Inflammatory mechanisms in myocardial infarction.
Myocardial infarction is associated with an inflammatory response, ultimately leading to healing and scar formation. Reperfused myocardial infarcts exhibit an enhanced inflammatory reaction, and are associated with improved cardiac repair and patient survival. This review summarizes our current knowledge of the inflammatory mechanisms mediating injury and repair following myocardial ischemia and reperfusion. Myocardial necrosis is associated with complement activation and free radical generation, triggering a cytokine cascade and chemokine upregulation. Interleukin (IL)-8 and C5a are released in the ischemic myocardium, and may have a crucial role in neutrophil recruitment. Extravasated neutrophils may induce potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. However, despite these potentially injurious effects, the post-reperfusion inflammatory response may significantly enhance healing. Monocyte Chemoattractant Protein (MCP)-1 is induced in the infarcted area and may regulate mononuclear cell recruitment. Accumulation of monocyte-derived macrophages, and mast cells may increase expression of growth factors inducing angiogenesis and fibroblast accumulation in the infarct. In addition, expression of cytokines inhibiting the inflammatory response, such as Interleukin (IL)-10 may suppress injury. Matrix Metalloproteinases (MMPs) and their inhibitors regulate extracellular matrix deposition and play an important role in mediating ventricular remodeling. Inflammatory mediators may induce recruitment of blood-derived primitive stem cells in the healing infarct, which may differentiate into endothelial cells and even lead to limited myocardial regeneration. Understanding the cellular and molecular steps involved in regulating infarct healing may lead to specific interventions aimed at optimizing cardiac repair.


Brain-based origins of change language: a beginning.
Motivational interviewing (MI) is a promising treatment for heavy drinking. Client change talk (CT), a critical component of MI, has been associated with differential brain activation. The goal of this study was to begin to deconstruct how and why CT may affect the brain. Specifically, we sought to determine whether simply repeating statements in favor of change would cause differential brain activation, or whether client statements must be spontaneously generated within a therapeutic milieu in order to influence brain activation. We therefore examined blood oxygenation level dependent (BOLD) response following two types of client language (CT; and sustain talk, ST) across two conditions: (1) Self-Generated: CT and ST were elicited during an MI session vs. (2) Experimenter-Selected: a pre-established list of CT and ST was provided to the individual in the absence of an MI session. Across both conditions, participants' CT and ST were visually and aurally presented during fMRI. We enrolled 39 recent binge drinkers (41% male; M age=19.9; n=18 in Self-Generated group; n=21 in Experimenter-Selected group). We found that both types of client language (CT and ST) elicited greater BOLD activation in the Self-Generated vs. the Experimenter-Selected group in the left inferior frontal gyrus/anterior insula and superior temporal gyri (p≤0.001). These findings indicate that the nature of client language matters. It appears that it is not just the words themselves, but the origin (naturally generated within a therapeutic session) that influences brain-based effects.


Neonatal Health Psychology [NNHP]: theories and practice.
By 1994, Health Psychology had been established as a discipline, and defined by Marie Johnston as the scientific study of the psychological processes and behaviour in health, illness and health care. Health Psychology, so far, has mainly related to the adult population, although increasing attention is now being paid to both pediatric and broadly-based child health psychology. It is noteworthy that attention devoted to pediatric and child health psychology has increased dramatically, but the great majority of published work refers to the child and not to the preterm neonate; yet being preterm means being born early, and sometimes too small, and is a stressful life event. In the field of Medicine, Neonatology has appeared as a sub-discipline, and both investigates and cares for at-risk babies, including risk for developmental disabilities. The time is consequently opportune for psychology to make an effective contribution to both the theory and care of the preterm neonate, viewed as a unique, emergent, coactional and hierarchical human being. The formal framework for this is Neonatal Health Psychology (NNHP), which is defined in the article as 'the scientific study of biopsychosocial and behavioural processes in health, illness, and health care of the preterm (and fullterm) neonate during his/her first 28 days of life, and the relationship of such processes with later outcome.' Early work in this category has shown that NNHP has profound interdisciplinary connotations, not least because of the diverse ways in which information has to be derived from the non-verbal neonates. The pathways and scope of NNHP are identified, and many examples of work with preterm neonates are summarised in the article. In making the case for the professional formalization of NNHP, descriptions are given of Neonatal Assessments and very-early interventions; the interdisciplinary character of much of the early work is shown to have been essential. Indication of theoretical frameworks for NNHP is given.


