Endoscopic endonasal transclival approach to the jugular tubercle.
The jugular tubercle is a rounded bony prominence that arises from the inferolateral margin of the clivus. In a previous publication, we described the surgical anatomy of the expanded endonasal approach to the jugular tubercle. To illustrate the translation of laboratory work to the operating room describing the anatomic and technical nuances of the endonasal approach to the jugular tubercle. We review the relevant surgical anatomy needed to perform an endonasal approach to the jugular tubercle, and we select 4 different lesions to illustrate the application of our laboratory findings. In the first case, exposure and partial drilling of the jugular tubercle was critical to gain an adequate corridor to the meningioma, particularly to its inferolateral margin. This allowed for early devascularization, safe extracapsular dissection, and preservation of surrounding neurovascular structures. In addition, the jugular tubercle was hyperostotic and its resection, along with generous dural removal, provided a grade I Simpson tumor resection. In the second (chondrosarcoma) and third (chordoma) cases, the jugular tubercle was infiltrated by tumor, and consequently its complete resection was essential to achieve total tumor removal. In the last case, an unusual adrenocorticotropic hormone-secreting adenoma recurrence at the jugular tubercle region, the technical modification of the transclival approach presented here was successfully applied to achieve complete resection and Cushing disease remission. The transjugular tubercle variant of the expanded endonasal transclival approach allows for direct access to ventrolateral lesions in the inferior clival/petroclival region with no cerebral or cerebellar retraction, or cranial nerve manipulation during the approach.


Inhibition of nuclear import mediated by the Rev-arginine rich motif by RNA molecules.
The HIV-1 Rev protein plays a pivotal role in viral replication, and therefore, inhibition of its function should block the progression of the virus-induced immune deficiency syndrome (AIDS). Here, RNA molecules have been shown to inhibit import of the HIV-1 Rev protein into nuclei of permeabilized cells. Nuclear uptake of biotinylated recombinant His-tagged Rev-GFP was assessed in nuclear extracts from digitonin-permeabilized cells by binding to either importin beta-receptors or nickel molecules immobilized on a microtiter plate. Using this method together with fluorescence microscopy, we determined that nuclear import of Rev is inhibited by the addition of a reticulocyte lysate which routinely is used as a source of nuclear import receptors. This inhibition was released by treatment with the RNase enzyme. Also t-RNA molecules and the oligoribonucleotide RRE IIB, namely, the second stem structure of the Rev responsive element (RRE) of the viral RNA, inhibit Rev nuclear import. Similar results were obtained when BSA molecules with covalently attached Rev-arginine rich motif (ARM) peptides were used as a nuclear transport substrate, indicating that the nuclear import inhibition of the Rev protein is due to the presence of the ARM domain. Binding experiments revealed that the RNA molecules inhibit the interaction between the ARM region and importin beta, implying that the RNA prevents the formation of the import complex. The implication of our results for the regulation of the nuclear import of Rev as well as for the use of RNA molecules as antiviral drugs is discussed.


Interventions for necrotising pancreatitis.
Acute necrotising pancreatitis carries significant mortality, morbidity, and resource use. There is considerable uncertainty as to how people with necrotising pancreatitis should be treated. To assess the benefits and harms of different interventions in people with acute necrotising pancreatitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 4), MEDLINE, EMBASE, Science Citation Index Expanded, and trials registers to April 2015 to identify randomised controlled trials (RCT). We also searched the references of included trials to identify further trials. We considered only RCTs performed in people with necrotising pancreatitis, irrespective of aetiology, presence of infection, language, blinding, or publication status for inclusion in the review. Two review authors independently identified trials and extracted data. We calculated the odds ratio (OR) and mean difference with 95% confidence intervals (CI) using Review Manager 5 based on an available-case analysis using fixed-effect and random-effects models. We planned a network meta-analysis using Bayesian methods, but due to sparse data and uncertainty about the transitivity assumption, performed only indirect comparisons and used Frequentist methods. We included eight RCTs with 311 participants in this review. After exclusion of five participants, we included 306 participants in one or more outcomes. Five trials (240 participants) investigated the three main treatments: open necrosectomy (121 participants), minimally invasive step-up approach (80 participants), and peritoneal lavage (39 participants) and were included in the network meta-analysis. Three trials (66 participants) investigated the variations in the main treatments: early open necrosectomy (25 participants), delayed open necrosectomy (11 participants), video-assisted minimally invasive step-up approach (12 participants), endoscopic minimally invasive step-up approach (10 participants), minimally invasive step-up approach (planned surgery) (four participants), and minimally invasive step-up approach (continued percutaneous drainage) (four participants). The trials included infected or sterile necrotising pancreatitis of varied aetiology.All the trials were at unclear or high risk of bias and the overall quality of evidence was low or very low for all the outcomes. Overall, short-term mortality was 30% and serious adverse events rate was 139 serious adverse events per 100 participants. The differences in short-term mortality and proportion of people with serious adverse events were imprecise in all the comparisons. The number of serious adverse events and adverse events were fewer in the minimally invasive step-up approach compared to open necrosectomy (serious adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study; adverse events: rate ratio 0.41, 95% CI 0.25 to 0.68; 88 participants; 1 study). The proportion of people with organ failure and the mean costs were lower in the minimally invasive step-up approach compared to open necrosectomy (organ failure: OR 0.20, 95% CI 0.07 to 0.60; 88 participants; 1 study; mean difference in costs: USD -11,922; P value < 0.05; 88 participants; 1 studies). There were more adverse events with video-assisted minimally invasive step-up approach group compared to endoscopic-assisted minimally invasive step-up approach group (rate ratio 11.70, 95% CI 1.52 to 89.87; 22 participants; 1 study), but the number of interventions per participant was less with video-assisted minimally invasive step-up approach group compared to endoscopic minimally invasive step-up approach group (difference in medians: 2 procedures; P value < 0.05; 20 participants; 1 study). The differences in any of the other comparisons for number of serious adverse events, proportion of people with organ failure, number of adverse events, length of hospital stay, and intensive therapy unit stay were either imprecise or were not consistent. None of the trials reported long-term mortality, infected pancreatic necrosis (trials that included participants with sterile necrosis), health-related quality of life at any time frame, proportion of people with adverse events, requirement for additional invasive intervention, time to return to normal activity, and time to return to work. Low to very low quality evidence suggested that the minimally invasive step-up approach resulted in fewer adverse events, serious adverse events, less organ failure, and lower costs compared to open necrosectomy. Very low quality evidence suggested that the endoscopic minimally invasive step-up approach resulted in fewer adverse events than the video-assisted minimally invasive step-up approach but increased the number of procedures required for treatment. There is currently no evidence to suggest that early open necrosectomy is superior or inferior to peritoneal lavage or delayed open necrosectomy. However, the CIs were wide and significant benefits or harms of different treatments cannot be ruled out. The TENSION trial currently underway in Netherlands is assessing the optimal way to perform the minimally invasive step-up approach (endoscopic drainage followed by endoscopic necrosectomy if necessary versus percutaneous drainage followed by video-assisted necrosectomy if necessary) and is assessing important clinical outcomes of interest for this review. Implications for further research on this topic will be determined after the results of this RCT are available.


Remembering and Communicating Climate Change Narratives - The Influence of World Views on Selective Recollection.
We examine how people remember stories about climate change and how they communicate these stories to others. Drawing on theories of reconstructive memory and cultural theory, we assume that recollection is systematically affected by an individual's world view as well as by the world view of the target audience. In an experimental study with a Norwegian representative sample (N = 266), participants read a story about three politicians, in which each protagonist was described as holding a specific world view and as trying to tackle climate change with a corresponding strategy (individualistic/free market oriented, hierarchical/technology-oriented, or egalitarian/sustainability-oriented). After 1 day and then after 1 week, participants were asked to retell the story as if to somebody who was characterized as being either an individualist, a hierarchist, or an egalitarian; in addition, a neutral recall control condition without a specified audience was included. Participants' own world view was assessed and they were classified as endorsing individualism, or hierarchism, or egalitarianism. We hypothesized that retellings would be selectively reconstructed according to the world view of the participant, as well as tuned to the audience's world view. We assessed the cognitive structure of the recollected story, and, using methods from computational text analysis, we computed similarities among retellings and the original narrative, and among retellings and world views. Results suggest that (i) retellings become less accurate over time, (ii) retelling to an audience with an explicit world view leads to more strongly filtered retellings than recalling without a specified audience, but the filter operates in a non-specific manner with respect to world views, (iii) the cognitive structure of the recollected story shows small but systematic differences concerning the link between story problem and solution as a function of the participant's and the audience's world view. No interaction was found between the world view of the participant and that of the audience. Results emphasize the role of world views in communicating climate change, and might help to better understand phenomena such as polarization and echo chamber effects.


