The role of biofilms in otolaryngologic infections: update 2007.
Biofilms have been shown to play a role in otitis media, sinusitis, cholesteatoma, tonsillitis, adenoiditis, and device infections. This article is written to review recent advances in the field. The role of biofilms in the persistence of chronic, mucosal-based ENT-related infections was first recognized in otitis media. Definitive proof was lacking until the demonstration of bacterial biofilms on the middle-ear mucosa of children, not only with chronic otitis media with effusion, but also with recurrent otitis media. Strains of Pseudomonas aeruginosa isolated from cholesteatoma are avid biofilm formers. Biofilms have been reported in the adenoids of children with chronic rhinosinusitis, helping to explain the clinical observation that adenoidectomy can be beneficial to children with chronic otitis or chronic rhinosinusiti. Additional studies have confirmed the presence of biofilms in chronic tonsillitis. Biofilms have also been shown to be involved in infected cochlear implants and tracheotomy tubes. The recognition that chronic otolaryngologic bacterial infections are biofilm related has been the impetus for the development of new technologies for the study of biofilms and their prevention and treatment. Understanding that chronic bacterial infections are biofilm related is fundamental to developing rationale strategies for treatment and prevention.


CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.
The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. Hoffmann-La Roche.


Suture Anchor Fixation in Osteoporotic Bone: A Biomechanical Study in an Ovine Model.
To evaluate the load to failure strength of anchor techniques suitable for osteoporotic bone. Using an osteoporotic ovine model in 72 humeri, 6 fixation techniques were tested. Group 1: two interlocking 5-mm anchors with fewer, wider threads; group 2: one 5-mm anchor; group 3: one 5-mm anchor reinforced laterally by a 6.5-mm cancellous screw; group 4: one 5-mm anchor in an area reinforced with a cancellous plug; group 5: two interlocking 5-mm anchors with smaller threads; group 6: one 5-mm smaller threaded anchor. After a 10-N preload, the specimens were cyclically loaded between 10 N and 30 N for 50 cycles and then destructively tested. Peak-to-peak displacement, cyclic elongation, ultimate load, stiffness, and failure mode were recorded. Group 1 had lower peak-to-peak displacement than group 3 (P = .001), group 5 (P = .001), and group 6 (P = .033). In addition, group 1 showed lower cyclic elongation than group 3 (P = .001), group 5 (P = .035), and group 6 (P = .001). Group 1 had a higher ultimate load than group 2 (P = .002), group 3 (P = .019), and group 6 (P = .006). Group 1 also showed higher stiffness than group 2 (P = .007) and group 3 (P = .022). Mode of failure was predominantly caused by anchor pullout for all of the groups except group 3, which mainly failed by suture rupture. Two interlocking suture anchors are stronger than a single anchor in osteoporotic bone. The anchor with fewer, wider threads and a smaller core diameter showed greater strength and less elongation than the other constructs. Reinforcement by cancellous autografting increased suture anchor strength. Considering concerns about suture anchor pullout from osteoporotic bone, interlocking a second suture anchor with the first increases load to failure resistance. Anchors with small core diameters and fewer but wider threads are more efficient in osteoporotic bone.


Verification bias.
This article is part of the Catalogue of Bias series. We present a description of verification bias, and outline its potential impact on research studies and the preventive steps to minimise its risk. We also present teaching slides in the online supplementary file. Verification bias (sometimes referred to as 'work-up bias') concerns the test(s) used to confirm a diagnosis within a diagnostic accuracy study. Verification bias occurs when only a proportion of the study participants receive confirmation of the diagnosis by the reference standard test, or if some participants receive a different reference standard test.


The impact of driver sleepiness on fixation-related brain potentials.
The effects of driver sleepiness are often quantified as deteriorated driving performance, increased blink durations and high levels of subjective sleepiness. Driver sleepiness has also been associated with increasing levels of electroencephalogram (EEG) power, especially in the alpha range. The present exploratory study investigated a new measure of driver sleepiness, the EEG fixation-related lambda response. Thirty young male drivers (23.6 ± 1.7 years old) participated in a driving simulator experiment in which they drove on rural and suburban roads in simulated daylight versus darkness during both the daytime (full sleep) and night-time (sleep deprived). The results show lower lambda responses during night driving and with longer time on task, indicating that sleep deprivation and time on task cause a general decrement in cortical responsiveness to incoming visual stimuli. Levels of subjective sleepiness and line crossings were higher under the same conditions. Furthermore, results of a linear mixed-effects model showed that low lambda responses are associated with high subjective sleepiness and more line crossings. We suggest that the fixation-related lambda response can be used to investigate driving impairment induced by sleep deprivation while driving and that, after further refinement, it may be useful as an objective measure of driver sleepiness.


Silicone wristbands compared with traditional polycyclic aromatic hydrocarbon exposure assessment methods.
Currently there is a lack of inexpensive, easy-to-use technology to evaluate human exposure to environmental chemicals, including polycyclic aromatic hydrocarbons (PAHs). This is the first study in which silicone wristbands were deployed alongside two traditional personal PAH exposure assessment methods: active air monitoring with samplers (i.e., polyurethane foam (PUF) and filter) housed in backpacks, and biological sampling with urine. We demonstrate that wristbands worn for 48 h in a non-occupational setting recover semivolatile PAHs, and we compare levels of PAHs in wristbands to PAHs in PUFs-filters and to hydroxy-PAH (OH-PAH) biomarkers in urine. We deployed all samplers simultaneously for 48 h on 22 pregnant women in an established urban birth cohort. Each woman provided one spot urine sample at the end of the 48-h period. Wristbands recovered PAHs with similar detection frequencies to PUFs-filters. Of the 62 PAHs tested for in the 22 wristbands, 51 PAHs were detected in at least one wristband. In this cohort of pregnant women, we found more significant correlations between OH-PAHs and PAHs in wristbands than between OH-PAHs and PAHs in PUFs-filters. Only two comparisons between PAHs in PUFs-filters and OH-PAHs correlated significantly (rs = 0.53 and p = 0.01; rs = 0.44 and p = 0.04), whereas six comparisons between PAHs in wristbands and OH-PAHs correlated significantly (rs = 0.44 to 0.76 and p = 0.04 to <0.0001). These results support the utility of wristbands as a biologically relevant exposure assessment tool which can be easily integrated into environmental health studies. Graphical abstract PAHs detected in samples collected from urban pregnant women.


Upper Vertical Spatial Neglect With A Right Temporal Lobe Stroke.
Individuals with a hemispheric infarction often reveal inattention to, or neglect of, contralesional lateral space (ie, hemispatial neglect). Individuals with a bilateral ventral temporal-occipital lesion have been shown to demonstrate upper vertical neglect, and those with a bilateral parietal-occipital lesion have been shown to demonstrate lower vertical neglect. However, to our knowledge, there have been no reports of individuals with vertical neglect from a unilateral hemispheric lesion. We report on a 72-year-old, right-handed male who developed transient left hemiparesis. On examination, he had left facial weakness and he bisected horizontal lines to the left of the midline (ie, ipsilesional neglect). In addition, on a line bisection test involving nine vertical line bisections, he demonstrated downward deviation in the majority of the trials; healthy individuals deviate upward. On brain imaging, our patient revealed a cerebral infarction, primarily affecting the right temporal lobe; the temporal lobes contain the ventral attentional network that allocates attention upward. There is also some evidence that, whereas the right hemisphere mediates attention upward, the left mediates attention downward. Therefore, injury to the right temporal lobe may account for our patient's upward neglect with downward deviation. However, further studies are needed to better understand the pathophysiology of vertical neglect.


The effect of perceived organisational justice on job satisfaction and burnout levels of haemodialysis nurses.
Organisational justice influences job satisfaction, the performance of individuals and the functioning of institutions. The lack of evidence-based studies investigating the relationship between hemodialysis nurses' perceptions of organisational justice, job satisfaction and burnout has created a research gap in this area. To investigate the effect of perceived organisational justice on professional satisfaction and burnout levels of haemodialysis nurses and to identify any relation ship with individual and organisational factors. The study was designed as a multi-centre descriptive study. The data were collected using the 'personal information form', the Organisational Justice Scale', the 'Maslach Burnout Inventory' and the 'Minnesota Satisfaction Questionnaire'. The distributive justice scores decreased as the depersonalisation scores of the nurses increased. As the personal accomplishment scores of the nurses increased, the interactional justice scores also increased. It was observed that the job satisfaction scores increased as the sub-dimensional scores of the organisational justice scale increased and exhaustion decreased. It was detected that there was a significant relationship between the organisational justice perception of nurses and their job satisfaction and level of burnout. Institutions are encouraged to adopt a fair policy towards nurses and promote personal development.


Stress Management Intervention to Prevent Post-Intensive Care Syndrome-Family in Patients' Spouses.
Post-intensive care syndrome-family (PICS-F) refers to acute and chronic psychological effects of critical care on family members of patients in intensive care units (ICUs). Evidence suggests that increased distress during the ICU stay increases risk of PICS-F. Sensation Awareness Focused Training (SĀF-T) is a new, promising stress management intervention, but the feasibility of such training during the ICU stay for family caregivers who are acting as the surrogate decision-maker for patients who are undergoing mechanical ventilation is unknown. To assess feasibility and acceptability of SĀF-T to inform a future larger randomized controlled trial. This randomized controlled trial of SĀF-T (n = 5) versus a control (n = 5) group was conducted at a level 1 trauma center. Participants assigned to SĀF-T completed 1 session daily for 3 days. Measures included enrollment rate, data completion rate, acceptability of SĀF-T, and symptoms of PICS-F. Scales used included Perceived Stress, Hospital Anxiety and Depression, Impact of Event, and National Institutes of Health Toolbox Emotion Battery. Mean age was 58 (SD, 12) years; 70% of participants were female. Predetermined feasibility criteria were met in enrollment rate (67%), outcome measures completion rate (> 90%), and SĀF-T acceptability (100% of doses completed during the ICU stay) without adverse events. Stress scores after SĀF-T were significantly lower than scores before SĀF-T (z = -3.5, P = .01). SĀF-T intervention during the ICU stay is feasible, acceptable, and may improve family caregivers' post-ICU outcomes. Larger clinical trial to assess the effectiveness of SĀF-T in preventing PICS-F seem warranted.