Ambulatory blood pressure and carotid intima media thickness in children with type 1 diabetes.
Blood pressure abnormalities may play an important role in macrovascular damage in type 1 diabetes. Little is known about blood pressure abnormalities and macrovascular damage in children with type 1 diabetes. Children with type 1 diabetes (n = 57) for a short (3 months-2 years; n = 24) or long duration (≥5 years; n = 33) and a group of control children without diabetes (n = 29) completed 24-h ambulatory blood pressure monitoring (ABPM). Carotid intima media thickness (cIMT), a subclinical indicator of atherosclerosis, was assessed by carotid ultrasound. ABPM abnormalities were more prevalent (57% vs 24%, respectively), and daytime, nighttime and 24-h systolic, diastolic, and mean arterial blood pressure indices were higher in children with type 1 diabetes compared to control children. The odds estimate of an ABPM abnormality was 6.68 (95% confidence interval: 1.95, 22.9; P = .003) in children with type 1 diabetes compared to controls after adjusting for age, sex, and BMI standardized for age and sex (zBMI). An interaction between ABPM and zBMI on cIMT was observed. In children with type 1 diabetes and ABPM abnormalities, every 1 SD increase in zBMI was associated with a 0.030 mm increase in cIMT (95% confidence interval: 0.002, 0.041; P = .031). This was not observed in control children with ABPM abnormalities or in children with normal ABPM, regardless of type 1 diabetes status. Children with type 1 diabetes have a high prevalence of ABPM abnormalities independent of disease duration and this is related to early indicators of cardiovascular damage.


Testosterone increases renal anti-aging klotho gene expression via the androgen receptor-mediated pathway.
Gender is known to be associated with longevity and oestrogen administration induced longevity-associated gene expression is one of the potential mechanisms underlying the benefits of oestrogen on lifespan, whereas the role of testosterone in the regulation of longevity-associated gene expressions remains largely unclear. The klotho gene, predominantly expressed in the kidney, has recently been discovered to be an aging suppressor gene. In the present study, we investigated the regulatory effects of testosterone on renal klotho gene expression in vivo and in vitro. In testosterone-administered mouse kidney and NRK-52E cells, increased klotho expression was accompanied by the up-regulation of the nuclear androgen receptor (AR). Overexpression of AR enhanced the expression of klotho mRNA and protein. Conversely, testosterone-induced klotho expression was attenuated in the presence of flutamide, an AR antagonist. A reporter assay and a chromatin immunoprecipitation (ChIP) assay demonstrated that AR directly binds to the klotho promoter via androgen response elements (AREs) which reconfirmed its importance for AR binding via the element mutation. In summary, our study demonstrates that testosterone up-regulates anti-aging klotho together with AR expression in the kidney in vivo and in vitro by recruiting AR on to the AREs of the klotho promoter.


A hybrid brain computer interface system based on the neurophysiological protocol and brain-actuated switch for wheelchair control.
Brain Computer Interfaces (BCIs) are developed to translate brain waves into machine instructions for external devices control. Recently, hybrid BCI systems are proposed for the multi-degree control of a real wheelchair to improve the systematical efficiency of traditional BCIs. However, it is difficult for existing hybrid BCIs to implement the multi-dimensional control in one command cycle. This paper proposes a novel hybrid BCI system that combines motor imagery (MI)-based bio-signals and steady-state visual evoked potentials (SSVEPs) to control the speed and direction of a real wheelchair synchronously. Furthermore, a hybrid modalities-based switch is firstly designed to turn on/off the control system of the wheelchair. Two experiments were performed to assess the proposed BCI system. One was implemented for training and the other one conducted a wheelchair control task in the real environment. All subjects completed these tasks successfully and no collisions occurred in the real wheelchair control experiment. The protocol of our BCI gave much more control commands than those of previous MI and SSVEP-based BCIs. Comparing with other BCI wheelchair systems, the superiority reflected by the index of path length optimality ratio validated the high efficiency of our control strategy. The results validated the efficiency of our hybrid BCI system to control the direction and speed of a real wheelchair as well as the reliability of hybrid signals-based switch control.


Care Burden and Self-Efficacy Levels of Family Caregivers of Elderly People in Turkey.
The aim of this research was to determine the level of burden and self-efficacy among family caregivers of elderly people in Turkey. This study is descriptive and cross-sectional. A total of 658 family caregivers of elderly people were included in the study. The data were collected with a caregiver's characteristics form, elderly people's characteristics form, the Zarit Burden Interview, the self-efficacy scale, and the Barthell Index. Data were analyzed using SPSS 16.0 program. What are care burden and self-efficacy levels of the caregivers? Is there a relationship between care burden and self-efficacy levels of the caregivers with variables such as age, duration of care, sex, status of education, type of relationship, and status of employment that belong to the caregiver? Is there a relationship between care burden and self-efficacy levels of the caregivers with variables such as age and Bartell Index that belong to the elderly? The caregiver burden score was 38.65 ± 13.73, which indicates a moderate level of burden. The self-efficacy score was 29.31 ± 6.09, which is in the low range of self-efficacy. There were statistically significant differences between the caregiver burden score and the sex of caregivers, status of education, type of relationship, and the elderly person's score on the Bartell Index (P < .05). The relationship between the employment status of caregivers (P = .01), the age of the elderly (P = .01), and the caregivers' score on the self-efficacy scale (P < .05) was found to be statistically significant. Study revealed that the majority of the caregivers experienced moderate levels of care burden and low levels of self-efficacy. These results will provide beneficial information for nurses to provide the holistic nursing care.