Asymmetries between convergence and divergence reveal tonic vergence is dependent upon phasic vergence function.
Horizontal vergence eye movements are controlled by two processes, phasic and slow-tonic. Slow-tonic responses are hypothesized to be stimulated by the faster, pulse-step neural output of the phasic system. This suggests that the general behavior of each system should be similar; however, this relationship has yet to be investigated directly. We characterize the relationship between phasic and tonic vergence by quantifying directional asymmetries in the response properties of each mechanism to the same disparity amplitudes. Four subjects viewed symmetric steps in disparity dichoptically at 40 cm while eye movements were recorded with infrared oculography. First- and second-order phasic and slow-tonic convergence response properties increased linearly with disparity demand (p < 0.01), whereas divergence responses did not (p > 0.05). Phasic divergence responses were slower than convergence (p = 0.012) and were associated with a higher frequency of saccades (p < 0.001). The average rate of slow-tonic change was correlated to the average peak velocity of phasic vergence at the same vergence demand in both directions, r = 0.78, p < 0.0001. Clear directional asymmetries were observed in phasic and tonic vergence responses. The response properties of the slow-tonic mechanism varied directly with the peak velocity of the complementary phasic system. These results provide empirical evidence of the relationship between phasic and slow-tonic vergence, suggesting that the latter depends on the motor function of the former, specifically the peak velocity. The recruitment of additional oculomotor mechanisms, such as saccades, improved the phasic response properties of the slower divergence mechanism but did not directly influence the response behavior of the slow-tonic mechanism.


Suicidality and Hostility following Involuntary Hospital Treatment.
Psychiatric patients showing risk to themselves or others can be involuntarily hospitalised. No data is available on whether following hospitalisation there is a reduction in psychopathological indicators of risk such as suicidality and hostility. This study aimed to assess changes in suicidality and hostility levels following involuntary admission and their patient-level predictors. A pooled analysis of studies on involuntary treatment, including 11 countries and 2790 patients was carried out. Suicidality and hostility were measured by the Brief Psychiatric Rating Scale. 2790 patients were included; 2129 followed-up after one month and 1864 after three months. 387 (13.9%) patients showed at least moderate suicidality when involuntarily admitted, 107 (5.0%) after one month and 97 (5.2%) after three months. Moderate or higher hostility was found in 1287 (46.1%) patients after admission, 307 (14.5%) after one month, and 172 (9.2%) after three months. Twenty-three (1.2%) patients showed suicidality, and 53 (2.8%) patients hostility at all time-points. Predictors of suicidality three months after admission were: suicidality at baseline, not having a diagnosis of psychotic disorder and being unemployed. Predictors of hostility were: hostility at baseline, not having a psychotic disorder, living alone, and having been hospitalized previously. After involuntary hospital admission, the number of patients with significant levels of suicidality and hostility decreases substantially over time, and very few patients show consistently moderate or higher levels of these symptoms. In patients with psychotic disorders these symptoms are more likely to improve. Social factors such as unemployment and isolation could hamper suicidality and hostility reduction and may be targeted in interventions to reduce risk in involuntarily admitted patients.


Bibliometric Study of the National Scientific Production of All Peruvian Schools of Dentistry in Scopus.
To perform a bibliometric analysis of the national scholarly output of all dental schools in Peru in Scopus through a retrospective study after the promulgation of the Peruvian University Law 30220 in 2014. This was a descriptive, comparative, retrospective, and cross-sectional study. A search of the Scopus database was performed to identify scholarly output in dentistry between 2014 and 2019. A total of 287 scientific articles with affiliation with the dental faculties of Peruvian public and private universities were evaluated. The data was extracted from Scopus using a complex formula developed from the words of the thesaurus MeSh (Medline) and Emtree (base) with words related to dentistry combined with the AF-IDs of the Peruvian universities. The Top 10 in the scholarly output of all the Peruvian public and private dental schools were as follows: firstly, the Universidad Peruana Cayetano Heredia (UPCH), with 79 scholarly outputs publications and 5.2 citations per article, followed by the Universidad Nacional Mayor de San Marcos (UNMSM) with 53 scholarly outputs publications and 2.6 citations per article, and in third place, the Universidad Cientifica del Sur (UCSUR) with 49 scholarly outputs publications. In general, it was found that, of the 30 Faculties of Dentistry in Peru, only 10 in the public and private universities have a scholarly output greater than 5 to belong to the top 10. In addition, it was found that, according to the share of publications per journal quartile by the CiteScore Percentile of all the public and private Peruvian Faculties of Dentistry, in 2019, it presented the highest number of scientific publications in all quartiles with 20,33,14 and 43 articles in the quartiles Q1, Q2, Q3, and Q4, respectively. The highest number of scientific publications was produced in 2019 with 20, 33, 14, and 43 articles in quartiles Q1, Q2, Q3, and Q4, respectively. The UPCH, UNMSM, and UCSUR dental schools were the most productive. Both public and private universities presented an evident increase in their scientific publications in Scopus after the promulgation of the University Law 30220 in 2014.


Properties of mitochondria isolated from cyanide-sensitive and cyanide-stimulated cultures of Acanthamoeba castellanii.
1. Mitochondria isolated from cultures of Acanthamoeba castellanii exhibit respiratory control and oxidize alpha-oxoglutarate, succinate and NADH with ADP:O ratios of about 2.4, 1.4 and 1.25 respectively. 2. Mitochondria from cultures of which the respiration was stimulated up to 50% by 1mm-cyanide (type-A mitochondria) and from cyanide-sensitive cultures (type-B mitochondria) had similar respiratory-control ratios and ADP:O ratios. 3. State-3 rates of respiration were generally more cyanide-sensitive than State-4 rates, and the respiration of type-A mitochondria was more cyanide-resistant than that of type-B mitochondria. 4. Salicylhydroxamic acid alone had little effect on respiratory activities of either type of mitochondria, but when added together with cyanide, irrespective of the order of addition, inhibition was almost complete. 5. Oxidation of externally added NADH by type-A mitochondria was mainly via an oxidase with a low affinity for oxygen (K(m)[unk]15mum), which was largely cyanide-sensitive and partially antimycin A-sensitive; this electron-transport pathway was inhibited by ADP. 6. Cyanide-insensitive but salicylhydroxamic acid-sensitive respiration was stimulated by AMP and ADP, and by ATP after incubation in the presence of MgCl(2). 7. Addition of rotenone to mitochondria oxidizing alpha-oxoglutarate lowered the ADP:O ratios by about one-third and rendered inhibition by cyanide more complete. 8. The results suggest that mitochondria of A. castellanii possess branched pathways of electron transport which terminate in three separate oxidases; the proportions of electron fluxes via these pathways vary at different stages of growth.


The Wnt inhibitor Dkk1 is required for maintaining the normal cardiac differentiation program in Xenopus laevis.
Wnt proteins can activate different intracellular signaling pathways. These pathways need to be tightly regulated for proper cardiogenesis. The canonical Wnt/β-catenin inhibitor Dkk1 has been shown to be sufficient to trigger cardiogenesis in gain-of-function experiments performed in multiple model systems. Loss-of-function studies however did not reveal any fundamental function for Dkk1 during cardiogenesis. Using Xenopus laevis as a model we here show for the first time that Dkk1 is required for proper differentiation of cardiomyocytes, whereas specification of cardiomyocytes remains unaffected in absence of Dkk1. This effect is at least in part mediated through regulation of non-canonical Wnt signaling via Wnt11. In line with these observations we also found that Isl1, a critical regulator for specification of the common cardiac progenitor cell (CPC) population, acts upstream of Dkk1.


Tracking the roots of reading ability: white matter volume and integrity correlate with phonological awareness in prereading and early-reading kindergarten children.
Developmental dyslexia, an unexplained difficulty in learning to read, has been associated with alterations in white matter organization as measured by diffusion-weighted imaging. It is unknown, however, whether these differences in structural connectivity are related to the cause of dyslexia or if they are consequences of reading difficulty (e.g., less reading experience or compensatory brain organization). Here, in 40 kindergartners who had received little or no reading instruction, we examined the relation between behavioral predictors of dyslexia and white matter organization in left arcuate fasciculus, inferior longitudinal fasciculus, and the parietal portion of the superior longitudinal fasciculus using probabilistic tractography. Higher composite phonological awareness scores were significantly and positively correlated with the volume of the arcuate fasciculus, but not with other tracts. Two other behavioral predictors of dyslexia, rapid naming and letter knowledge, did not correlate with volumes or diffusion values in these tracts. The volume and fractional anisotropy of the left arcuate showed a particularly strong positive correlation with a phoneme blending test. Whole-brain regressions of behavioral scores with diffusion measures confirmed the unique relation between phonological awareness and the left arcuate. These findings indicate that the left arcuate fasciculus, which connects anterior and posterior language regions of the human brain and which has been previously associated with reading ability in older individuals, is already smaller and has less integrity in kindergartners who are at risk for dyslexia because of poor phonological awareness. These findings suggest a structural basis of behavioral risk for dyslexia that predates reading instruction.


Identity statuses as developmental trajectories: a five-wave longitudinal study in early-to-middle and middle-to-late adolescents.
This study tested whether Marcia's original identity statuses of achievement, moratorium, early closure (a new label for foreclosure), and diffusion, can be considered identity status trajectories. That is, we examined whether these statuses are distinct and relatively stable, over-time configurations of commitment strength, levels of in-depth exploration of present commitments, and consideration of alternative commitments. The study examined identity development in a five-wave study of 923 early-to-middle (49.3% female) and 390 middle-to-late adolescents (56.7% female), covering the ages of 12-20. Using Latent class growth analysis (LCGA), the authors found that Marcia's (1966) statuses are indeed identity status trajectories. Two kinds of moratorium were also found: the classical moratorium and searching moratorium. Support was found for Waterman's developmental hypothesis of the identity status model: the number of achievers was significantly higher, and the number of diffusions lower, in middle-to-late adolescence than in early-to-middle adolescence. Females were more often in the advanced identity status trajectories, and stable differences were found between the trajectories in psychosocial adjustment. Study findings highlight that identity formation should be conceptualized as an over-time process.


