This randomised, double-blind, parallel-group trial was undertaken in 802 centres in 46 countries. Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were randomly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin. Patients and investigators were masked to treatment allocation. The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke, fatal or non-fatal myocardial infarction, or other vascular death (excluding haemorrhagic death). We planned a sequential statistical analysis of non-inferiority (margin 1·05) followed by analysis of superiority. Analysis was by intention to treat. The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee. This study is registered, number ISRCTN66157730. 9562 patients were assigned to terutroban (9556 analysed) and 9558 to aspirin (9544 analysed); mean follow-up was 28·3 months (SD 7·7). The primary endpoint occurred in 1091 (11%) patients receiving terutroban and 1062 (11%) receiving aspirin (hazard ratio [HR] 1·02, 95% CI 0·94-1·12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1147 [12%] vs 1045 [11%]; HR 1·11, 95% CI 1·02-1·21), but no significant differences in other safety endpoints. The trial did not meet the predefined criteria for non-inferiority, but showed similar rates of the primary endpoint with terutroban and aspirin, without safety advantages for terutroban. In a worldwide perspective, aspirin remains the gold standard antiplatelet drug for secondary stroke prevention in view of its efficacy, tolerance, and cost. Servier, France.


Augmented reality-assisted pedicle screw insertion: a cadaveric proof-of-concept study.
OBJECTIVE Augmented reality (AR) is a novel technology that has the potential to increase the technical feasibility, accuracy, and safety of conventional manual and robotic computer-navigated pedicle insertion methods. Visual data are directly projected to the operator's retina and overlaid onto the surgical field, thereby removing the requirement to shift attention to a remote display. The objective of this study was to assess the comparative accuracy of AR-assisted pedicle screw insertion in comparison to conventional pedicle screw insertion methods. METHODS Five cadaveric male torsos were instrumented bilaterally from T6 to L5 for a total of 120 inserted pedicle screws. Postprocedural CT scans were obtained, and screw insertion accuracy was graded by 2 independent neuroradiologists using both the Gertzbein scale (GS) and a combination of that scale and the Heary classification, referred to in this paper as the Heary-Gertzbein scale (HGS). Non-inferiority analysis was performed, comparing the accuracy to freehand, manual computer-navigated, and robotics-assisted computer-navigated insertion accuracy rates reported in the literature. User experience analysis was conducted via a user experience questionnaire filled out by operators after the procedures. RESULTS The overall screw placement accuracy achieved with the AR system was 96.7% based on the HGS and 94.6% based on the GS. Insertion accuracy was non-inferior to accuracy reported for manual computer-navigated pedicle insertion based on both the GS and the HGS scores. When compared to accuracy reported for robotics-assisted computer-navigated insertion, accuracy achieved with the AR system was found to be non-inferior when assessed with the GS, but superior when assessed with the HGS. Last, accuracy results achieved with the AR system were found to be superior to results obtained with freehand insertion based on both the HGS and the GS scores. Accuracy results were not found to be inferior in any comparison. User experience analysis yielded "excellent" usability classification. CONCLUSIONS AR-assisted pedicle screw insertion is a technically feasible and accurate insertion method.