The Generated Databases (GDBs) as a Source of 3D-shaped Building Blocks for Use in Medicinal Chemistry and Drug Discovery.
Drug discovery is in constant need of new molecules to develop drugs addressing unmet medical needs. To assess the chemical space available for drug design, our group investigates the generated databases (GDBs) listing all possible organic molecules up to a defined size, the largest of which is GDB-17 featuring 166.4 billion molecules up to 17 non-hydrogen atoms. While known drugs and bioactive compounds are mostly aromatic and planar, the GDBs contain a plethora of non-aromatic 3D-shaped molecules, which are very useful for drug discovery since they generally have more desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. Here we review GDB enumeration methods and the selection and synthesis of GDB molecules as modulators of ion channels. We summarize the constitution of GDB subsets focusing on fragments (FDB17), medicinal chemistry (GDBMedChem) and ChEMBL-like molecules (GDBChEMBL), and the ring system database GDB4c as a rich source of novel 3D-shaped chiral molecules containing quaternary centers, such as the recently reported trinorbornane.


Web-Based Cognitive Behavior Therapy for Depression in People With Diabetes Mellitus: A Randomized Controlled Trial.
Depression is twice as common in diabetes mellitus (DM) as the general population and is associated with adverse health outcomes, but access to evidence-based therapies such as cognitive behavioral therapy (CBT) is limited in routine diabetes care. Past research has shown that generic Internet-based cognitive behavioral therapy (iCBT) is an effective treatment for depression in the general population, but it has never been evaluated in people with comorbid depression and DM. The aim of our study was to examine the efficacy of a generic 6-lesson iCBT delivered over 10 weeks in people with major depressive disorder (MDD) and DM. Participants with comorbid MDD and DM (type 1 or 2) were recruited online and randomized to an iCBT program with therapist support provided by phone and email (n=42) or a treatment as usual (TAU, n=49) control group. Outcomes were assessed through Web-based self-report questionnaires and the trial was Web-based with no face-to-face components. Primary outcomes were self-reported depression (patient health questionnaire-9, PHQ-9), diabetes-related distress (problem areas in diabetes, PAID), and self-reported glycemic control (hemoglobin A1c, HbA1c). Secondary outcomes were general distress (Kessler 10-item psychological distress scale, K-10) and disability (short form 12-item, SF-12), generalized anxiety (generalized anxiety disorder 7-item, GAD-7), and somatization (PHQ-15). The iCBT group was assessed at 3 months. A total of 27 participants (66%; 27/41) completed the iCBT program. Analyses indicated between-group superiority of iCBT over TAU at posttreatment on PHQ-9 (g=0.78), PAID (g=0.80), K-10 (g=1.06), GAD-7 (g=0.72), and SF-12 mental well-being scores (g=0.66), but no significant differences in self-reported HbA1c levels (g=0.14), SF-12 physical well-being, or PHQ-15 scores (g=0.03-0.21). Gains were maintained at 3-month follow-up in the iCBT group, and the 87% (27/31) of iCBT participants who were interviewed no longer met criteria for MDD. Clinically significant change following iCBT on PHQ-9 scores was 51% (21/41) versus 18% (9/49) in TAU. iCBT for depression is an efficacious, accessible treatment option for people with diabetes. Future studies should explore whether tailoring of iCBT programs improves acceptability and adherence, and evaluate the long-term outcomes following iCBT. Australian and New Zealand Clinical Trials Registry (ACTRN): 12613001198718; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365208&isReview=true (Archived by WebCite at http://www.webcitation.org/6qCR8Fi9V).


Use of waggle dance information in honey bees is linked to gene expression in the antennae, but not in the brain.
Communication is essential for social animals, but deciding how to utilize information provided by conspecifics is a complex process that depends on environmental and intrinsic factors. Honey bees use a unique form of communication, the waggle dance, to inform nestmates about the location of food sources. However, as in many other animals, experienced individuals often ignore this social information and prefer to rely on prior experiences, i.e., private information. The neurosensory factors that drive the decision to use social information are not yet understood. Here we test whether the decision to use social dance information or private information is linked to gene expression differences in different parts of the nervous system. We trained bees to collect food from sugar water feeders and observed whether they utilize social or private information when exposed to dances for a new food source. We performed transcriptome analysis of four brain parts (11-16 bees per tissue type) critical for cognition: the subesophageal ganglion, the central brain, the mushroom bodies, and the antennal lobes but, unexpectedly, detected no differences between social or private information users. In contrast, we found 413 differentially expressed genes in the antennae, suggesting that variation in sensory perception mediates the decision to use social information. Social information users were characterized by the upregulation of biogenic amine genes, while private information users upregulated several genes coding for odour perception. These results highlight that decision-making in honey bees might also depend on peripheral processes of perception rather than higher-order brain centres of information integration.