Agreement on Web-based Diagnoses and Severity of Mental Health Problems in Norwegian Child and Adolescent Mental Health Services.
This study examined the agreement between diagnoses and severity ratings assigned by clinicians using a structured web-based interview within a child and adolescent mental health outpatient setting. Information on 100 youths was obtained from multiple informants through a web-based Development and Well-Being Assessment (DAWBA). Based on this information, four experienced clinicians independently diagnosed (according to the International Classification of Diseases Revision 10) and rated the severity of mental health problems according to the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) and the Children's Global Assessment Scale (C-GAS). Agreement for diagnosis was κ=0.69-0.82. Intra-class correlation for single measures was 0.78 for HoNOSCA and 0.74 for C-GAS, and 0.93 and 0.92, respectively for average measures. Agreement was good to excellent for all diagnostic categories. Agreement for severity was moderate, but improved to substantial when the average of the ratings given by all clinicians was considered. Therefore, we conclude that experienced clinicians can assign reliable diagnoses and assess severity based on DAWBA data collected online.


Meta-audit of laboratory ISO accreditation inspections: measuring the old emperor's clothes.
Accreditation to ISO/IEC 17025 is required for EC official food control and veterinary laboratories by Regulation (EC) No. 882/2004. Measurements in hospital laboratories and clinics are increasingly accredited to ISO/IEC 15189. Both of these management standards arose from command and control military standards for factory inspection during World War II. They rely on auditing of compliance and have not been validated internally as assessment bodies require of those they accredit. Neither have they been validated to criteria outside their own ideology such as the Cochrane principles of evidence-based medicine which might establish whether any benefit exceeds their cost. We undertook a retrospective meta-audit over 14 years of internal and external laboratory audits that checked compliance with ISO 17025 in a public health laboratory. Most noncompliances arose solely from clauses in the standard and would not affect users. No effect was likely from 91% of these. Fewer than 1% of noncompliances were likely to have consequences for the validity of results or quality of service. The ISO system of compliance auditing has the performance characteristics of a poor screening test. It adds substantially to costs and generates more noise (false positives) than informative signal. Ethical use of resources indicates that management standards should not be used unless proven to deliver the efficacy, effectiveness, and value required of modern healthcare interventions.


On interpretation and task selection in studies on the effects of noise on cognitive performance.
THIS PAPER DISCUSSES TWO THINGS RESEARCHERS SHOULD CONSIDER WHEN SELECTING TASKS FOR COGNITIVE NOISE STUDIES AND INTERPRETING THEIR FINDINGS: (a) The "process impurity" problem and (b) the propensity of sound to capture attention. Theoretical and methodological problems arise when the effects of noise on complex tasks (e.g., reading comprehension) are interpreted as reflecting an impairment of a specific cognitive process/system/skill. One reason for this is that complex tasks are, by definition, process impure (i.e., they involve several, distinct cognitive processes/systems/skills). Another reason is that sound can capture attention. When sound captures attention, the impairment to task scores is caused by an interruption, not by malfunctioning cognitive processes/systems/skills. Selecting more "process pure" tasks (e.g., the Stroop task) is not a solution to these problems. On the contrary, it introduces further problems with generalizability and representativeness. It is argued that cognitive noise researchers should employ representative noise, representative tasks (which are necessarily complex/process impure), and interpret the results on a behavioral level of analysis rather than on a cognitive level of analysis.


Exposure to ambient air pollution and blood lipids in adults: The 33 Communities Chinese Health Study.
Little information exists on the lipidemic effects of air pollution, particularly in developing countries. We aimed to investigate the associations of long-term exposure to ambient air pollutants with lipid levels and dyslipidemias in China. In 2009, a total of 15,477 participants aged 18-74 years were recruited from the 33 Communities Chinese Health Study conducted in three Northeastern China cities. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were measured in participants' blood specimens. Three year (2006-08) average air pollution concentrations were assessed using data from 33 communities (particles with diameters ≤1.0 μm (PM1) and ≤2.5 μm (PM2.5) were predicted using a spatial statistical model) or 11 air monitoring stations (particles with diameters ≤10 μm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3)). Associations were evaluated by two-level logistic and generalized linear regression models. We detected many significant associations between exposure to air pollutants (especially for PM1 and PM2.5) and blood lipid levels. Most of the associations suggested deleterious effects on blood lipid markers (e.g., a 10 μg/m3 increase in PM1 was associated with 1.6% (95% confidence interval (CI): 1.1, 2.0), 2.9% (95% CI: -3.3, 9.3), and 3.2% (95% CI: 2.6, 3.9) higher levels of TC, TG, and LDL-C, respectively, but 1.4% (95% CI: -1.8, -0.9) lower HDL-C levels), although beneficial associations were found for O3. In analysis with dyslipidemias, all the observed associations suggested deleterious lipidemic effects of air pollutants, and no significant beneficial association was observed for O3. Stratified analyses showed that the associations were stronger in overweight or obese participants; sex and age modified the associations, but the pattern of effects was mixed. Long-term ambient air pollution was associated with both altered lipid profiles and dyslipidemias, especially among overweight or obese participants.


Behavioural responses to thermal conditions affect seasonal mass change in a heat-sensitive northern ungulate.
Empirical tests that link temperature-mediated changes in behaviour (activity and resource selection) to individual fitness or condition are currently lacking for endotherms yet may be critical to understanding the effect of climate change on population dynamics. Moose (Alces alces) are thought to suffer from heat stress in all seasons so provide a good biological model to test whether exposure to non-optimal ambient temperatures influence seasonal changes in body mass. Seasonal mass change is an important fitness correlate of large herbivores and affects reproductive success of female moose. Using GPS-collared adult female moose from two populations in southern Norway we quantified individual differences in seasonal activity budget and resource selection patterns as a function of seasonal temperatures thought to induce heat stress in moose. Individual body mass was recorded in early and late winter, and autumn to calculate seasonal mass changes (n = 52 over winter, n = 47 over summer). We found large individual differences in temperature-dependent resource selection patterns as well as within and between season variability in thermoregulatory strategies. As expected, individuals using an optimal strategy, selecting young successional forest (foraging habitat) at low ambient temperatures and mature coniferous forest (thermal shelter) during thermally stressful conditions, lost less mass in winter and gained more mass in summer. This study provides evidence that behavioural responses to temperature have important consequences for seasonal mass change in moose living in the south of their distribution in Norway, and may be a contributing factor to recently observed declines in moose demographic performance. Although the mechanisms that underlie the observed temperature mediated habitat-fitness relationship remain to be tested, physiological state and individual variation in thermal tolerance are likely contributory factors. Climate-related effects on animal behaviour, and subsequently fitness, are expected to intensify as global warming continues.


Diversity of Bacteria Exhibiting Bile Acid-inducible 7α-dehydroxylation Genes in the Human Gut.
The secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), formed by gut microbiota from primary bile acids via a multi-step 7α-dehydroxylation reaction, have wide-ranging effects on host metabolism and play an important role in health and disease. A few 7α-dehydroxylating strains have been isolated, where bile acid-inducible (bai) genes were organized in a gene cluster and encoded major enzymes involved. However, only little is known on diversity and abundance of intestinal bacteria catalysing DCA/LCA formation in the human gut in situ. In this study, we took the opportunity to screen metagenome-assembled genomes (MAGs) from sequence data of stool samples provided by two recent studies along with newly available gut-derived isolates for the presence of the bai gene cluster. We revealed in total 765 and 620 MAGs encoding the potential to form DCA/LCA that grouped into 21 and 26 metagenomic species, respectively. The majority of MAGs (92.4 and 90.3%) were associated with a Ruminococcaceae clade that still lacks an isolate, whereas less MAGs belonged to Lachnospiraceae along with eight new isolates (n total = 11) that contained the bai genes. Only a few MAGs were linked to Peptostreptococcaceae. Signatures for horizontal transfer of bai genes were observed. This study gives a comprehensive overview of the diversity of bai-exhibiting bacteria in the human gut highlighting the application of metagenomics to unravel potential functions hidden from current isolates. Eventually, isolates of the identified main MAG clade are required in order to prove their capability of 7α-dehydroxylating primary bile acids.


Outcomes and Satisfaction with Endoscopic Carpal Tunnel Releases and the Predictors - A Retrospective Cohort Study.
Patient's final satisfaction with endoscopic carpal tunnel release (ECTR) is still unpredictable. The study aims to find the predictive factors for satisfaction in patients with carpal tunnel syndrome (CTS) treated by ECTR using the Boston CTS questionnaire. We conducted a retrospective chart review of 37 patients (55 hands) who received ECTR and completed Boston carpal tunnel questionnaire at preoperative visit, 1 month and 6 months after operation while a telephone interview was conducted at 2 years after operation. Independent risk variables, including mean symptom severity scale, functional status scale, each item in questionnaire at all the time points, ASA physical status scale, age, gender, dominant site lesion, bilateral lesions, duration of symptoms and anesthesia method were recorded. Final outcome was determined by the patient's satisfaction at the interval of 2 years. Predictors to outcome were analyzed by stepwise multiple regression analysis and tested with Pearson correlation test. A p value of less than 0.05 was considered significant. The severity of hand or wrist numbness during the daytime (Q6, explained 6.5% variances), the severity of numbness or tingling at night (Q9, explained 16.2% variances), the functional status of writing (q1, explained 13.9% variances), carrying grocery bags (q7, explained 13.6% variances) had significant predictive value (p<0.001). Other factors were not significant in the analysis including ASA, gender, age, dominant site lesion, bilateral lesions, anesthesia method and duration of symptoms. Boston questionnaire is a simple and reliable tool with high predictive values to evaluate patient's outcome and satisfaction in ECTR.