[Consumption of animal-derived foods and mouth and oropharyngeal cancer].
Evaluate the relationship between animal-derived foods and mouth and oropharyngeal cancer. Hospital-based case-control study matched by sex and age (± 5 years) with data collected between July of 2006 and June of 2008. The sample contained 296 patients with mouth and oropharyngeal cancer and 296 patients without a cancer history who were treated in four hospitals in the City of São Paulo, State of São Paulo, Brazil. A semistructured questionnaire was administered to collect data regarding socioeconomic condition and harmful habits (tobacco and alcoholic beverage consumption). To assess eating habits, a qualitative questionnaire that asked about the frequency of food consumption was used. The analysis was rendered by means of multivariate logistic regression models that considered the existing hierarchy among the characteristics studied. Among foods of animal origin, frequent consumption of beef (OR = 2.73; CI95% = 1.27-5.87; P < 0.001), bacon (OR = 2.48; CI95% = 1.30-4.74; P < 0.001) and eggs (OR = 3.04; CI95% = 1.51-6.15; P < 0.001) was linked to an increased risk of mouth and oropharyngeal cancer, in both the univariate and multivariate analyses. Among dairy products, milk showed a protective effect against the disease (OR = 0.41; CI95% = 0.21-0.82; P < 0.001). This study affirms the hypothesis that animal-derived foods can be etiologically linked to mouth and oropharyngeal cancer. This information can guide policies to prevent these diseases, generating public health benefits.


Non-coding RNA in transcription initiation.
Diverse classes of non-coding RNAs, including snRNAs (small nuclear RNAs), play fundamental regulatory roles in gene expression. For example, 7SK RNA and the components of the splicing apparatus U1-U6 snRNAs are implicated in the regulation of transcriptional elongation. The first evidence for the involvement of RNA in the regulation of transcriptional initiation is now emerging. TFIIH (transcription factor IIH), a general transcription initiation factor, appears to associate specifically with U1 snRNA, a core splicing component. Reconstituted transcription in vitro demonstrates an increase in the rate of formation of the first phosphodiester bond by RNA polymerase II in presence of U1 snRNA. Reconstituted re-initiation is also stimulated by U1 snRNA. These results suggest that U1 snRNA functions in the regulation of transcription by RNA polymerase II in addition to its role in RNA processing. The implications of these data extend to the development of new technologies that will allow the identification and analysis of diverse RNA species present as regulatory components in transcription-related ribonucleoprotein complexes.


Molecular dissection of internalization of Porphyromonas gingivalis by cells using fluorescent beads coated with bacterial membrane vesicle.
Porphyromonas gingivalis is one of the causative agents of adult periodontitis, and has been reported to be internalized by nonphagocytic epithelial cells. However, the mechanism for the internalization remains unclear. In the present study, we addressed this issue using fluorescent beads coated with bacterial membrane vesicles (MVs) that retain surface components of P. gingivalis. We established an assay system in which we could easily quantify the bead internalization to cells. MVs-coated beads were internalized by HeLa cells in kinetics similar to that of living bacteria. The internalization depended on dynamin but not clathrin. The beads were internalized through the actin-mediated pathway that is controlled by phosphatidylinositol (PI) 3-kinase. The dynamics of microtubule assembly and disassembly was also required. Further, the treatment of cells with cholesterol-binding reagents significantly inhibited bead internalization, and the internalized beads were apparently colocalized with ganglioside GM1 and caveolin-1, which suggest the involvement of the lipid raft in the process. These results suggest that P. gingivalis accomplishes its internalization utilizing membrane lipid raft and cytoskeletal functions of the target cells.


Development of an Agent-Based Model to Investigate the Impact of HIV Self-Testing Programs on Men Who Have Sex With Men in Atlanta and Seattle.
In the United States HIV epidemic, men who have sex with men (MSM) remain the most profoundly affected group. Prevention science is increasingly being organized around HIV testing as a launch point into an HIV prevention continuum for MSM who are not living with HIV and into an HIV care continuum for MSM who are living with HIV. An increasing HIV testing frequency among MSM might decrease future HIV infections by linking men who are living with HIV to antiretroviral care, resulting in viral suppression. Distributing HIV self-test (HIVST) kits is a strategy aimed at increasing HIV testing. Our previous modeling work suggests that the impact of HIV self-tests on transmission dynamics will depend not only on the frequency of tests and testers' behaviors but also on the epidemiological and testing characteristics of the population. The objective of our study was to develop an agent-based model to inform public health strategies for promoting safe and effective HIV self-tests to decrease the HIV incidence among MSM in Atlanta, GA, and Seattle, WA, cities representing profoundly different epidemiological settings. We adapted and extended a network- and agent-based stochastic simulation model of HIV transmission dynamics that was developed and parameterized to investigate racial disparities in HIV prevalence among MSM in Atlanta. The extension comprised several activities: adding a new set of model parameters for Seattle MSM; adding new parameters for tester types (ie, regular, risk-based, opportunistic-only, or never testers); adding parameters for simplified pre-exposure prophylaxis uptake following negative results for HIV tests; and developing a conceptual framework for the ways in which the provision of HIV self-tests might change testing behaviors. We derived city-specific parameters from previous cohort and cross-sectional studies on MSM in Atlanta and Seattle. Each simulated population comprised 10,000 MSM and targeted HIV prevalences are equivalent to 28% and 11% in Atlanta and Seattle, respectively. Previous studies provided sufficient data to estimate the model parameters representing nuanced HIV testing patterns and HIV self-test distribution. We calibrated the models to simulate the epidemics representing Atlanta and Seattle, including matching the expected stable HIV prevalence. The revised model facilitated the estimation of changes in 10-year HIV incidence based on counterfactual scenarios of HIV self-test distribution strategies and their impact on testing behaviors. We demonstrated that the extension of an existing agent-based HIV transmission model was sufficient to simulate the HIV epidemics among MSM in Atlanta and Seattle, to accommodate a more nuanced depiction of HIV testing behaviors than previous models, and to serve as a platform to investigate how HIV self-tests might impact testing and HIV transmission patterns among MSM in Atlanta and Seattle. In our future studies, we will use the model to test how different HIV self-test distribution strategies might affect HIV incidence among MSM.


Designing and evaluating dose-escalation studies made easy: The MoDEsT web app.
Dose-escalation studies are essential in the early stages of developing novel treatments, when the aim is to find a safe dose for administration in humans. Despite their great importance, many dose-escalation studies use study designs based on heuristic algorithms with well-documented drawbacks. Bayesian decision procedures provide a design alternative that is conceptually simple and methodologically sound, but very rarely used in practice, at least in part due to their perceived statistical complexity. There are currently very few easily accessible software implementations that would facilitate their application. We have created MoDEsT, a free and easy-to-use web application for designing and conducting single-agent dose-escalation studies with a binary toxicity endpoint, where the objective is to estimate the maximum tolerated dose. MoDEsT uses a well-established Bayesian decision procedure based on logistic regression. The software has a user-friendly point-and-click interface, makes changes visible in real time, and automatically generates a range of graphs, tables, and reports. It is aimed at clinicians as well as statisticians with limited expertise in model-based dose-escalation designs, and does not require any statistical programming skills to evaluate the operating characteristics of, or implement, the Bayesian dose-escalation design. MoDEsT comes in two parts: a 'Design' module to explore design options and simulate their operating characteristics, and a 'Conduct' module to guide the dose-finding process throughout the study. We illustrate the practical use of both modules with data from a real phase I study in terminal cancer. Enabling both methodologists and clinicians to understand and apply model-based study designs with ease is a key factor towards their routine use in early-phase studies. We hope that MoDEsT will enable incorporation of Bayesian decision procedures for dose escalation at the earliest stage of clinical trial design, thus increasing their use in early-phase trials.


Hollow-bone-graft dynamic hip screw can fix and promote bone union after femoral neck fracture: an experimental research.
Delayed bone union, nonunion or osteonecrosis often occur after femoral neck fractures in young adults. Secondary bone healing requires strong internal fixation, intramedullary pressure reduction and early functional exercise. To compare bone healing of femoral neck fractures treated with hollow-bone-graft dynamic hip screws (Hb-DHS) and standard dynamic hip screws (DHS) in an animal model. Testing of specifically designed fixation devices in a pig animal model. We designed Hb-DHS and DHS devices appropriate to the femoral neck and head of experimental animals and used them in eight pigs (4-month-old, male or female, 30-40 kg/each). Under anesthesia, we induced medium neck type, Garden III type femoral neck fractures in each pig with fracture gaps of 0.5 mm and then fixed each left femur with Hb-DHS and each right femur with DHS. We assessed the animals radiographically and by postmortem visual appraisal of evidence of bone healing 8 and 16 weeks postoperatively. There were significant differences in radiographic and general findings between the Hb-DHS and DHS groups at weeks 8 and 16 postoperatively. We found statistically significant differences between the Hb-DHS and DHS groups in bone healing scores, trabecular bone volume percentage and bone mineral density as assessed on plain radiographs and computed tomography images (P < 0.05). There were also significant differences between the Hb-DHS and DHS groups in postmortem visually assessed indicators of bone healing at both 8 and 16 weeks postoperatively. The Hb-DHS device promotes femoral neck bone union, stimulates trabecular bone formation, increases BMD and has advantages over DHS for internal fixation of femoral neck fractures. This animal experiment will contribute to developing optimal treatment for femoral neck fractures in young adults.