Climate teleconnections and recent patterns of human and animal disease outbreaks.
Recent clusters of outbreaks of mosquito-borne diseases (Rift Valley fever and chikungunya) in Africa and parts of the Indian Ocean islands illustrate how interannual climate variability influences the changing risk patterns of disease outbreaks. Although Rift Valley fever outbreaks have been known to follow periods of above-normal rainfall, the timing of the outbreak events has largely been unknown. Similarly, there is inadequate knowledge on climate drivers of chikungunya outbreaks. We analyze a variety of climate and satellite-derived vegetation measurements to explain the coupling between patterns of climate variability and disease outbreaks of Rift Valley fever and chikungunya. We derived a teleconnections map by correlating long-term monthly global precipitation data with the NINO3.4 sea surface temperature (SST) anomaly index. This map identifies regional hot-spots where rainfall variability may have an influence on the ecology of vector borne disease. Among the regions are Eastern and Southern Africa where outbreaks of chikungunya and Rift Valley fever occurred 2004-2009. Chikungunya and Rift Valley fever case locations were mapped to corresponding climate data anomalies to understand associations between specific anomaly patterns in ecological and climate variables and disease outbreak patterns through space and time. From these maps we explored associations among Rift Valley fever disease occurrence locations and cumulative rainfall and vegetation index anomalies. We illustrated the time lag between the driving climate conditions and the timing of the first case of Rift Valley fever. Results showed that reported outbreaks of Rift Valley fever occurred after ∼3-4 months of sustained above-normal rainfall and associated green-up in vegetation, conditions ideal for Rift Valley fever mosquito vectors. For chikungunya we explored associations among surface air temperature, precipitation anomalies, and chikungunya outbreak locations. We found that chikungunya outbreaks occurred under conditions of anomalously high temperatures and drought over Eastern Africa. However, in Southeast Asia, chikungunya outbreaks were negatively correlated (p<0.05) with drought conditions, but positively correlated with warmer-than-normal temperatures and rainfall. Extremes in climate conditions forced by the El Niño/Southern Oscillation (ENSO) lead to severe droughts or floods, ideal ecological conditions for disease vectors to emerge, and may result in epizootics and epidemics of Rift Valley fever and chikungunya. However, the immune status of livestock (Rift Valley fever) and human (chikungunya) populations is a factor that is largely unknown but very likely plays a role in the spatial-temporal patterns of these disease outbreaks. As the frequency and severity of extremes in climate increase, the potential for globalization of vectors and disease is likely to accelerate. Understanding the underlying patterns of global and regional climate variability and their impacts on ecological drivers of vector-borne diseases is critical in long-range planning of appropriate disease and disease-vector response, control, and mitigation strategies.


Outcomes of patients hospitalized after out-of-hospital cardiac arrest in relation to sex.
To describe characteristics and outcomes of patients hospitalized after out-of-hospital cardiac arrest in relation to sex. All patients in the community of Göteborg who between 1980 and 1996 suffered out-of-hospital cardiac arrest and were hospitalized alive. We calculated age-adjusted P values. In all 1038 patients were hospitalized alive of whom 29% were women. Women differed from men by being older and there being lower prevalences of previous acute myocardial infarction (AMI) and smoking and a higher prevalence of bronchial asthma among them. They had less commonly received cardio-pulmonary resuscitation (CPR) from bystanders (16 versus 25% of cases; P = 0.002) and were less commonly found to be in ventricular fibrillation when the ambulance crew arrived (55 versus 73% of cases; P < 0.0001). They were less commonly judged to have a cardiac etiology behind the arrest (87 versus 92% of cases; P = 0.016). Of women 31.3% could be discharged alive from hospital, compared with 41.8% of men (P = 0.001). While they were in hospital, women were less commonly subjected to exercise tests, coronary angiography, and coronary artery bypass grafting. Among patients who suffered out-of-hospital cardiac arrest and were hospitalized alive, women had less commonly received CPR from bystanders, were less commonly found in ventricular fibrillation, less commonly underwent coronary angiography and coronary artery bypass grafting and had a lower survival rate than did men.


Elucidation of the mechanism of selective inhibition of mammalian DNA polymerase alpha by 2-butylanilinopurines: development and characterization of 2-(p-n-butylanilino)adenine and its deoxyribonucleotides.
2-(p-n-Butylanilino)adenine (BuAA), an homolog of the DNA polymerase alpha (pol alpha)-specific inhibitor, N2-(p-n-butylphenyl)guanine (BuPG), was transformed to its 2'-deoxyribonucleoside, BuAdA, and the corresponding 2'-deoxyribonucleoside 5'-phosphates, BuAdAMP, BuAdADP, and BuAdATP. All five forms of BuAA are highly selective inhibitors of mammalian pol alpha, and the action of each is subject to specific competitive antagonism by dATP. BuAdADP, and BuAdATP, like the corresponding forms of BuPG, are very potent pol alpha inhibitors, displaying apparent Ki's of less than 3 nanomolar on natural activated templates. BuAdATP, like BuPdGTP, also inhibits pol alpha-catalysed reactions directed by non-complementary, thymine-deficient templates, and it does so via a mechanism subject to specific antagonism by its natural homolog, dATP. The results of the BuAdATP-homopolymer experiments complement those of analogous experiments with BuPdGTP and the dCTP-specific pol alpha inhibitor, aphidicolin, and strengthen the suggestion that mammalian pol alpha contains dNDP and dNTP binding sites which can recognize specific bases without direction by templates.


Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes.
Thirteen patients with epithelial ovarian cancer, who did not show any detectable lesion after cisplatin-containing chemotherapy following primary operation, were treated with adoptive transfer of tumor-infiltrating lymphocytes (TIL group). Eleven patients with almost equivalent conditions of disease, who were treated with only chemotherapy following primary operation, served as a control group. The median time of follow-up was 36 (range, 23-44) months in the TIL group and 33 (range, 14-48) months in the control group. The estimated 3-year overall survival rate of disease-free patients in the TIL group and in the control group was 100% and 67.5%, respectively. A significant difference was noticed between the overall survival rate of the TIL group and the control group (P < 0.01). Furthermore, the estimated 3-year disease-free survival rate of the patients in the TIL group and in the control group was 82.1% and 54.5%, respectively. The disease-free survival rate of patients in the TIL group and in the control group was significantly different (P < 0.05). These results suggest that the adoptive transfer of TILs after all chemotherapy has been finished might be one promising method to achieve complete cure of advanced epithelial ovarian cancer.


Effects of continuous versus intermittent transport on plasma constituents and antibody response of lambs.
Recommendations for transportation of lambs, horses, calves, and pigs from a committee of the European Commission, which required rest stops of 6 or 24 h, every 8 h, were evaluated using Rambouillet x Suffolk lambs. The lambs of 17.6 +/- 0.5 kg of BW were randomly assigned to 1 of 3 treatments: transported for 22 h (continuous; n = 15); transported for 8 h, unloaded and rested for 6 h, transported for 8 h, unloaded and rested for 24 h, transported for 6 h (rested, n = 15); or remained in the home pasture throughout the study (control, n = 16). Off-trailer rest with food and water occurred in novel pens. Food deprivation in the continuous lambs was reflected by a decrease (P < 0.001) in plasma concentrations of glucose and an increase (P < 0.02) in plasma concentrations of blood urea nitrogen, creatinine, and total bilirubin relative to rested or control lambs. Electrolytes varied within and among all 3 treatments (P < 0.05), but no distinct pattern indicating dehydration was evident. Serum concentrations of cortisol were elevated in continuous and rested lambs compared with control lambs at 22 h (P < 0.05). Plasma immunoglobulin G antibody response to ovalbumin was suppressed (P < 0.05) in the continuous and rested lambs relative to the control lambs. Differences (P < 0.05) between continuous and rested lambs indicated the rest stops were sufficient to maintain BW during transport; however, these results were confounded by the control lambs losing a similar (P = 0.50) percentage of their initial BW as the continuous lambs at 22 h. The rest stops eliminated the physiological indicators of food deprivation and maintained BW but did not alleviate evidence of immunosuppression, and 52 h was required to complete the otherwise 22-h-long trip.


Comparison of alternative adhesive cementation concepts for zirconia ceramic: glaze layer vs zirconia primer.
Zirconia-based ceramics offer strong restorations in dentistry, but the adhesive bond strength of resin cements to such ceramics is not optimal. This study evaluated the bond strength of silane/adhesive/resin cement and zirconia primer/resin cement combinations on non-glazed and glazed zirconia surfaces before and after aging. Disk-shaped zirconia ceramic specimens (diameter: 8 mm; thickness: 2 mm) (N = 80, n = 10 per group) were randomly divided into 2 groups. While half of the specimens received one coat of glaze and were later finished by grinding, the other half was only ground using 1200-grit silicone carbide abrasives under water. The glazed specimens were then conditioned with 9.5% HF acid gel for 60 s, rinsed with water for 90 s, and neutralized. The glazed and non-glazed specimens were further divided into two groups. Two resin cements, namely, Variolink II and Multilink Automix were adhered onto the zirconia surfaces with their corresponding adhesive systems. In the Variolink II group, zirconia surfaces were silanized (Monobond-S), and adhesive resin (Heliobond) was applied and photopolymerized. In the Multilink Automix group, one coat of Metal/Zirconia Primer was applied with a microbrush, left to react for 180 s, and dried using oil-free air. Half of the specimens in each cement group were subjected to 5000 thermocycles (5°C to 55°C) and the other half was kept in the dark for 24 h at 37°C prior to testing. Specimens were mounted in the jig of the universal testing machine, and force was applied to the ceramic/cement interface until failure occurred (1 mm/min). After evaluating all debonded specimens under SEM, the failure types were defined as either "adhesive" with no cement left on the zirconia (score 0) or "mixed" with less than half of the cement left on the surface with no cohesive failure of the substrate (score 1). Data were analyzed using three-way ANOVA and Dunnett-T3 post-hoc tests. Application of a glaze layer significantly improved the bond strength in the silane/adhesive/Variolink II group (p < 0.05), but no significant effect was found in the zirconia primer/Multilink Automix group (p > 0.05) (three-way ANOVA). Interaction terms were also significant (p < 0.05) (Dunnett-T3). Thermocycling did not decrease the results significantly in any of the groups (p > 0.05). Failure analysis revealed exclusively adhesive failures (score 0: 40 out of 40) in the non-glazed groups, but predominantly mixed failures (score 1: 34 out of 40) in the glazed groups. The silane (Monobond S)/adhesive (Heliobond)/Variolink II resin cement combination benefitted from glazing the zirconia surface, but the zirconia primer/Multilink Automix resin cement combination alone also provided sufficient bond strength to zirconia.