Resting energy expenditure and delayed-onset muscle soreness after full-body resistance training with an eccentric concentration.
The purpose of this investigation was to determine the effect of an acute bout of high-volume, full-body resistance training with an eccentric concentration on resting energy expenditure (REE) and indicators of delayed-onset muscle soreness (DOMS). Eight resistance trained (RT) and eight untrained (UT) participants (mean: age = 23.5 years; height = 180.76 cm; weight = 87.58 kg; body fat = 19.34%; lean mass = 68.71 kg) were measured on four consecutive mornings for REE and indicators of DOMS: creatine kinase (CK) and rating of perceived muscle soreness (RPMS). Delayed-onset muscle soreness was induced by performing eight exercises, eight sets, and six repetitions using a 1-second concentric and 3-second eccentric muscle action duration. A two-factor repeated-measures analysis of variance revealed that REE was significantly (p < 0.05) elevated at 24, 48, and 72 hours post compared with baseline measures for both UT and RT groups. Ratings of perceived muscle soreness were significantly elevated within groups for UT and RT at 24 and 48 hours post and for UT only at 72 hours post compared with baseline (p < 0.05). Nonparametric analyses revealed that CK was significantly increased at 24 hours post for both UT and RT and at 48 and 72 hours post for UT only compared with baseline (p < 0.05). Resting energy expenditure and indicators of DOMS were higher in UT compared with RT on all measures, but no significant differences were determined. The main finding of this investigation is that full-body resistance training with an eccentric concentration significantly increased REE up to 72 hours postexercise in UT and RT participants.


Chemical Sensors Generated on Wafer-Scale Epitaxial Graphene for Application to Front-Line Drug Detection.
Generation of large areas of graphene possessing high quality and uniformity will be a critical factor if graphene-based devices/sensors are to be commercialized. In this work, epitaxial graphene on a 2" SiC wafer was used to fabricate sensors for the detection of illicit drugs (amphetamine or cocaine). The main target application is on-site forensic detection where there is a high demand for reliable and cost-efficient tools. The sensors were designed and processed with specially configured metal electrodes on the graphene surface by utilizing a series of anchors where the metal contacts are directly connected on the SiC substrate. This has been shown to improve adhesion of the electrodes and decrease the contact resistance. A microfluidic system was constructed to pump solutions over the defined graphene surface that could then act as a sensor area and react with the target drugs. Several prototypic systems were tested where non-covalent interactions were used to localize the sensing components (antibodies) within the measurement cell. The serendipitous discovery of a wavelength-dependent photoactivity for amphetamine and a range of its chemical analogs, however, limited the general application of these prototypic systems. The experimental results reveal that the drug molecules interact with the graphene in a molecule dependent manner based upon a balance of π -stacking interaction of the phenyl ring with graphene (p-doping) and the donation of the amine nitrogens lone pair electrons into the π - π *-system of graphene (n-doping).


Ovarian endometrioma vascularization in women with pelvic pain.
To assess whether a correlation exists between angiogenesis in ovarian endometrioma with the presence of pelvic pain. Prospective study. Tertiary-care university hospital. Sixty-five patients (mean age, 33.3 years; range, 20-49 years) were diagnosed as having suspected cystic ovarian endometriosis, and were scheduled for surgery. Patients were classified into two groups according to clinical complaints: group A, asymptomatic patients or patients presenting mild dysmenorrhea; and group B, severe dysmenorrhea and/or chronic pelvic pain and/or dyspareunia. Transvaginal power-Doppler ultrasonography and immunohistochemical staining for CD-34 in histological specimens. The amount of blood flow, lowest pulsatility and resistance indexes, and microvessel density (MVD). Five patients were excluded after surgery because no ovarian endometriosis was found in histological analysis. Thirty women were included in each group. Ovarian endometriomas were more frequently vascularized in group B (87%) than in group A (60%). The lowest pulsatility and resistance indexes were significantly lower, and MVD was significantly higher, in group B compared with group A. There was a correlation between the degree of vascularization detected by power-Doppler ultrasound and MVD. We conclude that vascularization of ovarian endometriomas evaluated by transvaginal color Doppler and MVD is higher in patients who present with pelvic pain than in asymptomatic patients. This could be an indicator of the activity of endometriosis.


Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder.
In patients with fibromyalgia syndrome (FMS) and temporomandibular disorder (TMD), stress and pain may chronically enhance sympathetic activity, altering cardiovascular responses and worsening pain. This study examined cardiovascular, epinephrine (EPI), norepinephrine (NE), cortisol and clinical pain responses in 54 female patients with these disorders and 34 controls. In a subsample of 10 FMS, 10 TMD patients and 16 controls, using a counterbalanced, double-blind, crossover design, the same responses were assessed after intravenous administration of low dose propranolol vs placebo. Testing included baseline, postural, speech and ischemic pain stressors. FMS patients showed lesser heart rate (HR) increases to posture challenge but greater blood pressure (BP) increases to postural and speech tasks than controls, as well as higher overall BP and greater total vascular resistance (TVR) than TMDs or controls. TMDs showed higher overall cardiac output and lower TVR than controls. Both FMS and TMD groups showed lower baseline NE than controls, and TMDs showed lower overall EPI and NE levels. Group differences in HR, EPI and NE were abolished after propranolol although BP, CO and TVR differences persisted. In both FMS and TMD, the number of painful body sites and ratings of total clinical pain obtained 4 times during each session were significantly lower after beta-blockade vs placebo. These findings support the hypothesis that both FMS and TMD may frequently involve dysregulation of beta-adrenergic activity that contributes to altered cardiovascular and catecholamine responses and to severity of clinical pain. Acute treatment with low-dose propranolol led to short-term improvement in all these domains.


Dental Occlusion and Ophthalmology: A Literature Review.
Stomatognathic system is strictly correlated to other anatomical regions; many studies investigated relationship between temporomandibular joint and posture, several articles describe cranio-facial pain from dental causes, such as trigger points. Until now less interest has been given to connections between dental occlusion and ophthalmology, even if they are important and involving. Clinical experience in dental practice claims that mandibular latero-deviation is connected both to eye dominance and to defects of ocular convergence. The trigeminal nerve is the largest and most complex of the twelve cranial nerves. The trigeminal system represents the connection between somitic structures and those derived from the branchial arches, collecting the proprioception from both somitic structures and oculomotor muscles. The intermedius nucleus of the medulla is a small perihypoglossal brainstem nucleus, which acts to integrate information from the head and neck and relays it on to the nucleus of the solitary tract where autonomic responses are generated. This intriguing neurophysiological web led our research group to investigate anatomical and functional associations between dental occlusion and vision. In conclusion, nervous system and functional pathways strictly connect vision and dental occlusion, and in the future both dentists and oculists should be more and more aware of this correlation for a better diagnosis and therapy.


18F-FDG uptake in the stomach on screening PET/CT: value for predicting Helicobacter pylori infection and chronic atrophic gastritis.
The aim of this study was to determine the value of 18F-FDG uptake on screening PET/CT images for the prediction of Helicobacter pylori (H. pylori) infection and chronic atrophic gastritis. Among subjects who underwent 18F-FDG PET/CT for cancer screening from April 2005 to November 2015, PET/CT images were analyzed in 88 subjects who had gastrointestinal fiberscopy within 6 months. The volumes of interest (VOIs) were placed in the fornix, corpus and antrum of the stomach to determine maximal standardized uptake value (SUVmax) and mean SUV (SUVmean). Receiver operating characteristic curve (ROC) analysis was performed to determine the diagnostic performance of SUV indicators in predicting H. pylori infection and chronic atrophic gastritis. SUV indicators of the stomach were significantly higher in subjects with H. pylori infection than those without (from P < 0.001 to P < 0.05). ROC analysis revealed that SUVmean had the highest performance in predicting H. pylori infection (AUC 0.807) and chronic atrophic gastritis (AUC 0.784). SUVmean exhibited the sensitivity of 86.5 % and the specificity of 70.6 % in predicting H. pylori infection, and the sensitivity of 75.0 % and 78.6 % in predicting chronic atrophic gastritis. Assessment of 18F-FDG uptake in the stomach reflecting active inflammation is useful in predicting patients with H. pylori infection and subsequent chronic atrophic gastritis which is closely associated with the risk of gastric neoplasms.


Track changing by use of the phase response of microspheres and resonators.
A microsphere or resonator that is side coupled to an incident optical beam induces a phase response in the beam. In the so-called overcoupled regime, the amplitude of the incident beam remains unmodulated, whereas the phase goes through a shift of p at resonance. This shift is insensitive to the details of the coupling geometry or the resonant mode. In conjunction with an interferometer, the phase response can be used to switch the beam between two well-defined outputs, thus offering a robust means of deploying microspheres and other microresonators in practical photonic devices.


Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu.
Hypoglycaemia is a common side-effect of glucose-lowering therapies for type-2 diabetic patients, which may cause cognitive/neurological impairment. Although the effects of hypoglycaemia in the brain have been extensively studied in neurons, how hypoglycaemia impacts the viability of adult neural stem cells (NSCs) has been poorly investigated. In addition, the cellular and molecular mechanisms of how hypoglycaemia regulates NSCs survival have not been characterized. Recent work others and us have shown that the pituitary adenylate cyclase-activating polypeptide (PACAP) and the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 stimulate NSCs survival against glucolipoapoptosis. The aim of this study was to establish an in vitro system where to study the effects of hypoglycaemia on NSC survival. Furthermore, we determine the potential role of PACAP and Exendin-4 in counteracting the effect of hypoglycaemia. A hypoglycaemic in vitro milieu was mimicked by exposing subventricular zone-derived NSC to low levels of glucose. Moreover, we studied the potential involvement of apoptosis and endoplasmic reticulum stress by quantifying protein levels of Bcl-2, cleaved caspase-3 and mRNA levels of CHOP. We show that PACAP via PAC-1 receptor and PKA activation counteracts impaired NSC viability induced by hypoglycaemia. The protective effect induced by PACAP correlated with endoplasmic reticulum stress, Exendin-4 was ineffective. The results show that hypoglycaemia decreases NSC viability and that this effect can be substantially counteracted by PACAP via PAC-1 receptor activation. The data supports a potential therapeutic role of PAC-1 receptor agonists for the treatment of neurological complications, based on neurogenesis impairment by hypoglycaemia.


A fast sol-gel synthesis leading to highly crystalline birnessites under non-hydrothermal conditions.
Manganese oxides from the compound family of layered birnessites have attracted interest for their use as cathode materials in Li-ion batteries, as supercapacitors, and as water oxidation catalysts. Furthermore, birnessites are also excellent precursors for low-temperature syntheses of manganese oxide-based materials such as LiMn2O4 (spinel and hollandite). Most syntheses leading to highly crystalline birnessites either require hydrothermal conditions for extended periods of time ranging from days to months or a high post-treatment temperature (400-500 °C). Here, we present a novel sol-gel synthesis route leading to the formation of highly crystalline birnessites within one hour without the need for any post-treatment to enhance crystallinity. Small birnessite crystals form virtually immediately upon mixing of the reactants, albeit initially of lower crystallinity. The size of the fully developed monoclinic birnessite platelets is in the micrometer-range with a thickness of about 20-50 nm. Under the studied conditions, the presence of Li+, Na+, and K+ is necessary for the formation of well-crystallized birnessites, and the crystal size can be tuned by variation of the synthesis time. This is suggested to be linked to an increase of the Na+ content in the birnessite with increasing synthesis time.


Transoceanic drift and the domestication of African bottle gourds in the Americas.
Bottle gourd (Lagenaria siceraria) was one of the first domesticated plants, and the only one with a global distribution during pre-Columbian times. Although native to Africa, bottle gourd was in use by humans in east Asia, possibly as early as 11,000 y ago (BP) and in the Americas by 10,000 BP. Despite its utilitarian importance to diverse human populations, it remains unresolved how the bottle gourd came to be so widely distributed, and in particular how and when it arrived in the New World. A previous study using ancient DNA concluded that Paleoindians transported already domesticated gourds to the Americas from Asia when colonizing the New World [Erickson et al. (2005) Proc Natl Acad Sci USA 102(51):18315-18320]. However, this scenario requires the propagation of tropical-adapted bottle gourds across the Arctic. Here, we isolate 86,000 base pairs of plastid DNA from a geographically broad sample of archaeological and living bottle gourds. In contrast to the earlier results, we find that all pre-Columbian bottle gourds are most closely related to African gourds, not Asian gourds. Ocean-current drift modeling shows that wild African gourds could have simply floated across the Atlantic during the Late Pleistocene. Once they arrived in the New World, naturalized gourd populations likely became established in the Neotropics via dispersal by megafaunal mammals. These wild populations were domesticated in several distinct New World locales, most likely near established centers of food crop domestication.


Methods for characterizing protein acetylation during viral infection.
Lysine acetylation is a prevalent posttranslational modification that acts as a regulator of protein function, subcellular localization, and interactions. A growing body of work has highlighted the importance of temporal alterations in protein acetylation during infection with a range of human viruses. It has become clear that both cellular and viral proteins are decorated by lysine acetylations, and that these modifications contribute to core host defense and virus replication processes. Further defining the extent and dynamics of protein acetylation events during the progression of an infection can provide an important new perspective on the intricate mechanisms underlying the biology and pathogenesis of virus infections. Here, we provide protocols for identifying, quantifying, and probing the regulation of lysine acetylations during viral infection. We describe the use of acetyl-lysine immunoaffinity purification and quantitative mass spectrometry for assessing the cellular acetylome at different stages of an infection. As an alternative to traditional antibody-mediated western blotting, we discuss the benefits of targeted mass spectrometry approaches for detecting and quantifying site-specific acetylations on proteins of interest. Specifically, we provide a protocol using parallel reaction monitoring (PRM). We further discuss experimental considerations that are specific to studying viral infections. Finally, we provide a brief overview of the types of assays that can be employed to characterize the function of an acetylation event in the context of infection. As a method to interrogate the regulation of acetylation, we describe the Fluor de Lys assay for monitoring the enzymatic activities of deacetylases.


A longitudinal study of cannabis use and risk for cognitive and functional decline among older adults with HIV.
Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50-84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology-this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.


Surgical palliative care consultations over time in relationship to systemwide frailty screening.
The need for integrating palliative care into surgical services has been established within the surgical literature. The ability to effectively screen, obtain an appropriately timed consultation, and determine the effect of consultation remains problematic. To examine surgical palliative care consultations over time and their relationship to the initiation and implementation of a systemwide frailty-screening program. We reviewed all surgical palliative care consultations performed between January 1, 2006, and August 31, 2013, and abstracted the referring service (medicine/surgery), date of surgery (if any), date of death (if any), and all variables required to calculate a frailty score using the risk analysis index. We examined changes in mortality and referral patterns before and after implementation of the frailty-screening program using multivariable logistic regression. Surgical palliative care consultations, including frailty screening. The primary study outcomes were 30-, 180-, and 360-day mortality. From 2006 to 2013, a total of 310 palliative care consultations were ordered for surgical patients: 160 before initiation of frailty screening (January 1, 2011) and 150 after initiation of the program. The groups had similar demographics, comorbidities, and frailty scores. After initiation, we observed dramatically decreased mortality at 30, 180, and 360 days (21.3% vs 31.9%, 44.0% vs 70.6%, and 66.0% vs 78.8%, respectively; all P < .05). This coincided with an increased rate of palliative care consultations from 32 per year to 56 per year. After initiation of the program, consultations were more likely to be requested by surgeons (56.7% vs 24.4%; P < .05) and were more likely to occur before the index operation (52.0% vs 26.3%; P < .05). Implementation of the screening program was associated with a 33% reduction in 180-day mortality (odds ratio [OR], 0.37; 95% CI, 0.22-0.62; P < .001) even after controlling for age, frailty, and whether the patients had surgery. Modeled mortality was also reduced when the palliative care consultation was ordered by a surgeon (OR, 0.50; CI, 0.30-0.83; P = .007) or ordered before the operation (OR, 0.52; CI, 0.30-0.90; P = .02). Our data suggest that a systematic frailty-screening program effectively identifies at-risk surgical patients and is associated with a significant reduction in mortality for patients undergoing palliative care consultation. Analysis also suggests that preoperative palliative care consultations ordered by surgeons are associated with reduced mortality rates.


Dominant Allele Phylogeny and Constitutive Subgenome Haplotype Inference in Bananas Using Mitochondrial and Nuclear Markers.
Cultivated bananas (Musa spp.) have undergone domestication patterns involving crosses of wild progenitors followed by long periods of clonal propagation. Majority of cultivated bananas are polyploids with different constitutive subgenomes and knowledge on phylogenies to their progenitors at the species and subspecies levels is essential. Here, the mitochondrial (NAD1) and nuclear (CENH3) markers were used to phylogenetically position cultivated banana genotypes to diploid progenitors. The CENH3 nuclear marker was used to identify a minimum representative haplotype number in polyploids and diploid bananas based on single nucleotide polymorphisms. The mitochondrial marker NAD1 was observed to be ideal in differentiating bananas of different genomic constitutions based on size of amplicons as well as sequence. The genotypes phylogenetically segregated based on the dominant genome; AAB genotypes grouped with AA and AAA, and the ABB together with BB. Both markers differentiated banana sections, but could not differentiate subspecies within the A genomic group. On the basis of CENH3 marker, a total of 13 haplotypes (five in both diploid and triploid, three in diploids, and rest unique to triploids) were identified from the genotypes tested. The presence of haplotypes, which were common in diploids and triploids, stipulate possibility of a shared ancestry in the genotypes involved in this study. Furthermore, the presence of multiple haplotypes in some diploid bananas indicates their being heterozygous. The haplotypes identified in this study are of importance because they can be used to check the level of homozygozity in breeding lines as well as to track segregation in progenies.