Efficacy and safety of ketamine in the management of anxiety and anxiety spectrum disorders: a review of the literature.
Anxiety disorders are among the most prevalent psychiatric conditions. Despite many proven pharmacological and non-pharmacological treatments available, high rates of partial response and low rates of long-term remission remain. Ketamine has been receiving increasing attention as an interventional treatment modality in psychiatry, especially among refractory conditions, including major depressive disorder. There is limited yet growing evidence to support the use of ketamine in anxiety disorders. In this review of the literature, we present case reports, case series, and controlled trials demonstrating proof-of-concept for its potential role in the treatment of anxiety and anxiety spectrum disorders. Its unique mechanism of action, rapid onset, and high rate of response have driven its use in clinical practice. Ketamine is generally well tolerated by patients and has a limited side effect profile; however, the effects of long-term use are unknown. While there is a growing body of research and increasing clinical experience to suggest ketamine may have clinical applications in the treatment of refractory anxiety disorders, further research to determine long-term safety and tolerability is indicated.


Epidemiological effects of seasonal oscillations in birth rates.
Seasonal oscillations in birth rates are ubiquitous in human populations. These oscillations might play an important role in infectious disease dynamics because they induce seasonal variation in the number of susceptible individuals that enter populations. We incorporate seasonality of birth rate into the standard, deterministic susceptible-infectious-recovered (SIR) and susceptible-exposed-infectious-recovered (SEIR) epidemic models and identify parameter regions in which birth seasonality can be expected to have observable epidemiological effects. The SIR and SEIR models yield similar results if the infectious period in the SIR model is compared with the "infected period" (the sum of the latent and infectious periods) in the SEIR model. For extremely transmissible pathogens, large amplitude birth seasonality can induce resonant oscillations in disease incidence, bifurcations to stable multi-year epidemic cycles, and hysteresis. Typical childhood infectious diseases are not sufficiently transmissible for their asymptotic dynamics to be likely to exhibit such behaviour. However, we show that fold and period-doubling bifurcations generically occur within regions of parameter space where transients are phase-locked onto cycles resembling the limit cycles beyond the bifurcations, and that these phase-locking regions extend to arbitrarily small amplitude of seasonality of birth rates. Consequently, significant epidemiological effects of birth seasonality may occur in practice in the form of transient dynamics that are sustained by demographic stochasticity.


Prediction of infarction and reperfusion in stroke by flow- and volume-weighted collateral signal in MR angiography.
In proximal anterior circulation occlusive strokes, collateral flow is essential for good outcome. Collateralized vessel intensity in TOF- and contrast-enhanced MRA is variable due to different acquisition methods. Our purpose was to quantify collateral supply by using flow-weighted signal in TOF-MRA and blood volume-weighted signal in contrast-enhanced MRA to determine each predictive contribution to tissue infarction and reperfusion. Consecutively (2009-2013), 44 stroke patients with acute proximal anterior circulation occlusion met the inclusion criteria with TOF- and contrast-enhanced MRA and penumbral imaging. Collateralized vessels in the ischemic hemisphere were assessed by TOF- and contrast-enhanced MRA using 2 methods: 1) visual 3-point collateral scoring, and 2) collateral signal quantification by an arterial atlas-based collateral index. Collateral measures were tested by receiver operating characteristic curve and logistic regression against 2 imaging end points of tissue-outcome: final infarct volume and percentage of penumbra saved. Visual collateral scores on contrast-enhanced MRA but not TOF were significantly higher in patients with good outcome. Visual collateral scoring on contrast-enhanced MRA was the best rater-based discriminator for final infarct volume < 90 mL (area under the curve, 0.81; P < .01) and percentage of penumbra saved >50% (area under the curve, 0.67; P = .04). Atlas-based collateral index of contrast-enhanced MRA was the overall best independent discriminator for final infarct volume of <90 mL (area under the curve, 0.94; P < .01). Atlas-based collateral index combining the signal of TOF- and contrast-enhanced MRA was the overall best discriminator for effective reperfusion (percentage of penumbra saved >50%; area under the curve, 0.89; P < .001). Visual scoring of contrast-enhanced but not TOF-MRA is a reliable predictor of infarct outcome in stroke patients with proximal arterial occlusion. By atlas-based collateral assessment, TOF- and contrast-enhanced MRA both contain predictive signal information for penumbral reperfusion. This could improve risk stratification in further studies.


Chromosome divergence during evolution of the tetraploid clawed frogs, Xenopus mellotropicalis and Xenopus epitropicalis as revealed by Zoo-FISH.
Whole genome duplication (WGD) generates new species and genomic redundancy. In African clawed frogs of the genus Xenopus, this phenomenon has been especially important in that (i) all but one extant species are polyploid and (ii) whole genome sequences of some species provide an evidence for genomic rearrangements prior to or after WGD. Within Xenopus in the subgenus Silurana, at least one allotetraploidization event gave rise to three extant tetraploid (2n = 4x = 40) species-Xenopus mellotropicalis, X. epitropicalis, and X. calcaratus-but it is not yet clear the degree to which these tetraploid genomes experienced rearrangements prior to or after allotetraploidization. To explore genome evolution during diversification of these species, we performed cytogenetic analyses of X. mellotropicalis, including assessment of the localization of nucleolar organizer region, chromosome banding, and determination of the p/q arm ratios for each chromosome pair. We compared these data to a previously characterized karyotype of X. epitropicalis. Morphometric, C-banding and Zoo-FISH data support a previously hypothesized common allotetraploid predecessor of these species. Zoo-FISH with whole chromosome painting (WCP) probes derived from the closely related diploid species X. tropicalis confirmed the existence of ten chromosomal quartets in X. mellotropicalis somatic cells, as expected by its ploidy level and tetraploid ancestry. The p/q arm ratio of chromosome 2a was found to be substantially different between X. mellotropicalis (0.81) and X. epitropicalis (0.67), but no substantial difference between these two species was detected in this ratio for the homoeologous chromosome pair 2b, or for other chromosome pairs. Additionally, we identified variation between these two species in the locations of a heterochromatic block on chromosome pair 2a. These results are consistent with a dynamic history of genomic rearrangements before and/or after genome duplication, a surprising finding given the otherwise relatively conserved genomic structure of most frogs.


The conduct of Australian Indigenous primary health care research focusing on social and emotional wellbeing: a systematic review.
Objectives and importance of study: Values and ethics: guidelines for ethical conduct in Aboriginal and Torres Strait Islander health research (Values and ethics) describes key values that should underpin Aboriginal and Torres Strait Islander (Indigenous)-focused health research. It is unclear how research teams address this document in primary health care research. We systematically review the primary health care literature focusing on Indigenous social and emotional wellbeing (SEWB) to identify how Values and ethics and community preferences for standards of behaviour (local protocols) are addressed during research. Systematic review in accordance with PRISMA Guidelines and MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies. We searched four databases and one Indigenous-specific website for qualitative, quantitative and mixed-method studies published since Values and ethics was implemented (2003). Included studies were conducted in primary health care services, focused on Indigenous SEWB and were conducted by research teams. Using standard data extraction forms, we identified actions taken (reported by authors or identified by us) relating to Values and ethics and local protocols. A total of 25 studies were included. Authors of two studies explicitly mentioned the Values and ethics document, but neither reported how their actions related to the document's values. In more than half the studies, we identified at least three actions relating to the values. Some actions related to multiple values, including use of culturally sensitive research processes and involving Indigenous representatives in the research team. Local protocols were rarely reported. Addressing Values and ethics appears to improve research projects. The academic community should focus on culturally sensitive research processes, relationship building and developing the Indigenous research workforce, to facilitate acceptable research that affects health outcomes. For Values and ethics to achieve its full impact and to improve learning between research teams, authors should be encouraged to report how the principles are addressed during research, including barriers and enablers that are encountered.


A Review of the Effectiveness of Neuroimaging Modalities for the Detection of Traumatic Brain Injury.
The incidence of traumatic brain injury (TBI) in the United States was 3.5 million cases in 2009, according to the Centers for Disease Control and Prevention. It is a contributing factor in 30.5% of injury-related deaths among civilians. Additionally, since 2000, more than 260,000 service members were diagnosed with TBI, with the vast majority classified as mild or concussive (76%). The objective assessment of TBI via imaging is a critical research gap, both in the military and civilian communities. In 2011, the Department of Defense (DoD) prepared a congressional report summarizing the effectiveness of seven neuroimaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], transcranial Doppler [TCD], positron emission tomography, single photon emission computed tomography, electrophysiologic techniques [magnetoencephalography and electroencephalography], and functional near-infrared spectroscopy) to assess the spectrum of TBI from concussion to coma. For this report, neuroimaging experts identified the most relevant peer-reviewed publications and assessed the quality of the literature for each of these imaging technique in the clinical and research settings. Although CT, MRI, and TCD were determined to be the most useful modalities in the clinical setting, no single imaging modality proved sufficient for all patients due to the heterogeneity of TBI. All imaging modalities reviewed demonstrated the potential to emerge as part of future clinical care. This paper describes and updates the results of the DoD report and also expands on the use of angiography in patients with TBI.