Variability of eye movements when viewing dynamic natural scenes.
How similar are the eye movement patterns of different subjects when free viewing dynamic natural scenes? We collected a large database of eye movements from 54 subjects on 18 high-resolution videos of outdoor scenes and measured their variability using the Normalized Scanpath Saliency, which we extended to the temporal domain. Even though up to about 80% of subjects looked at the same image region in some video parts, variability usually was much greater. Eye movements on natural movies were then compared with eye movements in several control conditions. "Stop-motion" movies had almost identical semantic content as the original videos but lacked continuous motion. Hollywood action movie trailers were used to probe the upper limit of eye movement coherence that can be achieved by deliberate camera work, scene cuts, etc. In a "repetitive" condition, subjects viewed the same movies ten times each over the course of 2 days. Results show several systematic differences between conditions both for general eye movement parameters such as saccade amplitude and fixation duration and for eye movement variability. Most importantly, eye movements on static images are initially driven by stimulus onset effects and later, more so than on continuous videos, by subject-specific idiosyncrasies; eye movements on Hollywood movies are significantly more coherent than those on natural movies. We conclude that the stimuli types often used in laboratory experiments, static images and professionally cut material, are not very representative of natural viewing behavior. All stimuli and gaze data are publicly available at http://www.inb.uni-luebeck.de/tools-demos/gaze.


Correlation of clinical, biochemical and skeletal responses to 1alpha-hydroxyvitamin D3 in renal bone disease.
Thirty-five patients with bone disease and chronic renal failure (twenty-four on maintenance haemodialysis) were treated for 7--39 months with 1alpha-hydroxyvitamin D3, 2--2.5 microgram daily by mouth. Symptoms (bone pain and muscle weakness) and radiographic appearances improved and plasma alkaline phosphatase returned to normal in the majority of patients (87, 76 and 75% respectively). In contrast, histological appearances in bone improved in only 46% twenty-three patients from whom paired biopsies were available, and this change was not greatly different from that seen in a comparable group of untreated patients. Significant correlations were noted in individual patients between the changes in symptoms, X-rays, plasma alkaline phosphatase and immunoreactive parathyroid hormone and these, in turn, were related to histological changes in bone, although these latter changes were often small. It is concluded that 1alpha-hydroxyvitamin D3 is a useful new drug in the treatment of renal bone disease, but that the evaluation of the response depends critically on the method of assessment used.


Load sharing and kinematics of threaded cages for lumbar interbody fusion.
The load-sharing characteristics of threaded interbody cages before and after cyclic loading are poorly understood. In the current study, lumbar interbody cages were filled with epoxy, sectioned longitudinally, and pressure sensors were placed between halves of the cages to measure the distribution of loads between and within the cages. Human lumbar spine segments were instrumented anteriorly with bilateral cages and subjected to cyclic compression loads combined with flexion and extension moments. Sagittal plane motion between vertebrae on either side of the cages also was measured during application of cyclic compression and flexion loads. A small but statistically significant asymmetry was found in the distribution of load between the left and right cages, and the extent of asymmetry varied during compression and flexion loading. With ligament tension only, 66% of the load was supported by the posterior regions of the cages, whereas during peaks in the combined compression and flexion loading, only 33% of the load was supported by the posterior regions. The cages reduced intervertebral motion 78% during forward flexion, whereas extension resulted in a 100% increase in motion. Surgeons should recognize that bilateral cages may not share loads equally, and the results of this study suggest that early extension should be restricted after the placement of anterior lumbar interbody cages.


Health impact on women using solid cooking fuels in rural area of Cuttack district, Odisha.
Around 3 billion people use solid fuels (biomass and coal) for cooking and heating, and this number is expected to grow until at least 2030. Around 73.7% of households in rural Odisha use wood for cooking. This current study is an attempt to evaluate the impact of solid cooking fuels on health of rural women in age group of 20-40 years and to study the relationship between the duration of exposure to cooking fuels and various health problems. This cross-sectional study was carried out in a village which is under the field practice area of the rural health and training centre, under Department of Community Medicine, Kalinga Institute of Medical Sciences. Universal sampling technique was adopted for sample selection. Chi-square test was used to find the association between cooking fuel usage and self-reported symptoms. Dry cough was the most common presenting symptom (15.03%), followed by eye and nose irritation present in nearly 12% each among the study participants. Headache, dry cough, and hypertension (HT) was found to associated with number of cooking years and was also found to be statistically significant (P = 0.03, 0.02 and 0.0065, respectively). Our study clearly indicated that the exposure to biomass fuel smoke is significantly associated with the prevalence of symptoms of headache, dry cough, and HT. Further research is required for improving information on dose-response relationships between indoor air pollution and various health effects. Conclusion: The morbidities were increased with increase in duration of cooking . Knowledge related to health effects of cooking fuels seems to be poor among the participants.