Oxidative damage and protection of the RPE.
This review provides a model for the role of oxidative stress in the etiology of age-related macular degeneration (AMD). Epidemiological studies of diet, environmental and behavioral risk factors suggest that oxidative stress is a contributing factor of AMD. Pathological studies indicate that damage to the retinal pigment epithelium (RPE) is an early event in AMD. In vitro studies show that oxidant treated RPE cells undergo apoptosis, a possible mechanism by which RPE cells are lost during early phase of AMD. The main target of oxidative injury seems to be mitochondria, an organelle known to accumulate genomic damages in other postmitotic tissues during aging. The thiol antioxidant GSH and its amino acid precursors protect RPE cells from oxidant-induced apoptosis. Similar protection occurs with dietary enzyme inducers which increase GSH synthesis. These results indicate that therapeutic or nutritional intervention to enhance the GSH antioxidant capacity of RPE may provide an effective way to prevent or treat AMD.


Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial.
Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. Cancer Research UK and AstraZeneca.


Novel optoelectronic devices based on single semiconductor nanowires (nanobelts).
Semiconductor nanowires (NWs) or nanobelts (NBs) have attracted more and more attention due to their potential application in novel optoelectronic devices. In this review, we present our recent work on novel NB photodetectors, where a three-terminal metal-semiconductor field-effect transistor (MESFET) device structure was exploited. In contrast to the common two-terminal NB (NW) photodetectors, the MESFET-based photodetector can make a balance among overall performance parameters, which is desired for practical device applications. We also present our recent work on graphene nanoribbon/semiconductor NW (SNW) heterojunction light-emitting diodes (LEDs). Herein, by taking advantage of both graphene and SNWs, we have fabricated, for the first time, the graphene-based nano-LEDs. This achievement opens a new avenue for developing graphene-based nano-electroluminescence devices. Moreover, the novel graphene/SNW hybrid devices can also find use in other applications, such as high-sensitivity sensor and transparent flexible devices in the future.


Reliability of the Brazilian version of HCR-20 Assessing Risk for Violence.
Assessing risk for violence is a complex task often based on not objective or structured clinical evaluations. HCR-20 Assessing Risk for Violence has been used in several countries to increase the accuracy of this exam. The purpose of this study was to inform on central aspects of this instrument, as well as the results of the reliability assessment of the HCR-20 Assessing Risk for Violence in a Brazilian inpatient criminal population. Two examiners independently assessed a random sample of 30 patients that were under criminal commitment at the Mauricio Cardoso Forensic Psychiatric Institute Mean consensus values means were as follows: Historical = 13.1; Clinical = 4.8 and Risk management = 5.8. The value of the Intraclass Correlation Coefficient for the score of subscale Historical was 0.97, for subscale Clinical it was 0.94, and for subscale Risk management, 0.96. As to the individual items of the HCR-20 Assessing Risk for Violence, the result of the Intraclass Correlation Coefficient was good to excellent (mean = 0.97; interval, from 0.60 to 0.99). The interrater reliability of the Brazilian version of the HCR-20 Assessing Risk for Violence scale was similar to the results of studies in other countries.


Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production.
The mechanism of endothelin-1 (ET-1)-induced nitric oxide (NO) production, MMP-1 production and MMP-13 production was investigated in human osteoarthritis chondrocytes. The cells were isolated from human articular cartilage obtained at surgery and were cultured in the absence or presence of ET-1 with or without inhibitors of protein kinase or LY83583 (an inhibitor of soluble guanylate cyclase and of cGMP). MMP-1, MMP-13 and NO levels were then measured by ELISA and Griess reaction, respectively. Additionally, inducible nitric oxide synthase (iNOS) and phosphorylated forms of p38 mitogen-activated protein kinase, p44/42, stress-activated protein kinase/Jun-N-terminal kinase and serine-threonine Akt kinase were determined by western blot. Results show that ET-1 greatly increased MMP-1 and MMP-13 production, iNOS expression and NO release. LY83583 decreased the production of both metalloproteases below basal levels, whereas the inhibitor of p38 kinase, SB202190, suppressed ET-1-stimulated production only. Similarly, the ET-1-induced NO production was partially suppressed by the p38 kinase inhibitor and was completely suppressed by the protein kinase A kinase inhibitor KT5720 and by LY83583, suggesting the involvement of these enzymes in relevant ET-1 signalling pathways. In human osteoarthritis chondrocytes, ET-1 controls the production of MMP-1 and MMP-13. ET-1 also induces NO release via iNOS induction. ET-1 and NO should thus become important target molecules for future therapies aimed at stopping cartilage destruction.


Magnetic Properties of FePt Nanoparticles Prepared by a Micellar Method.
FePt nanoparticles with average size of 9 nm were synthesized using a diblock polymer micellar method combined with plasma treatment. To prevent from oxidation under ambient conditions, immediately after plasma treatment, the FePt nanoparticle arrays were in situ transferred into the film-growth chamber where they were covered by an SiO2 overlayer. A nearly complete transformation of L10 FePt was achieved for samples annealed at temperatures above 700 °C. The well control on the FePt stoichiometry and avoidance from surface oxidation largely enhanced the coercivity, and a value as high as 10 kOe was obtained in this study. An evaluation of magnetic interactions was made using the so-called isothermal remanence (IRM) and dc-demagnetization (DCD) remanence curves and Kelly-Henkel plots (ΔM measurement). The ΔM measurement reveals that the resultant FePt nanoparticles exhibit a rather weak interparticle dipolar coupling, and the absence of interparticle exchange interaction suggests no significant particle agglomeration occurred during the post-annealing. Additionally, a slight parallel magnetic anisotropy was also observed. The results indicate the micellar method has a high potential in preparing FePt nanoparticle arrays used for ultrahigh density recording media.


Synchronisation in the beta frequency-band--the bad boy of parkinsonism or an innocent bystander?
Excessive synchronisation of basal ganglia neuronal activity in the beta frequency band has been implicated in Parkinson's disease. In a recent issue of Experimental Neurology, Bronte-Stewart, H., Barberini, C., Koop, M.M., Hill, B.C., Henderson, J.M., Wingeier, B., 2009. The STN beta-band profile in Parkinson's disease is stationary and shows prolonged attenuation after deep brain stimulation. Exp. Neurol. 215, 20-28. demonstrate that such activity is consistent over time and provide further evidence that deep brain stimulation is associated with its suppression. However, the extent to which beta synchrony has a mechanistic (rather than epiphenomenal) role in parkinsonism remains unclear, and the suppression of this activity by deep brain stimulation is contentious. This commentary discusses the evidence for and against a role for excessive beta synchrony in mediating the parkinsonian phenotype and in providing a possible mechanism to explain the therapeutic effects of deep brain stimulation in Parkinson's disease.


Oxycodone for cancer-related pain.
Many patients with cancer experience moderate to severe pain that requires treatment with strong opioids, of which oxycodone and morphine are examples. Strong opioids are, however, not effective for pain in all patients, nor are they well-tolerated by all patients. The aim of this review was to assess whether oxycodone is associated with better pain relief and tolerability than other analgesic options for patients with cancer pain. To assess the effectiveness and tolerability of oxycodone for pain in adults with cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE and MEDLINE In-Process (Ovid), EMBASE (Ovid), Science Citation Index, Conference Proceedings Citation Index - Science (ISI Web of Science), BIOSIS (ISI), PsycINFO (Ovid) and PubMed to March 2014. We also searched Clinicaltrials.gov, metaRegister of Controlled Trials (mRCT), EU Clinical Trials Register and World Health Organization International Clinical Trials Registry Platform (ICTRP). We checked the bibliographic references of relevant identified studies and contacted the authors of the included studies to find additional trials not identified by the electronic searches. No language, date or publication status restrictions were applied to the search. We included randomised controlled trials (parallel-group or cross-over) comparing oxycodone (any formulation or route of administration) with placebo or an active drug (including oxycodone) for cancer background pain in adults. Two authors independently extracted study data (study design, participant details, interventions and outcomes) and independently assessed the quality of the included studies according to standard Cochrane methodology. Where possible, we meta-analysed the pain intensity data using the generic inverse variance method, otherwise these data were summarised narratively along with the adverse event and patient preference data. The overall quality of the evidence for each outcome was assessed according to the GRADE approach. We included 17 studies which enrolled/randomised 1390 patients with 1110 of these analysed for efficacy and 1170 for safety. The studies examined a number of different drug comparisons. Four studies compared controlled release (CR) oxycodone to immediate release (IR) oxycodone and pooled analysis of three of these studies showed that the effects of CR and IR oxycodone on pain intensity after treatment were similar (standardised mean difference (SMD) 0.1, 95% confidence interval (CI) -0.06 to 0.26; low quality evidence). This was in line with the finding that none of the included studies reported differences in pain intensity between the treatment groups. Three of the four studies also found similar results for treatment acceptability and adverse events in the IR and CR groups; but one study reported that, compared to IR oxycodone, CR oxycodone was associated with significantly fewer adverse events.Six studies compared CR oxycodone to CR morphine and pooled analysis of five of these studies indicated that pain intensity did not differ significantly between the treatments (SMD 0.14, 95% CI -0.04 to 0.32; low quality evidence). There were no marked differences in adverse event rates, treatment acceptability or quality of life ratings.The remaining seven studies either compared oxycodone in various formulations or compared oxycodone to different alternative opioids. None of them found any clear superiority or inferiority of oxycodone for cancer pain, neither as an analgesic agent nor in terms of adverse event rates and treatment acceptability.The quality of this evidence base was limited by the risk of bias of the studies and by small sample sizes for many outcomes. Random sequence generation and allocation concealment were under-reported, and the results were substantially compromised by attrition with data missing from more than 20% of the enrolled/randomised patients for efficacy and from more than 15% for safety. Overall, the data included within this review suggest that oxycodone offers similar levels of pain relief and adverse events to other strong opioids including morphine, which is commonly considered the gold standard strong opioid. Our conclusions are consistent with other recent reviews and suggest that while the reliability of the evidence base is low, given the absence of important differences within this analysis it seems unlikely that larger head to head studies of oxycodone versus morphine will be justified. This means that for clinical purposes oxycodone or morphine can be used as first line oral opioids for relief of cancer pain.


Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations.
Acute variceal bleeding (AVB) is a medical emergency and associated with a mortality of 20% at 6 weeks. Significant advances have occurred in the recent past and hence there is a need to update the existing consensus guidelines. There is also a need to include the literature from the Eastern and Asian countries where majority of patients with portal hypertension (PHT) live. The expert working party, predominantly from the Asia-Pacific region, reviewed the existing literature and deliberated to develop consensus guidelines. The working party adopted the Oxford system for developing an evidence-based approach. Only those statements that were unanimously approved by the experts were accepted. AVB is defined as a bleed in a known or suspected case of PHT, with the presence of hematemesis within 24 h of presentation, and/or ongoing melena, with last melanic stool within last 24 h. The time frame for the AVB episode is 48 h. AVB is further classified as active or inactive at the time of endoscopy. Combination therapy with vasoactive drugs (<30 min of hospitalization) and endoscopic variceal ligation (door to scope time <6 h) is accepted as first-line therapy. Rebleeding (48 h of T (0)) is further sub-classified as very early rebleeding (48 to 120 h from T (0)), early rebleeding (6 to 42 days from T (0)) and late rebleeding (after 42 days from T (0)) to maintain uniformity in clinical trials. Emphasis should be to evaluate the role of adjusted blood requirement index (ABRI), assessment of associated comorbid conditions and poor predictors of non-response to combination therapy, and proposed APASL (Asian Pacific Association for Study of the Liver) Severity Score in assessing these patients. Role of hepatic venous pressure gradient in AVB is considered useful. Antibiotic (cephalosporins) prophylaxis is recommended and search for acute ischemic hepatic injury should be done. New guidelines have been developed for management of variceal bleed in patients with non-cirrhotic PHT and variceal bleed in pediatric patients. Management of acute variceal bleeding in Asia-Pacific region needs special attention for uniformity of treatment and future clinical trials.


Declining population trends of European mountain birds.
Mountain areas often hold special species communities, and they are high on the list of conservation concern. Global warming and changes in human land use, such as grazing pressure and afforestation, have been suggested to be major threats for biodiversity in the mountain areas, affecting species abundance and causing distribution shifts towards mountaintops. Population shifts towards poles and mountaintops have been documented in several areas, indicating that climate change is one of the key drivers of species' distribution changes. Despite the high conservation concern, relatively little is known about the population trends of species in mountain areas due to low accessibility and difficult working conditions. Thanks to the recent improvement of bird monitoring schemes around Europe, we can here report a first account of population trends of 44 bird species from four major European mountain regions: Fennoscandia, UK upland, south-western (Iberia) and south-central mountains (Alps), covering 12 countries. Overall, the mountain bird species declined significantly (-7%) during 2002-2014, which is similar to the declining rate in common birds in Europe during the same period. Mountain specialists showed a significant -10% decline in population numbers. The slope for mountain generalists was also negative, but not significantly so. The slopes of specialists and generalists did not differ from each other. Fennoscandian and Iberian populations were on average declining, while in United Kingdom and Alps, trends were nonsignificant. Temperature change or migratory behaviour was not significantly associated with regional population trends of species. Alpine habitats are highly vulnerable to climate change, and this is certainly one of the main drivers of mountain bird population trends. However, observed declines can also be partly linked with local land use practices. More efforts should be undertaken to identify the causes of decline and to increase conservation efforts for these populations.


Low molecular weight heparin for the out-of-hospital treatment of venous thrombosis: rationale and clinical results.
LMWH preparations have been proven to be safe and effective in the out-patient management of acute DVT. Although LMWHs are more expensive than unfractionated heparin, the lack of need for laboratory monitoring of LMWHs and their potential for out-patient treatment more than offsets the drug related cost difference and results in a net cost savings in favour of LMWH. LMWHs have undergone limited investigation for the secondary prevention of venous thromboembolism after an initial in-patient course of unfractionated heparin. To data, LMWHs have been given in prophylactic doses in these trials. In this setting, the LMWHs are associated with a similar risk of bleeding as fixed, intermediate dose unfractionated heparin in patients with a high risk of bleeding. In patients with no increase in bleeding risk, fixed prophylactic dose LMWH appears to be associated with both a lower risk of bleeding than warfarin (target INR of 2.0 to 3.0) and an increased risk of recurrence, although these findings need to be confirmed in larger trials.


Drivers of Bird Species Richness within Moist High-Altitude Grasslands in Eastern South Africa.
Moist high-altitude grasslands in South Africa are renowned for high avifaunal diversity and are priority areas for conservation. Conservation management of these areas conflicts with management for other uses, such as intensive livestock agriculture, which requires annual burning and leads to heavy grazing. Recently the area has become target for water storage schemes and renewable electricity energy projects. There is therefore an urgent need to investigate environmental factors and habitat factors that affect bird species richness in order to optimise management of those areas set aside for conservation. A particularly good opportunity to study these issues arose at Ingula in the eastern South African high-altitude grasslands. An area that had been subject to intense grazing was bought by the national power utility that constructed a pumped storage scheme on part of the land and set aside the rest for bird conservation. Since the new management took over in 2005 the area has been mostly annually burned with relatively little grazing. The new management seeks scientific advice on how to maintain avian species richness of the study area. We collected bird occurrence and vegetation data along random transects between 2006 and 2010 to monitor the impact of the new management, and to study the effect of the habitat changes on bird species richness. To achieve these, we convert bird transect data to presence only data to investigate how bird species richness were related to key transect vegetation attributes under this new grassland management. First we used generalised linear mixed models, to examine changes in vegetation grass height and cover and between burned and unburned habitats. Secondly, we examined how total bird species richness varied across seasons and years. And finally we investigated which habitat vegetation attributes were correlated with species richness of a group of grassland depended bird species only. Transects that were burned showed a larger decrease in vegetation cover compared to transects that were not burned. Grass height increased over time. Bird species richness was highest in summer compared to other seasons and increased over time. Overall bird species richness increased over the three summer surveys but species richness of birds that prefer heavily grazed habitat showed little change over the three years. Changes in bird species richness were best explained by the model with grass height for combined species richness of grassland depended birds but also for birds that prefer heavy grazing when treated alone. On one hand birds that prefer moderate grazing were best explained by a null model. However, overall bird species richness was better positively correlated to grass height than grass cover or dead grass. We conclude that frequent burning alone with relatively reduced grazing led to higher but less dense grass, which benefited some species and disadvantaged others. We suggest that management of this grassland use combination of fire and grazing and leave some areas unburned to accommodates birds of various habitat needs.


Inverse opal structured α-Fe2O3 on graphene thin films: enhanced photo-assisted water splitting.
A graphene interlayer was successfully inserted into inverse opaline hematite (α-Fe(2)O(3)) photoanodes for solar water splitting using the template assisted electrodeposition method. Finding the optimal thermal annealing temperature is crucial for the successful attainment of the inverse opaline hematite nanostructure on a graphene thin film. This is because an appropriate temperature is required to convert pre-deposited Fe(0) into hematite with optimum crystalline structure and to simultaneously remove the soft polystyrene template without thermal degradation of the graphene film on a transparent conductive substrate. Different from the conventional strategies based on graphene-semiconductor systems, this novel mechanism has been proposed whereby the graphene interlayer can act as both an electron transfer layer and an electrolyte blocking barrier, by which it not only reduces the charge recombination at the substrate-electrolyte interface but also helps electron transportation from α-Fe(2)O(3) to the substrate of the photoanode. Therefore, both photocurrent density and incident photon-to-current efficiency (IPCE) have been remarkably improved, which are several times higher than those of the pure inverse opaline hematite photoanode.


Reliable and Sensitive Detection of Acidovorax citrulli in Cucurbit Seed Using a Padlock-Probe-Based Assay.
A method was developed using a padlock probe (PLP) and dot-blot hybridization for detecting Acidovorax citrulli in cucurbit seed. The PLP was designed based on the 16S-23S internal transcribed spacer ribosomal DNA sequence from A. citrulli. The detection threshold for the PLP assay was 100 fg of genomic DNA, and A. citrulli was detected in 100% of artificially infested seedlots with 0.1% infestation or greater. In addition, using the PLP assay, 4 of 8 melon seedlots collected from Xinjang province and 15 of 47 watermelon seedlots collected from Ningxia province were positive for A. citrulli. In contrast, a conventional polymerase chain reaction (PCR) assay that relied on primers WFB1 and WFB2 facilitated A. citrulli detection in 1 of 8 and 5 of 47 seedlots from Xinjiang and Ningxia provinces, respectively. These data indicate that the PLP and dot-blot hybridization technique was more effective than conventional PCR for seed health testing.