Quantitative analysis of left ventricular regional wall motion with color kinesis during abdominal aortic cross-clamping.
The authors aimed to establish a technique for quantitative analysis of regional wall motion abnormality (RWMA) using color kinesis (CK) of transesophageal echocardiography (TEE) in surgical patients. This technique was used to determine whether RWMAs develop de novo after infrarenal aortic cross-clamping in patients undergoing vascular surgery with a preoperative dipyridamole thallium stress test (DTST). An observational study. University hospital. Thirty-eight patients undergoing infrarenal abdominal aortic aneurysm resection or aortofemoral bypass. CK images of the left ventricle (LV) were obtained from the midventricular transgastric short-axis view before and after infrarenal aortic cross-clamping using TEE and analyzed off-line using custom software. The predictive value of the category "reversible perfusion defect" (RD) was also estimated from DTST for predicting new RWMAs with CK. CK analysis is suitable for clinical use based on the comparison with conventional two-dimensional echocardiogram measurements and interobserver variability. CK analysis showed all 7 patients with persistent perfusion defects on DTST had RWMAs. New RWMAs occurred in 2 of 9 patients with RD and in 2 of 15 patients with normal DTST, indicating that there was no significant difference between RD and normal DTST in the incidence of new RWMAs. A new method is available for clinical use, which is capable of visualizing RWMAs. These results suggest that new RWMAs introduced by aortic cross-clamping occur irrespective of the risk as assessed by preoperative DTST. CK with the new analysis method might be a useful tool to quantitatively evaluate RWMAs during surgery.


Unique Francisella Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid.
Virulent Francisella tularensis subsp. tularensis (Ftt) is a dynamic, intracellular, bacterial pathogen. Its ability to evade and rapidly suppress host inflammatory responses is considered a key element for its profound virulence. We previously established that Ftt lipids play a role in inhibiting inflammation, but we did not determine the lipid species mediating this process. Here, we show that a unique, abundant, phosphatidylethanolamine (PE), present in Francisella, contributes to driving the suppression of inflammatory responses in human and mouse cells. Acyl chain lengths of this PE, C24: 0 and C10: 0, were key to the suppressive capabilities of Francisella PE. Addition of synthetic PE 24: 0-10: 0 resulted in the accumulation of PE in host cells for up to 24 h of incubation, and recapitulated the inhibition of inflammatory responses observed with native Ftt PE. Importantly, this novel PE significantly inhibited inflammatory responses driven by a medically and globally important flavivirus, dengue fever virus. Thus, targeting these lipids and/or the pathways that they manipulate represents a new strategy to combat immunosuppression engendered by Ftt, but they also show promise as a novel therapeutic intervention for significant viral infections.


Divalent metal ions promote the formation of the 5'-splice site recognition complex in a self-splicing group II intron.
Group II introns are ribozymes occurring in genes of plants, fungi, lower eukaryotes, and bacteria. These large RNA molecular machines, ranging in length from 400 to 2500 nucleotides, are able to catalyze their own excision from pre-mRNA, as well as to reinsert themselves into RNA or sometimes even DNA. The intronic domain 1 contains two sequences (exon binding sites 1 and 2, EBS1 and EBS2) that pair with their complementary regions at the 3'-end of the 5'-exon (intron binding sites 1 and 2, IBS1 and IBS2) such defining the 5'-splice site. The correct recognition of the 5'-splice site stands at the beginning of the two steps of splicing and is thus crucial for catalysis. It is known that metal ions play an important role in folding and catalysis of ribozymes in general. Here, we characterize the specific metal ion requirements for the formation of the 5'-splice site recognition complex from the mitochondrial yeast group II intron Sc.ai5gamma. Circular dichroism studies reveal that the formation of the EBS1.IBS1 duplex does not necessarily require divalent metal ions, as large amounts of monovalent metal ions also promote the duplex, albeit at a 5000 times higher concentration. Nevertheless, micromolar amounts of divalent metal ions, e.g. Mg2+ or Cd2+, strongly promote the formation of the 5'-splice site. These observations illustrate that a high charge density independent of the nature of the ion is needed for binding EBS1 to IBS1, but divalent metal ions are presumably the better players.


Vibrio vulnificus RtxA Is a Major Factor Driving Inflammatory T Helper Type 17 Cell Responses in vitro and in vivo.
T helper type 17 (Th17) cells are a subset of pro-inflammatory T helper cells that mediate host defense and pathological inflammation. We have previously reported that host dendritic cells (DCs) infected with Vibrio vulnificus induce Th17 responses through the production of several pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. V. vulnificus produces RTX toxin (RtxA), an important virulence factor that determines successful pathophysiology. In this study, we investigated the involvement of RtxA from V. vulnificus in Th17 cell induction through the activation and maturation of DCs. The increased expression of the DC surface marker CD40 caused by V. vulnificus wild-type infection was reduced by rtxA gene mutation in V. vulnificus. The mRNA and protein levels of Th17 polarization-related cytokines also decreased in V. vulnificus rtxA mutant-infected DCs. In addition, the co-culture of Th cells and DCs infected with rtxA mutant V. vulnificus resulted in reduction in DC-mediated Th17 responses. Th17 cell responses in the small intestinal lamina propria decreased in mice inoculated with V. vulnificus rtxA mutant as compared to those inoculated with the wild-type strain. These decreases in DC maturation, Th17-polarizing cytokine secretion, and Th17 responses attributed to rtxA mutation were restored following infection with the rtxA revertant strain. Furthermore, the mutation in the hlyU gene encoding the activator of rtxA1 gene reproduced the results observed with rtxA mutation. Taken together, V. vulnificus, by means of RtxA, induces inflammatory Th17 responses, which may be associated with adaptive responses of the host against V. vulnificus infection.


Neurodegeneration mutations in dynactin impair dynein-dependent nuclear migration.
Neurodegenerative disease in humans and mice can be caused by mutations affecting the microtubule motor dynein or its biochemical regulator, dynactin, a multiprotein complex required for dynein function (1-4). A single amino acid change, G59S, in the conserved cytoskeletal-associated protein glycine-rich (CAP-Gly) domain of the p150(glued) subunit of dynactin can cause motor neuron degeneration in humans and mice, which resembles ALS (2, 5-8). The molecular mechanism by which G59S impairs the function of dynein is not understood. Also, the relevance of the CAP-Gly domain for dynein motility has not been demonstrated in vivo. Here, we generate a mutant that is analogous to G59S in budding yeast, and show that this mutation produces a highly specific phenotype related to dynein function. The effect of the point mutation is identical to that of complete loss of the CAP-Gly domain. Our results demonstrate that the CAP-Gly domain has a critical role in the initiation and persistence of dynein-dependent movement of the mitotic spindle and nucleus, but it is otherwise dispensable for dynein-based movement. The need for this function appears to be context-dependent, and we speculate that CAP-Gly activity may only be necessary when dynein needs to overcome high force thresholds to produce movement.


Stimulation of mitogen-activated protein kinase by gonadotropin-releasing hormone in human granulosa-luteal cells.
The present study investigated the activation of mitogen-activated protein kinases (MAPKs) by a GnRH agonist (GnRHa) in human granulosa-luteal cells (hGLCs). The phosphorylation state of p44 and p42 MAPK was examined using antibodies that distinguish phospho-p44/42 MAPK (Thr(202)/Tyr(204)) from total p44/42 MAPK (activated plus inactivated). Activation of MAPK by GnRHa was observed within 5 min and was sustained for 60 min after treatment. GnRHa stimulated MAPK activation in a dose-dependent manner, with maximum stimulation (6.7-fold over basal levels) at 10(-7) M. Pretreatment with a protein kinase C (PKC) inhibitor, GF109203X, completely blocked GnRHa-induced MAPK activation. In addition, pretreatment with a PKC activator, phorbol-12-myristate 13-acetate, potentiated GnRH-induced MAPK activation. These results indicate that GnRHa stimulates MAPK activation through a PKC-dependent pathway in hGLCs, possibly coupled to G(q)alpha protein. MAPK activation was also observed in response to 8-bromo-cAMP or cholera toxin, but not pertussis toxin. Forskolin (50 microM) substantially stimulated a rapid cAMP accumulation, whereas GnRHa (10(-7) M) or pertussis toxin (100 mg/ml) did not affect basal intracellular cAMP levels. Cotreatment of GnRHa (10(-7) M) did not attenuate forskolin- or hCG-stimulated cAMP accumulation. These results suggest that the GnRH receptor is probably not coupled to G(s)alpha or G(i)alpha in hGLCs. Finally, GnRHa (10(-7) M) stimulated a significant increase in Elk-1 phosphorylation and c-fos messenger RNA expression, as revealed by an in vitro kinase assay and Northern blot analysis, respectively. These results clearly demonstrate that GnRH activates the MAPK cascade through a PKC-dependent pathway in the human ovary.


Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study.
Typical antipsychotic drugs act on the dopaminergic system, blocking the dopamine type 2 (D2) receptors. Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors, and a high degree of occupancy of the serotoninergic receptors 5-HT2A. Whether these different pharmacological actions produce different effects on brain structure remains unclear. We explored the effects of different types of antipsychotic treatment on brain structure in an epidemiologically based, nonrandomized sample of patients at the first psychotic episode. Subjects were recruited as part of a large epidemiological study (AESOP: aetiology and ethnicity in schizophrenia and other psychoses). We evaluated 22 drug-free patients, 32 on treatment with typical antipsychotics and 30 with atypical antipsychotics. We used high-resolution MRI and voxel-based methods of image analysis. The MRI analysis suggested that both typical and atypical antipsychotics are associated with brain changes. However, typicals seem to affect more extensively the basal ganglia (enlargement of the putamen) and cortical areas (reductions of lobulus paracentralis, anterior cingulate gyrus, superior and medial frontal gyri, superior and middle temporal gyri, insula, and precuneus), while atypical antipsychotics seem particularly associated with enlargement of the thalami. These changes are likely to reflect the effect of antipsychotics on the brain, as there were no differences in duration of illness, total symptoms scores, and length of treatment among the groups. In conclusion, we would like to suggest that even after short-term treatment, typical and atypical antipsychotics may affect brain structure differently.