Single-Institution Financial Analysis of Biologic Versus Synthetic Mesh Hernia Repair: A Retrospective Analysis of Patients Readmitted for Hernia Repair.
The advent and proliferation of commercially available biologic mesh material has expanded the repertoire of hernia repair materials available to the surgeon. Given the higher initial cost of these mesh materials relative to synthetic materials such as polypropylene, there has been debate regarding the purported benefit of the use of biologic mesh. This study is a single-institution review of complex hernia repairs using both biologic and synthetic mesh materials. The patients included in the analyses were admitted to the institution at least twice for management of hernia; this permitted specific evaluation of a given diagnosis, hernia, in the same patient, but at different points in time. In a subset of patients, hernia repair was performed upon the second admission with conversion from biologic or synthetic mesh, which had been placed at the initial repair. The objective of this study was to evaluate the financial implications of mesh choice. Specific parameters reviewed included type of mesh used, total costs of hospitalization, direct cost associated with the hernia repair, total collections, and percentage of collections relative to total charges. Through such analysis, our aim was to determine whether there were any variances in revenue and costs associated with the application of either mesh material or the associated clinical scenarios.


Neural correlates of the affective properties of spontaneous and volitional laughter types.
Previous investigations of vocal expressions of emotion have identified acoustic and perceptual distinctions between expressions of different emotion categories, and between spontaneous and volitional (or acted) variants of a given category. Recent work on laughter has identified relationships between acoustic properties of laughs and their perceived affective properties (arousal and valence) that are similar across spontaneous and volitional types (Bryant & Aktipis, 2014; Lavan et al., 2016). In the current study, we explored the neural correlates of such relationships by measuring modulations of the BOLD response in the presence of itemwise variability in the subjective affective properties of spontaneous and volitional laughter. Across all laughs, and within spontaneous and volitional sets, we consistently observed linear increases in the response of bilateral auditory cortices (including Heschl's gyrus and superior temporal gyrus [STG]) associated with higher ratings of perceived arousal, valence and authenticity. Areas in the anterior medial prefrontal cortex (amPFC) showed negative linear correlations with valence and authenticity ratings across the full set of spontaneous and volitional laughs; in line with previous research (McGettigan et al., 2015; Szameitat et al., 2010), we suggest that this reflects increased engagement of these regions in response to laughter of greater social ambiguity. Strikingly, an investigation of higher-order relationships between the entire laughter set and the neural response revealed a positive quadratic profile of the BOLD response in right-dominant STG (extending onto the dorsal bank of the STS), where this region responded most strongly to laughs rated at the extremes of the authenticity scale. While previous studies claimed a role for right STG in bipolar representation of emotional valence, we instead argue that this may in fact exhibit a relatively categorical response to emotional signals, whether positive or negative.


CCR5 structural plasticity shapes HIV-1 phenotypic properties.
CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M-tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs.


The progression of cognition, psychiatric symptoms, and functional abilities in dementia with Lewy bodies and Alzheimer disease.
Although dementia with Lewy bodies (DLB) may be one of most common forms of dementia, relatively little is known about its cognitive and functional course. To compare change over time in general cognitive status, memory test performance, psychiatric symptoms, neurological signs, and functional abilities in patients with probable DLB and probable Alzheimer disease (AD). Twenty-eight patients who met diagnostic criteria for DLB were recruited into the study from 3 sites. Patients with AD (n = 55) were selected from a larger cohort and matched 2 to 1 to the patients with DLB on age and baseline global cognitive status. Patients were followed up at 6-month intervals for an average of 6.2 visits and assessed at each visit with tests of global cognitive functioning and verbal learning and memory and measures of psychiatric, neurological, and functional status. At the baseline evaluation, patients with DLB performed more poorly on a measure of constructional praxis and all measures of functional status. They also had more severe psychiatric symptoms and neurological signs than the AD group. Despite these initial differences, generalized estimating equations applied to regression analyses with repeated measures determined that the only difference between the 2 groups in change in cognitive test performance was on a measure of recognition memory; patients with AD declined, while patients with DLB remained relatively stable. Patients with DLB had relatively stable behavioral symptoms and visual illusions, whereas patients with AD had a significant increase in these symptoms over time. Neurological and functional changes over time were similar in the 2 groups. Both baseline and longitudinal differences between patients with DLB and patients with AD were noted; these have implications for clinical diagnosis and treatment.


Calculated versus Measured MVV-Surrogate Marker of Ventilatory Capacity in Pediatric CPET.
Maximum voluntary ventilation (MVV), a surrogate marker of maximum ventilatory capacity, allows for measuring ventilatory reserve during cardiopulmonary exercise testing (CPET), which is necessary to assess ventilatory limitation. MVV can be measured directly during a patient maneuver or indirectly by calculating from forced expiratory volume in 1 s (FEV1 × 40). We investigated for a potential difference between calculated MVV and measured MVV in pediatric subjects, and which better represents maximum ventilatory capacity during CPET. Data were collected retrospectively from CPET conducted in pediatric subjects for exercise-induced dyspnea from January 2014 to June 2015 at Akron Children's Hospital. Subjects with neuromuscular weakness, morbid obesity, and suboptimal effort during the testing were excluded from the study. Thirty-five subjects (mean ± SD, age = 13.8 ± 2.7 yr, range = 7-18 yr) fulfilled the criteria. Measured MVV was significantly lower than calculated MVV (89.9 ± 26.4 vs 122.4 ± 34.5 L·min; P < 0.01). The ventilatory reserve based on measured MVV was also significantly lower than ventilatory reserve based on calculated MVV (12.4% ± 19.6% vs 36.1% ± 13.2%; P < 0.01). Calculated MVV (as well as ventilatory reserve based on calculated MVV) was significantly correlated with ventilatory parameters. By contrast, no significant correlations were found between measured MVV (or ventilatory reserve based on measured MVV) and ventilatory parameters except for peak ventilation (peak V˙E). The measured MVV was significantly lower than the calculated MVV in our pediatric subjects. The calculated MVV was a better surrogate of maximum ventilatory capacity as shown by significant correlation to other ventilatory parameters during CPET.