Phospholipase D-modified low density lipoprotein is taken up by macrophages at increased rate. A possible role for phosphatidic acid.
Macrophage uptake of modified forms of LDL leads to cellular cholesterol accumulation. Upon incubation of LDL with phospholipase D (PLase D), a time- and enzyme dose-dependent production of phosphatidic acid (PA), paralleled by a rapid reduction in LDL phosphatidyl choline content (up to 65% within 15 min of incubation) was noted. No lipid peroxidation could be found in PLase D-modified LDL. Upon in vitro incubation of PLase D-LDL with copper ions, however, this modified LDL was substantially oxidized. The addition of 100 micrograms PA/ml to native LDL for the period of its in vitro oxidation resulted in a 63% elevation in the lipoprotein peroxides content. Incubation of PLase D-LDL with J-774A.1 macrophage-like cell line resulted in an increase in its cellular binding and degradation (up to 91 and 110%, respectively) in comparison with native LDL (via the LDL receptor). When PA was added to LDL before its incubation with the macrophages, a PA dose-dependent elevation in the cellular uptake of LDL (by up to twofold) was noted in comparison with LDL that was incubated without PA, suggesting that PA production in PLase D-LDL may be involved in the increased cellular uptake of PLase D-LDL. PLase D activity towards LDL was demonstrated in J-774A.1 macrophages. Human plasma was also shown to possess PLase D activity. Thus, PLase D modification of LDL may take place under certain pathological conditions and PLase D-LDL interaction with arterial wall macrophages can potentially lead to foam cell formation.


Do maximal aerobic power and blood lactate concentration affect Specific Judo Fitness Test performance in female judo athletes?
The Special Judo Fitness Test (SJFT) has become the test most widely used by coaches and physical trainers for assessment of competitors' judo-specific physical aptitude and training programme prescription. The aim of this study was to investigate the relationship between the SJFT performance indices and both maximal aerobic power and the level of blood lactate concentrations in female judo athletes. Seventeen female judokas (age: 21.9±1.6 years, body mass: 74.6±27.4 kg, height: 164.5±8.6 cm; BMI: 27.1±8.0 kg · m-2) took part in this study. All participants performed the SJFT, 20 m multi-stage shuttle run test (MSRT), and 30 m straight sprint test (SST), from which we calculated both acceleration (10 m) and the maximal anaerobic speed (MAnS: flying 20 m sprint). A blood sample was taken 3 min after the SJFT. The number of throws was significantly correlated with estimated VO2max (r=0.795, p=0.0001) and both acceleration (r=0.63, p =0.006) and MAnS (r=0.76, p=0.0004). Peak blood lactate recorded after the SJFT was 13.90±1.39 mmol · l-1. No significant correlation was found between blood lactate concentration and the SJFT performance indices. The lack of significant correlation between blood lactate and SJFT performance suggests that lactic anaerobic metabolism has no effect on this type of judo-specific supra-maximal exercise. The observed results can provide coaches and strength and conditioning professionals with relevant information for the interpretation of SJFT performance and the prescription of specific training programmes for female judo athletes.


Transduction of CD34+ cells with lentiviral vectors enables the production of large quantities of transgene-expressing immature and mature dendritic cells.
Genetically engineered dendritic cells (DC) presenting specific antigens to T cells may be of great interest for immunotherapy. For this reason, the production of transgene-expressing DC derived from CD34 + cells transduced either shortly after ex vivo purification or during their differentiation into DC were evaluated. CD34+ cells were transduced with lentivectors encoding for GFP before or after 21 days of culture with FLT3-ligand, thrombopoietin and stem cell factor and induction into DC with GM-CSF+IL-4 (G4) or G4+TNF (GT4). GFP and DC-specific marker expression was assessed by flow cytometry, and allostimulatory capacity was evaluated on GFP+ and GFP- sorted cells. Immature (G4-induced) DC obtained from amplified CD34 + cells were transducible by lentiviral vectors while mature (GT4-induced) DC were rather refractory. Moreover, since differentiated DC did not proliferate, large quantities of vectors were required to generate transgene-expressing cells with this protocol. In contrast, greater numbers of both immature and mature GFP- expressing DC were obtained with CD34+ cells exposed to lentivector shortly after purification. By the time of DC induction, GFP+ cells had increased by approximately 170-fold. After DC induction with G4, 32% of CD1a+, HLA-DR+, or CD40+ cells expressed GFP. CD1a+E-cadherin+ GFP+ Langerhans-like DC were also obtained. Incubation with TNF induced mature CD83+GFP+ DC that displayed a higher allostimulatory capacity than cells induced with G4 alone. The transduction of a small number of CD34+ cells with minimal doses of lentivector may allow for the production of a large number of DC expressing selected antigens useful for immunotherapy.


Can we assess dynamic cerebral autoregulation in stroke patients with high rates of cardiac ectopicity?
It is unclear whether physiological recordings containing high numbers of ectopic heartbeats can be used to measure the cerebral autoregulation (CA) of blood flow. This study evaluated the utility of such data for assessing dynamic CA capacity. Physiological recordings of cerebral blood flow velocity, heart rate, end-tidal CO2 and beat-to-beat blood pressure from acute ischaemic stroke (AIS) patients (n = 46) containing ectopic heartbeats of varying number (0.2 to 25 occurrences per minute) were analysed. Dynamic CA was determined using the autoregulation index (ARI) and the normalised mean square error (NMSE) was used to evaluate the fitting of the step response between BP and CBFV to Tiecks' model. We fitted linear mixed models on the CA variables incorporating ectopic burden, age, sex and hemisphere as predictor variables. Ectopic activity demonstrated an association with mean coherence (p = 0.006) but not with ARI (p = 0.162), impaired CA based on dichotomised ARI (p = 0.859) or NMSE (p = 0.671). Dynamic CA could be reliably assessed in AIS patients using physiological recordings with high rates of cardiac ectopic activity. This provides supportive data for future studies evaluating CA capability in AIS patients, with the potential to develop more individualised treatment strategies. Graphical Abstract.


Fcγ receptors inhibit mouse and human basophil activation.
Besides high-affinity IgE receptors (FcεRI), human basophils express activating (FcγRIIA) and inhibitory (FcγRIIB) low-affinity IgG receptors. IgG receptors (FcγR) were also found on mouse basophils, but not identified. We investigated in this study FcγR and the biological consequences of their engagement in basophils of the two species. We found the following: (1) that mouse basophils also express activating (FcγRIIIA) and inhibitory (FcγRIIB) low-affinity FcγR; (2) that activating FcγR can activate both human and mouse basophils, albeit with different efficacies; (3) that negative signals triggered by inhibitory FcγR are dominant over positive signals triggered by activating FcγR, thus preventing both human and mouse basophils from being activated by IgG immune complexes; (4) that the coengagement of FcεRI with inhibitory and activating FcγR results in a FcγRIIB-dependent inhibition of IgE-induced responses of both human and mouse basophils; (5) that FcγRIIB has a similar dominant inhibitory effect in basophils from virtually all normal donors; and (6) that IL-3 upregulates the expression of both activating and inhibitory FcγR on human basophils from normal donors, but further enhances FcγRIIB-dependent inhibition. FcγR therefore function as a regulatory module, made of two subunits with antagonistic properties, that prevents IgG-induced and controls IgE-induced basophil activation in both mice and humans.


Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer.
The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a 'Pathology of Bladder Cancer Work Group,' have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting.


Endothelium-dependent and -independent relaxation and VASP serines 157/239 phosphorylation by cyclic nucleotide-elevating vasodilators in rat aorta.
Endothelium-dependent vasodilation is thought to be mediated primarily by the NO/cGMP signaling pathway whereas cAMP-elevating vasodilators are considered to act independent of the endothelial cell layer. However, recent functional data suggest that cAMP-elevating vasodilators such as beta-receptor agonists, adenosine or forskolin may also be endothelium-dependent. Here we used functional and biochemical assays to analyze endothelium-dependent, cGMP- and cAMP-mediated signaling in rat aorta. Acetylcholine and sodium nitroprusside (SNP) induced a concentration-dependent relaxation of phenylephrine-precontracted aorta. This response was reflected by the phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), a validated substrate of cGMP- and cAMP-dependent protein kinases (cGK, cAK), on Ser(157) and Ser(239). As expected, the effects of acetylcholine were endothelium-dependent. However, relaxation induced by the beta-receptor agonist isoproterenol was also almost completely impaired after endothelial denudation. At the biochemical level, acetylcholine- and isoproterenol-evoked cGK and cAK activation, respectively, as measured by VASP Ser(239) and Ser(157) phosphorylation, was strongly diminished. Furthermore, the effects of isoproterenol were repressed by eNOS inhibition when endothelium was present. We also observed that the relaxing and biochemical effects of forskolin were at least partially endothelium-dependent. We conclude that cAMP-elevating vasodilators, i.e. isoproterenol and to a lesser extent also forskolin, induce vasodilation and concomitant cyclic nucleotide protein kinase activation in the vessel wall in an endothelium-dependent way.


Principles of spin-echo modulation by J-couplings in magic-angle-spinning solid-state NMR.
In magic-angle-spinning solid-state NMR, the homonuclear J-couplings between pairs of spin-1/2 nuclei may be determined by studying the modulation of the spin echo induced by a pi-pulse, as a function of the echo duration. We present the theory of J-induced spin-echo modulation in magic-angle-spinning solids, and derive a set of modulation regimes which apply under different experimental conditions. In most cases, the dominant spin-echo modulation frequency is exactly equal to the J-coupling. Somewhat surprisingly, the chemical shift anisotropies and dipole-dipole couplings tend to stabilise--rather than abscure--the J-modulation. The theoretical conclusions are supported by numerical simulations and experimental results obtained for three representative samples containing 13C spin pairs.