Reduced functional connectivity within the primary motor cortex of patients with brachial plexus injury.
This study aims at the effects of traumatic brachial plexus lesion with root avulsions (BPA) upon the organization of the primary motor cortex (M1). Nine right-handed patients with a right BPA in whom an intercostal to musculocutaneous (ICN-MC) nerve transfer was performed had post-operative resting state fMRI scanning. The analysis of empirical functional correlations between neighboring voxels revealed faster correlation decay as a function of distance in the M1 region corresponding to the arm in BPA patients as compared to the control group. No differences between the two groups were found in the face area. We also investigated whether such larger decay in patients could be attributed to a gray matter diminution in M1. Structural imaging analysis showed no difference in gray matter density between groups. Our findings suggest that the faster decay in neighboring functional correlations without significant gray matter diminution in BPA patients could be related to a reduced activity in intrinsic horizontal connections in M1 responsible for upper limb motor synergies.


[Daily mortality in the Madrid community during 1986-1991 for the group between 45 and 64 year of age: its relationship to air temperature].
There are many types of work which relate mortality with different environmental factors. These focus on the general population or in the over-65 age-group, but are relatively few in those with reference to the 45-64 age group in which mortality has a large economic and social impact. The object of the present article is to analyse the existant association between daily mortality, from both diverse specific causes, as well as the air temperature in this group in Madrid. Madrid's extreme climatic characteristics make this work of special interest. The ARIMA model was used according to the Box-Jenkins methodology for the infiltration of the daily series of mortality regarding temperature. Amongst the residuals, interrelated functions were established which establish an association between series eliminating communal seasonal factors as well as determining the length of disequilibrium between thermal extremes and excesses in mortality. There is a V-shaped relationship between total daily mortality and temperature. The minimum mortality rate is established at a maximum daily temperature of 33 degrees C. Excess mortality is 0.8% for each degree below 33 degrees C, while that for each degree above is 3.0%. The functions of interrelated correlation indicate that this association is clear in males regarding general mortality as well as for circulatory diseases. In the case of high temperature the effect is immediate, while in lower temperatures we have to add a delay of 10-13 days. There is a significant statistical association between mortality and temperature extremes in people of this age group. Lost life expectancy indicates the extent of the problem and the need to implement preventative measures.


Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death.
The ubiquitious enzyme topoisomerase I can be targeted by drugs which turn these enzymes into cellular poisons and subsequently induce cell death. Drugs like staurosporine, which do not target topoisomerase I directly, can also lead to stabilization of topoisomerase I-DNA cleavable complexes by an indirect process of reactive oxygen species (ROS) generation and subsequent oxidative DNA damage. In this study, we show that betulinic acid, a catalytic inhibitor of topoisomerases, inhibits the formation of apoptotic topoisomerase I-DNA cleavable complexes in prostate cancer cells induced by drugs like camptothecin, staurosporine, and etoposide. Although events like ROS generation, oxidative DNA damage, and DNA fragmentation were observed after betulinic acid treatment, there is no topoisomerase I-DNA cleavable complex formation, which is a key step in ROS-induced apoptotic processes. We have shown that betulinic acid interacts with cellular topoisomerase I and prohibits its interaction with the oxidatively damaged DNA. Using oligonucleotide containing 8-oxoguanosine modification, we have shown that betulinic acid inhibits its cleavage by topoisomerase I in vitro. Whereas silencing of topoisomerase I gene by small interfering RNA reduces cell death in the case of staurosporine and camptothecin, it cannot substantially reduce betulinic acid-induced cell death. Thus, our study provides evidence that betulinic acid inhibits formation of apoptotic topoisomerase I-DNA complexes and prevents the cellular topoisomerase I from directly participating in the apoptotic process.


Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients.
Sedation reduces patient levels of anxiety and stress, facilitates the delivery of care and ensures safety. Alpha-2 agonists have a range of effects including sedation, analgesia and antianxiety. They sedate, but allow staff to interact with patients and do not suppress respiration. They are attractive alternatives for long-term sedation during mechanical ventilation in critically ill patients. To assess the safety and efficacy of alpha-2 agonists for sedation of more than 24 hours, compared with traditional sedatives, in mechanically-ventilated critically ill patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 10, 2014), MEDLINE (1946 to 9 October 2014), EMBASE (1980 to 9 October 2014), CINAHL (1982 to 9 October 2014), Latin American and Caribbean Health Sciences Literature (1982 to 9 October 2014), ISI Web of Science (1987 to 9 October 2014), Chinese Biological Medical Database (1978 to 9 October 2014) and China National Knowledge Infrastructure (1979 to 9 October 2014), the World Health Organization international clinical trials registry platform (to 9 October 2014), Current Controlled Trials metaRegister of controlled trials active registers (to 9 October 2014), the ClinicalTrials.gov database (to 9 October 2014), the conference proceedings citation index (to 9 October 2014) and the reference lists of included studies and previously published meta-analyses and systematic reviews for relevant studies. We imposed no language restriction. We included all randomized and quasi-randomized controlled trials comparing alpha-2 agonists (clonidine or dexmedetomidine) versus alternative sedatives for long-term sedation (more than 24 hours) during mechanical ventilation in critically ill patients. Two review authors independently assessed study quality and extracted data. We contacted study authors for additional information. We performed meta-analyses when more than three studies were included, and selected a random-effects model due to expected clinical heterogeneity. We calculated the geometric mean difference for continuous outcomes and the risk ratio for dichotomous outcomes. We described the effects by values and 95% confidence intervals (CIs). We considered two-sided P < 0.05 to be statistically significant. Seven studies, covering 1624 participants, met the inclusion criteria. All included studies investigated adults and compared dexmedetomidine with traditional sedatives, including propofol, midazolam and lorazepam. Compared with traditional sedatives, dexmedetomidine reduced the geometric mean duration of mechanical ventilation by 22% (95% CI 10% to 33%; four studies, 1120 participants, low quality evidence), and consequently the length of stay in the intensive care unit (ICU) by 14% (95% CI 1% to 24%; five studies, 1223 participants, very low quality evidence). There was no evidence that dexmedetomidine decreased the risk of delirium (RR 0.85; 95% CI 0.63 to 1.14; seven studies, 1624 participants, very low quality evidence) as results were consistent with both no effect and appreciable benefit. Only one study assessed the risk of coma, but lacked methodological reliability (RR 0.69; 95% CI 0.55 to 0.86, very low quality evidence). Of all the adverse events included, the most commonly reported one was bradycardia, and we observed a doubled (111%) increase in the incidence of bradycardia (RR 2.11; 95% CI 1.39 to 3.20; six studies, 1587 participants, very low quality evidence). Our meta-analysis provided no evidence that dexmedetomidine had any impact on mortality (RR 0.99; 95% CI 0.79 to 1.24; six studies, 1584 participants, very low quality evidence). We observed high levels of heterogeneity in risk of delirium (I² = 70%), but due to the limited number of studies we were unable to determine the source of heterogeneity through subgroup analyses or meta-regression. We judged six of the seven studies to be at high risk of bias. In this review, we found no eligible studies for children or for clonidine. Compared with traditional sedatives, long-term sedation using dexmedetomidine in critically ill adults reduced the duration of mechanical ventilation and ICU length of stay. There was no evidence for a beneficial effect on risk of delirium and the heterogeneity was high. The evidence for risk of coma was inadequate. The most common adverse event was bradycardia. No evidence indicated that dexmedetomidine changed mortality. The general quality of evidence ranged from very low to low, due to high risks of bias, serious inconsistency and imprecision, and strongly suspected publication bias. Future studies could pay more attention to children and to using clonidine


Efficacy of Curcumin and Topical Steroids in the Treatment for Oral Submucous Fibrosis: A Comparative study.
Oral submucous fibrosis (OSMF) is a chronic debilitating disease of the oral cavity, characterized by inflammation and progressive fibrosis of the submucosal tissues. The main agent involved in the pathogenesis of OSMF is areca nut. A wide range of treatment, including drug management, surgical therapy, and physiotherapy, has been attempted till date, with varying degrees of benefit. The objective of this study was to assess efficacy of curcumin for the treatment of OSMF; to asses efficacy of topical steroids for the treatment of OSMF; and to compare the efficacy of curcumin and topical steroid for the treatment of OSMF. Participants were assessed based subjective and objective feature of OSMF, i.e., burning sensation of the oral cavity and interincisal distance, respectively. Thirty participants were categorized into two groups: Group A was administered curcumin and Group B was administered topical steroids for a period of 3 months and followed up after 6 months. The assessment was based on maximal incisal opening and burning sensation for spicy food on Visual Analog Scale score. Independent t test was applied for comparison within the group, ANOVA Bonferroni post hoc test was applied for multiple comparison of mean and Mann-Whitney U test was applied to compare the groups. The statistical analysis revealed curcumin to be more efficient than topical steroid. The present study demonstrates the efficiency of curcumin and topical steroid to alleviate the clinical findings of OSMF. However, curcumin is comparatively more efficient than steroids for the treatment of OSMF.


Oesophageal Chemoradiotherapy in the UK--current practice and future directions.
The SCOPE 1 trial closed to recruitment in early 2012 and has demonstrably improved the quality of UK radiotherapy. It has also shown that there is an enthusiastic upper gastrointestinal clinical oncology community that can successfully complete trials and deliver high-quality radiotherapy. Following on from SCOPE 1, this paper, authored by a consensus of leading UK upper gastrointestinal radiotherapy specialists, attempts to define current best practice and the questions to be answered by future clinical studies. The two main roles for chemoradiotherapy (CRT) in the management of potentially curable oesophageal cancer are definitive (dCRT) and neoadjuvant (naCRT). The rates of local failure after dCRT are consistently high, showing the need to evaluate more effective treatments, both in terms of optimal local and systemic therapeutic components. This will be the primary objective of the next planned UK dCRT trial and here we discuss the role of dose escalation and systemic therapeutic options that will form the basis of that trial. The publication of the Dutch 'CROSS' trial of naCRT has shown that this pre-operative approach can both be given safely and offer a significant survival benefit over surgery alone. This has led to the development of the UK NeoSCOPE trial, due to open in 2013. There will be a translational substudy to this trial and currently available data on the role of biomarkers in predicting response to therapy are discussed. Postoperative reporting of the pathology specimen is discussed, with recommendations for the NeoSCOPE trial. Both of these CRT approaches may benefit from recent developments, such as positron emission tomography/computed tomography and four-dimensional computed tomography for target volume delineation, planning techniques such as intensity-modulated radiotherapy and 'type b' algorithms and new treatment verification methods, such as cone-beam computed tomography. These are discussed here and recommendations made for their use.


Stimulation of rat liver beta-galactosidase activity by ions.
1. The p-nitrophenyl beta-D-galactosidase asctivity in rat liver homogenates of lysosome-rich fractions was shown to be markedly affected by the ionic composition of the medium. A stimulation of the reaction rate at pH 5 was produced by most of the salts tested, which contained anions such as acetate, SO4(2-) and Cl-, and cations such as Na+, K= and Mg2+. The most pronounced effect was observed with MgCl2. Only potassium glutamate was inhibitory. 2. Five peaks of beta-galactosidase activity obtained by DEAE-cellulose chromatography were equally sensitive to changes in the ionic composition of the medium. In the presence of added NaC1, the whole rate-pH curve was displaced towards higher pH values, the optimum being shifted from 2.0-2.5 to 3.5. The stimulation at pH 5.0 appeared to be mainly due to changes in Vmax., whereas the apparent Km was slightly modified. 3. Unlike the total, the free beta-galactosidase activity remained unchanged or even declined when KC1 was added to the reaction medium.


Characteristics and outcomes of patients who achieve high workload (≥10 metabolic equivalents) during treadmill exercise echocardiography.
To determine the frequency and prognostic significance of abnormal exercise echocardiographic results for patients achieving a workload of 10 or more metabolic equivalents during treadmill exercise echocardiography. Patients who underwent treadmill exercise echocardiography from November 1, 2003, through December 31, 2008, and exercised for 9 or more minutes using the Bruce protocol (N=7236) were included. Clinical and exercise echocardiographic characteristics and outcomes were evaluated. Variables associated with abnormal exercise echocardiographic results and mortality were identified. Exercise echocardiographic results were positive for ischemia in 862 patients (12%). Extensive ischemia developed in 265 patients (4%). For patients with normal exercise echocardiographic results, all-cause and cardiovascular mortality rates were 0.30% and 0.05% per person-year of follow-up, respectively. For patients who had extensive ischemia, all-cause and cardiovascular mortality rates were 0.84% and 0.25% per person-year of follow-up, respectively. Patients at highest risk were those who had extensive and severe regional wall motion abnormalities at rest (n=58), and their all-cause and cardiovascular mortality rates were 2.65% and 0.76% per person-year of follow-up. Exercise echocardiographic variables did not identify sizable patient subgroups at risk for death and did not provide incremental prognostic information (C statistic was 0.74 compared with 0.73 for the clinical plus exercise electrocardiography model). Patients achieving a workload of 10 or more metabolic equivalents during treadmill exercise testing do not often have extensive ischemic abnormalities on exercise echocardiography. Although exercise echocardiographic results provide some prognostic information, it is not of incremental value for these patients, whose short-term and medium-term prognosis is excellent.


Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy.
This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.


Common and distinct elements in cellular signaling via EGF and FGF receptors.
Signaling pathways that are activated by epidermal growth factor (EGF) or fibroblast growth factor (FGF) receptors have been identified and compared (detailed Connections Maps are available at Science's Signal Transduction Knowledge Environment). Both receptors stimulate a similar complement of intracellular signaling pathways. However, whereas activated EGF receptors (EGFRs) function as the main platform for recruitment of signaling proteins, signaling through the FGF receptors (FGFRs) is mediated primarily by assembly of a multidocking protein complex. Moreover, FGFR signaling is subject to additional intracellular and extracellular control mechanisms that do not affect EGFR signaling. The differential circuitry of the intracellular networks that are activated by EGFR and FGFR may affect signal specificity and physiological responses.


Perinatal psychiatric episodes: a population-based study on treatment incidence and prevalence.
Perinatal psychiatric episodes comprise various disorders and symptom severity, which are diagnosed and treated in multiple treatment settings. To date, no studies have quantified the incidence and prevalence of perinatal psychiatric episodes treated in primary and secondary care, which we aimed to do in the present study. We designed a descriptive prospective study and included information from Danish population registers to study first-time ever and recurrent psychiatric episodes during the perinatal period, including treatment at psychiatric facilities and general practitioners (GPs). This was done for all women who had records of one or more singleton births from 1998 until 2012. In total, we had information on 822 439 children born to 491 242 unique mothers. Results showed first-time psychiatric episodes treated at inpatient facilities were rare during pregnancy, but increased significantly shortly following childbirth (0.02 vs 0.25 per 1000 births). In comparison, first-time psychiatric episodes treated at outpatient facilities were more common, and showed little variation across pregnancy and postpartum. For every single birth resulting in postpartum episodes treated at inpatient psychiatric facilities, 2.5 births were followed by an episode treated at outpatient psychiatric facility and 12 births by GP-provided pharmacological treatment. We interpret our results the following way: treated severe and moderate psychiatric disorders have different risk patterns in relation to pregnancy and childbirth, which suggests differences in the underlying etiology. We further speculate varying treatment incidence and prevalence in pregnancy vs postpartum may indicate that the current Diagnostic and Statistical Manual of Mental Disorders-5 peripartum specifier not adequately describes at-risk periods across moderate and severe perinatal psychiatric episodes.


Instillation of normal saline before suctioning reduces the incidence of pneumonia in intubated and ventilated adults.
Does the instillation of normal saline before suctioning reduce the incidence of ventilator-associated pneumonia in intubated and ventilated adults? Randomised, controlled trial with blinded outcome assessment. The medical/surgical intensive care unit of a tertiary oncology hospital in Brazil. Adults expected to require at least 72 hours of mechanical ventilation via an endotracheal or tracheostomy tube. Previous ventilation within the past month and contraindications to bronchoscopy were exclusion criteria. Randomisation of 262 participants allotted 130 to the intervention group and 132 to a control group. Closed tracheal suction systems with heat and moisture exchangers were used with both groups and were changed regularly. All patients were nursed with backrest elevation to 45 degrees. medical or nursing staff, who were blinded to group allocations, requested suctioning when any of the following occurred: visible or audible secretions, ventilator-patient asynchrony, and increased peak inspiratory pressures or decreased tidal volumes attributed to secretions. Respiratory therapists performed the suctioning according to a standardised procedure that included preoxygenation. The therapists instilled 8 mL of normal saline prior to suctioning in the intervention group only. The primary outcome was the incidence of ventilator-associated pneumonia (VAP). If VAP was suspected because of radiographic evidence plus either fever, leukocytosis, or purulent secretions, a bronchoscopy with standardised lavage was performed. VAP was considered confirmed if the bacterial density of the lavage fluid exceeded 1000 colony-forming units/mL. Secondary outcome measures included time to VAP, duration of mechanical ventilation, length of stay and mortality in the intensive care unit, unscheduled ventilation circuitry changes due to secretions, and number of suctions per day. all participants completed the study. Significantly fewer participants in the saline group developed VAP (14/130) than in the control group (31/132), relative risk reduction 0.54 (95% CI 0.18 to 0.74). This indicates that one patient will avoid developing VAP for every 8 patients in which saline instillation is used. Significant benefits of saline instillation were also seen in the incidence of VAP (9 vs 21 per 1000 days of mechanical ventilation, p = 0.01) and in the time to first VAP (p = 0.02). The groups did not differ significantly on the remaining secondary outcomes. Instillation of normal saline before tracheal suctioning decreases the incidence of VAP in mechanically ventilated adults.


Hypoxia-ischemia induces an endogenous reparative response by local neural progenitors in the postnatal mouse telencephalon.
Perinatal hypoxia-ischemia in the preterm neonate commonly results in white matter injury for which there is no specific therapy. The subventricular zone (SVZ) of the brain harbors neural stem cells and more committed progenitors including oligodendroglial progenitor cells that might serve as replacement cells for treating white matter injury. Data from rodent models suggest limited replacement of mature oligodendroglia by endogenous cells. Rare newly born mature oligodendrocytes have been reported within the striatum, corpus callosum and infarcted cortex 1 month following hypoxia-ischemia. Whether these oligodendrocytes arise in situ or emigrate from the SVZ is unknown. We used a postnatal day 9 mouse model of hypoxia-ischemia, BrdU labeling of mitotic cells, immunofluorescence and time-lapse multiphoton microscopy to determine whether hypoxia-ischemia increases production of oligodendroglial progenitors within the SVZ with emigration toward injured areas. Although cells of the oligodendroglial lineage increased in the brain ipsilateral to hypoxic-ischemic injury, they did not originate from the SVZ but rather arose within the striatum and cortex. Furthermore, they resulted from proliferation within the striatum but not within the cortex. Thus, an endogenous regenerative oligodendroglial response to postnatal hypoxia-ischemia occurs locally, with minimal long-distance contribution by cells of the SVZ.


Localization and expression of p27KIP1 in multistage colorectal carcinogenesis.
The cyclin-dependent kinase inhibitor p27Kip1 can inhibit the G1 to S transition of the cell cycle and is a putative tumor suppressor. However, our laboratory found that a variety of human cancer cell lines express relatively high levels of this protein and that this is often associated with increased expression of cyclin D1 or cyclin E. Therefore, in the present study we analyzed by immunohistochemistry the expression of p27Kip1 in a series of human tissue samples representing various stages of colon carcinogenesis, using 20 samples of normal colon mucosa, 20 hyperplastic polyps, 19 samples of adenomatous polyps, and 40 samples of various types of colorectal carcinomas. Parallel immunostaining was done for cyclin D1 and also for Ki67 to evaluate cell proliferation. An additional 17 human colon carcinoma samples, together with paired adjacent normal mucosa samples, were analyzed for levels of expression of the p27Kip1 protein by Western blot analysis, and 7 of these pairs of samples were examined by Northern blot analysis for levels of p27Kip1 mRNA. We did not find a positive or negative correlation between p27Kip1 expression and cell proliferation in the normal mucosa and tumor samples. There was, however, an inverse correlation between p27Kip1 and Ki67 expression in the lymphoid follicles present in the colonic mucosa. There was no evidence for a consistent increase or decrease in p27Kip1 expression in the mucosal cells during colon carcinogenesis, because the mean values for percentage p27Kip1-positive cells were similar in the normal mucosa, adenomatous polyps, and carcinoma samples. This is in contrast to Ki67 and cyclin D1 expression, which did show significant increases in mean values with tumor development. A subset (35%) of the carcinomas displayed diffuse cytoplasmic staining, in addition to nuclear staining, for p27Kip1, and in these cases the percentage of cells that were positive for p27Kip1 was higher than in cases that had only nuclear staining. There was a significant correlation between p27Kip1 expression and tumor grade; ie., well and moderately differentiated carcinomas had high p27Kip1 expression, whereas poorly differentiated carcinomas had lower expression. The Western blot analysis data on p27Kip1 expression confirmed this correlation. Comparisons of Northern and Western blots did not show a correlation between the level of p27Kip1 mRNA and the corresponding protein, a finding consistent with evidence that the p27Kip1 protein is regulated mainly via a posttranscriptional mechanism. The immunostaining studies revealed a significant correlation between high p27Kip1 protein expression and high cyclin D1 expression in the adenomatous polyps and in the subset of carcinomas that had only nuclear p27Kip1 expression. This may reflect the existence of a homeostatic feedback mechanism that is lost in the high-grade carcinomas that express low levels of p27Kip1.


Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis.
It is uncertain whether all adults with bacterial meningitis benefit from treatment with adjunctive dexamethasone. We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone in 435 patients over the age of 14 years who had suspected bacterial meningitis. The goal was to determine whether dexamethasone reduced the risk of death at 1 month and the risk of death or disability at 6 months. A total of 217 patients were assigned to the dexamethasone group, and 218 to the placebo group. Bacterial meningitis was confirmed in 300 patients (69.0%), probable meningitis was diagnosed in 123 patients (28.3%), and an alternative diagnosis was made in 12 patients (2.8%). An intention-to-treat analysis of all the patients showed that dexamethasone was not associated with a significant reduction in the risk of death at 1 month (relative risk, 0.79; 95% confidence interval [CI], 0.45 to 1.39) or the risk of death or disability at 6 months (odds ratio, 0.74; 95% CI, 0.47 to 1.17). In patients with confirmed bacterial meningitis, however, there was a significant reduction in the risk of death at 1 month (relative risk, 0.43; 95% CI, 0.20 to 0.94) and in the risk of death or disability at 6 months (odds ratio, 0.56; 95% CI, 0.32 to 0.98). These effects were not found in patients with probable bacterial meningitis. Results of multivariate analysis indicated that dexamethasone treatment for patients with probable bacterial meningitis was significantly associated with an increased risk of death at 1 month, an observation that may be explained by cases of tuberculous meningitis in the treatment group. Dexamethasone does not improve the outcome in all adolescents and adults with suspected bacterial meningitis; a beneficial effect appears to be confined to patients with microbiologically proven disease, including those who have received prior treatment with antibiotics. (Current Controlled Trials number, ISRCTN42986828 [controlled-trials.com] .).


Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome.
Rett syndrome (RTT) is a severe form of mental retardation, which is caused by spontaneous mutations in the X-linked gene MECP2. How the loss of MeCP2 function leads to RTT is currently unknown. Mice lacking the Mecp2 gene initially show normal postnatal development but later acquire neurological phenotypes, including heightened anxiety, that resemble RTT. The MECP2 gene encodes a methyl-CpG-binding protein that can act as a transcriptional repressor. Using cDNA microarrays, we found that Mecp2-null animals differentially express several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for serum glucocorticoid-inducible kinase 1 (Sgk) and FK506-binding protein 51 (Fkbp5) were observed before and after onset of neurological symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 is bound to the Fkbp5 and Sgk genes in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, our data raise the possibility that disruption of MeCP2-dependent regulation of stress-responsive genes contributes to the symptoms of RTT.


Molecular analysis of Aedes aegypti classical protein tyrosine phosphatases uncovers an ortholog of mammalian PTP-1B implicated in the control of egg production in mosquitoes.
Protein Tyrosine Phosphatases (PTPs) are enzymes that catalyze phosphotyrosine dephosphorylation and modulate cell differentiation, growth and metabolism. In mammals, PTPs play a key role in the modulation of canonical pathways involved in metabolism and immunity. PTP1B is the prototype member of classical PTPs and a major target for treating human diseases, such as cancer, obesity and diabetes. These signaling enzymes are, hence, targets of a wide array of inhibitors. Anautogenous mosquitoes rely on blood meals to lay eggs and are vectors of the most prevalent human diseases. Identifying the mosquito ortholog of PTP1B and determining its involvement in egg production is, therefore, important in the search for a novel and crucial target for vector control. We conducted an analysis to identify the ortholog of mammalian PTP1B in the Aedes aegypti genome. We identified eight genes coding for classical PTPs. In silico structural and functional analyses of proteins coded by such genes revealed that four of these code for catalytically active enzymes. Among the four genes coding for active PTPs, AAEL001919 exhibits the greatest degree of homology with the mammalian PTP1B. Next, we evaluated the role of this enzyme in egg formation. Blood feeding largely affects AAEL001919 expression, especially in the fat body and ovaries. These tissues are critically involved in the synthesis and storage of vitellogenin, the major yolk protein. Including the classical PTP inhibitor sodium orthovanadate or the PTP substrate DiFMUP in the blood meal decreased vitellogenin synthesis and egg production. Similarly, silencing AAEL001919 using RNA interference (RNAi) assays resulted in 30% suppression of egg production. The data reported herein implicate, for the first time, a gene that codes for a classical PTP in mosquito egg formation. These findings raise the possibility that this class of enzymes may be used as novel targets to block egg formation in mosquitoes.


Determination of aluminium using high performance chelation ion chromatography.
The suitability of high performance chelation ion chromatography (HPCIC) using postcolumn reaction for the separation and determination of dissolved aluminium in complex samples was investigated. Use of a chelating ion-exchanger allowed for differentiation between kinetically labile and kinetically stable species of aluminium. Separation through a combination of chelation and cation-exchange was achieved using a 200 x 4.0 mm id column packed with particles of silica functionalised with iminodiacetic acid, with nitric acid-potassium chloride eluents. A temperature anomaly causing a five-fold increase in column efficiency for aluminium is believed to be a result of localised temperature effects in the particular type of instrument used. Postcolumn reagents investigated for the photometric detection included Tiron, Pyrocatechol Violet, Chrome Azurol S, and Eriochrome Cyanine R. The lowest detection limit (2.7 microg/L for a 100 microL sample volume) was achieved using 0.25 mM Eriochrome Cyanine R in 0.2 M hexamine (pH 6.1) with 1 mM cetyltrimethylpyridium bromide (CTAB). The optimised HPCIC system was applied successfully to the quantification of labile aluminium in paper mill process water.


Computational investigation of dynamical transitions in Trp-cage miniprotein powders.
We investigate computationally the dynamical transitions in Trp-cage miniprotein powders, at three levels of hydration: 0.04, 0.26 and 0.4 g water/g protein. We identify two distinct temperatures where transitions in protein dynamics occur. Thermal motions are harmonic and independent of hydration level below Tlow ≈ 160 K, above which all powders exhibit harmonic behavior but with a different and enhanced temperature dependence. The second onset, which is often referred to as the protein dynamical transition, occurs at a higher temperature TD that decreases as the hydration level increases, and at the lowest hydration level investigated here (0.04 g/g) is absent in the temperature range we studied in this work (T ≤ 300 K). Protein motions become anharmonic at TD, and their amplitude increases with hydration level. Upon heating above TD, hydrophilic residues experience a pronounced enhancement in the amplitude of their characteristic motions in hydrated powders, whereas it is the hydrophobic residues that experience the more pronounced enhancement in the least hydrated system. The dynamical transition in Trp-cage is a collective phenomenon, with every residue experiencing a transition to anharmonic behavior at the same temperature.


Accelerometer-determined sedentary and physical activity estimates among older adults with diabetes: considerations by demographic and comorbidity characteristics.
Understanding of the objectively measured physical activity (PA) and sedentary patterns of adults with diabetes at the population level is currently limited. Therefore, the purpose of this study was to report accelerometer-determined PA and sedentary patterns among a national sample of U.S. adults with and without evidence of diabetes and to also explore differences across other comorbidity characteristics. Data from the 2003-2006 National Health and Nutrition Examination Survey were used. Four hundred seven participants had evidence of diabetes (mean age = 73.4 years), and 1,346 did not have diabetes (mean age = 74.3 years). Results showed that few older adults meet PA guidelines; the majority of their time is spent in sedentary activities; very few engage in more light-intensity PA than sedentary behavior; and older adults with multiple comorbidities engage in less PA and more sedentary behavior than their counterparts. The development and implementation of feasible, effective PA programs for older adults with multiple comorbidities are warranted.


Optical amplification and optical filter based signal processing for cost and energy efficient spatial multiplexing.
Spatial division multiplexing has been proposed as an option for further capacity increase of transmission fibers. Application of this concept is attractive only, if cost and energy efficient implementations can be found. In this work, optical amplification and optical filter based signal processing concepts are investigated. Deployment of multi mode fibers as the waveguide type for erbium doped fiber amplifiers potentially offers cost and energy efficiency advantages compared to using multi core fibers in preamplifier as well as booster stages. Additional advantages can be gained from optimization of the amplifier module design. Together with transponder design optimizations, they can increase the attractiveness of inverse spatial multiplexing, which is proposed as an intermediate step. Signal processing based on adaptive passive optical filters offers an alternative approach for the separation of channels at the receiver which have experienced mode coupling along the link. With this optical filter based approach, fiber capacity can potentially be increased faster and more energy efficiently than with solutions relying solely on electronic signal processing.


Hydrolysis of woody biomass by a biomass-derived reusable heterogeneous catalyst.
Biomass is the sole carbon-based renewable resource for sustaining the chemical and fuel demands of our future. Lignocellulose, the primary constituent of terrestrial plants, is the most abundant non-food biomass, and its utilisation is a grand challenge in biorefineries. Here we report the first reusable and cost-effective heterogeneous catalyst for the depolymerisation of lignocellulose. Air oxidation of woody biomass (Eucalyptus) provides a carbonaceous material bearing an aromatic skeleton with carboxylic groups (2.1 mmol g-1) and aliphatic moieties. This catalyst hydrolyses woody biomass (Eucalyptus) to sugars in high yields within 1 h in trace HCl aq. Furthermore, after the reaction, the solid residue composed of the catalyst and insoluble ingredients of woody biomass is easily transformed back to fresh catalyst by the same air oxidation method. This is a self-contained system using woody biomass as both the catalyst source and substrate for realising facile catalyst preparation and recycling.


Synthesis of a multi-functional DNA nanosphere barcode system for direct cell detection.
Nucleic acid-based technologies have been applied to numerous biomedical applications. As a novel material for target detection, DNA has been used to construct a barcode system with a range of structures. This paper reports multi-functionalized DNA nanospheres (DNANSs) by rolling circle amplification (RCA) with several functionalized nucleotides. DNANSs with a barcode system were designed to exhibit fluorescence for coding enhanced signals and contain biotin for more functionalities, including targeting through the biotin-streptavidin (biotin-STA) interaction. Functionalized deoxynucleotide triphosphates (dNTPs) were mixed in the RCA process and functional moieties can be expressed on the DNANSs. The anti-epidermal growth factor receptor antibodies (anti-EGFR Abs) can be conjugated on DNANSs for targeting cancer cells specifically. As a proof of concept, the potential of the multi-functional DNANS barcode was demonstrated by direct cell detection as a simple detection method. The DNANS barcode provides a new route for the simple and rapid selective recognition of cancer cells.


Genome-wide mapping of sister chromatid exchange events in single yeast cells using Strand-seq.
Homologous recombination involving sister chromatids is the most accurate, and thus most frequently used, form of recombination-mediated DNA repair. Despite its importance, sister chromatid recombination is not easily studied because it does not result in a change in DNA sequence, making recombination between sister chromatids difficult to detect. We have previously developed a novel DNA template strand sequencing technique, called Strand-seq, that can be used to map sister chromatid exchange (SCE) events genome-wide in single cells. An increase in the rate of SCE is an indicator of elevated recombination activity and of genome instability, which is a hallmark of cancer. In this study, we have adapted Strand-seq to detect SCE in the yeast Saccharomyces cerevisiae. We provide the first quantifiable evidence that most spontaneous SCE events in wild-type cells are not due to the repair of DNA double-strand breaks.


The characteristic features of optical coherence tomography in posterior uveitis.
To describe the different retinal morphological characteristics that can present on optical coherence topography (OCT) in a spectrum of uveitic diseases. We reviewed the literature and our own OCT image archive for characteristic features that may be suggestive of a particular disease process. OCT demonstrates a variety of characteristic morphological changes, some that may point towards a specific disease process. We describe the various forms of macular oedema found in uveitis as well as OCT features typically found in multifocal choroiditis, serpiginous chorioretinitis, toxoplasma chorioretinitis, Vogt-Koyanagi-Harada, sympathetic ophthalmia and the vitreomacular traction syndrome. Ophthalmologists should be aware of the variety of retinal morphological characteristics that can present on OCT in uveitic disease. Recognition may aid in the diagnostic process, which is complementary to conventional fundal photography and fluorescein angiography. This can facilitate earlier diagnosis and, more importantly, the initiation of specific treatment.


Gender, type of treatment, dysfunctional attitudes, social support, life events, and depressive symptoms over naturalistic follow-up.
The present study investigated gender differences in depressive symptoms during a naturalistic follow-up for outpatients with major depressive disorder in the National Institute of Mental Health Treatment of Depression Collaborative Research Program. Specifically, the study investigated whether gender interacted with type of treatment received, dysfunctional attitudes, life events, or social support to predict severity of depressive symptoms. In addition, aspects of these psychosocial factors (need for approval, interpersonal life events, and close friendships), hypothesized to be more salient for women, were examined to determine if they had a differential impact on level of depressive symptoms in men and women. Assessments conducted 6, 12, and 18 months after treatment included measures of depressive symptoms, dysfunctional attitudes, current life events, and social support. Data were available for 188 subjects (134 women and 54 men). Regression analyses were conducted to examine whether gender as a main effect, or interacting with dysfunctional attitudes, life events, social support, or subtypes of these variables, predicted cross-sectional or longitudinal measures of depressive symptoms during follow-up. A consistent finding of the study was that over the 18 months of this naturalistic follow-up, there were no main effects for gender or any significant interactions involving gender and any of the variables of interest. The study demonstrated that life events and social support were related to severity of depressive symptoms for both genders. Despite differential prevalence rates of major depression for men and women, findings do not support a different process in outcome of illness for men and women.


A Programmable Mechanical Maxwell's Demon.
We introduce and investigate a simple and explicitly mechanical model of Maxwell's demon-a device that interacts with a memory register (a stream of bits), a thermal reservoir (an ideal gas) and a work reservoir (a mass that can be lifted or lowered). Our device is similar to one that we have briefly described elsewhere, but it has the additional feature that it can be programmed to recognize a chosen reference sequence, for instance, the binary representation of π . If the bits in the memory register match those of the reference sequence, then the device extracts heat from the thermal reservoir and converts it into work to lift a small mass. Conversely, the device can operate as a generalized Landauer's eraser (or copier), harnessing the energy of a dropping mass to write the chosen reference sequence onto the memory register, replacing whatever information may previously have been stored there. Our model can be interpreted either as a machine that autonomously performs a conversion between information and energy, or else as a feedback-controlled device that is operated by an external agent. We derive generalized second laws of thermodynamics for both pictures. We illustrate our model with numerical simulations, as well as analytical calculations in a particular, exactly solvable limit.


Long-range ferrimagnetic order in a two-dimensional supramolecular Kondo lattice.
Realization of long-range magnetic order in surface-supported two-dimensional systems has been challenging, mainly due to the competition between fundamental magnetic interactions as the short-range Kondo effect and spin-stabilizing magnetic exchange interactions. Spin-bearing molecules on conducting substrates represent a rich platform to investigate the interplay of these fundamental magnetic interactions. Here we demonstrate the direct observation of long-range ferrimagnetic order emerging in a two-dimensional supramolecular Kondo lattice. The lattice consists of paramagnetic hexadeca-fluorinated iron phthalocyanine (FeFPc) and manganese phthalocyanine (MnPc) molecules co-assembled into a checkerboard pattern on single-crystalline Au(111) substrates. Remarkably, the remanent magnetic moments are oriented in the out-of-plane direction with significant contribution from orbital moments. First-principles calculations reveal that the FeFPc-MnPc antiferromagnetic nearest-neighbour coupling is mediated by the Ruderman-Kittel-Kasuya-Yosida exchange interaction via the Au substrate electronic states. Our findings suggest the use of molecular frameworks to engineer novel low-dimensional magnetically ordered materials and their application in molecular quantum devices.


Improving Guideline-Based Streptococcal Pharyngitis Testing: A Quality Improvement Initiative.
Acute pharyngitis is a common diagnosis in ambulatory pediatrics. The Infectious Diseases Society of America (IDSA) clinical practice guideline for group A streptococcal (GAS) pharyngitis recommends strict criteria for GAS testing to avoid misdiagnosis and unnecessary treatment of children who are colonized with group A Streptococcus. We sought to improve adherence to the IDSA guideline for testing and treatment of GAS pharyngitis in a large community pediatrics practice. The Model for Improvement was used, and iterative Plan-Do-Study-Act cycles were completed. The quality improvement project was approved for American Board of Pediatrics Part 4 Maintenance of Certification credit. Interventions included provider education, modification of existing office procedure, communication strategies, and patient and family education. Outcomes were assessed by using statistical process control charts. An absolute reduction in unnecessary GAS testing of 23.5% (from 64% to 40.5%) was observed during the project. Presence of viral symptoms was the primary reason for unnecessary testing. Appropriate antibiotic use for GAS pharyngitis did not significantly change during the project; although, inappropriate use was primarily related to unnecessary testing. At the end of the intervention period, the majority of providers perceived an improvement in their ability to communicate with families about the need for GAS pharyngitis testing and about antibiotic use. The majority of GAS pharyngitis testing in this practice before intervention was inconsistent with IDSA guideline recommendations. A quality improvement initiative, which was approved for Part 4 Maintenance of Certification credit, led to improvement in guideline-based testing for GAS pharyngitis.