A graph-based approach for designing extensible pipelines.
In bioinformatics, it is important to build extensible and low-maintenance systems that are able to deal with the new tools and data formats that are constantly being developed. The traditional and simplest implementation of pipelines involves hardcoding the execution steps into programs or scripts. This approach can lead to problems when a pipeline is expanding because the incorporation of new tools is often error prone and time consuming. Current approaches to pipeline development such as workflow management systems focus on analysis tasks that are systematically repeated without significant changes in their course of execution, such as genome annotation. However, more dynamism on the pipeline composition is necessary when each execution requires a different combination of steps. We propose a graph-based approach to implement extensible and low-maintenance pipelines that is suitable for pipeline applications with multiple functionalities that require different combinations of steps in each execution. Here pipelines are composed automatically by compiling a specialised set of tools on demand, depending on the functionality required, instead of specifying every sequence of tools in advance. We represent the connectivity of pipeline components with a directed graph in which components are the graph edges, their inputs and outputs are the graph nodes, and the paths through the graph are pipelines. To that end, we developed special data structures and a pipeline system algorithm. We demonstrate the applicability of our approach by implementing a format conversion pipeline for the fields of population genetics and genetic epidemiology, but our approach is also helpful in other fields where the use of multiple software is necessary to perform comprehensive analyses, such as gene expression and proteomics analyses. The project code, documentation and the Java executables are available under an open source license at http://code.google.com/p/dynamic-pipeline. The system has been tested on Linux and Windows platforms. Our graph-based approach enables the automatic creation of pipelines by compiling a specialised set of tools on demand, depending on the functionality required. It also allows the implementation of extensible and low-maintenance pipelines and contributes towards consolidating openness and collaboration in bioinformatics systems. It is targeted at pipeline developers and is suited for implementing applications with sequential execution steps and combined functionalities. In the format conversion application, the automatic combination of conversion tools increased both the number of possible conversions available to the user and the extensibility of the system to allow for future updates with new file formats.


An adaptive group sequential design for phase II/III clinical trials that select a single treatment from several.
There is increasing interest in combining Phases II and III of clinical development into a single trial in which one of a small number of competing experimental treatments is ultimately selected and where a valid comparison is made between this treatment and the control treatment. Such a trial usually proceeds in stages, with the least promising experimental treatments dropped as soon as possible. In this paper we present a highly flexible design that uses adaptive group sequential methodology to monitor an order statistic. By using this approach, it is possible to design a trial which can have any number of stages, begins with any number of experimental treatments, and permits any number of these to continue at any stage. The test statistic used is based upon efficient scores, so the method can be easily applied to binary, ordinal, failure time, or normally distributed outcomes. The method is illustrated with an example, and simulations are conducted to investigate its type I error rate and power under a range of scenarios.


Perineal wound closure using gluteal turnover flap or primary closure after abdominoperineal resection for rectal cancer: study protocol of a randomised controlled multicentre trial (BIOPEX-2 study).
Abdominoperineal resection (APR) for rectal cancer is associated with high morbidity of the perineal wound, and controversy exists about the optimal closure technique. Primary perineal wound closure is still the standard of care in the Netherlands. Biological mesh closure did not improve wound healing in our previous randomised controlled trial (BIOPEX-study). It is suggested, based on meta-analysis of cohort studies, that filling of the perineal defect with well-vascularised tissue improves perineal wound healing. A gluteal turnover flap seems to be a promising method for this purpose, and with the advantage of not having a donor site scar. The aim of this study is to investigate whether a gluteal turnover flap improves the uncomplicated perineal wound healing after APR for rectal cancer. Patients with primary or recurrent rectal cancer who are planned for APR will be considered eligible in this multicentre randomised controlled trial. Exclusion criteria are total exenteration, sacral resection above S4/S5, intersphincteric APR, biological mesh closure of the pelvic floor, collagen disorders, and severe systemic diseases. A total of 160 patients will be randomised between gluteal turnover flap (experimental arm) and primary closure (control arm). The total follow-up duration is 12 months, and outcome assessors and patients will be blinded for type of perineal wound closure. The primary outcome is the percentage of uncomplicated perineal wound healing on day 30, defined as a Southampton wound score of less than two. Secondary outcomes include time to perineal wound closure, incidence of perineal hernia, the number, duration and nature of the complications, re-interventions, quality of life and urogenital function. The uncomplicated perineal wound healing rate is expected to increase from 65 to 85% by using the gluteal turnover flap. With proven effectiveness, a quick implementation of this relatively simple surgical technique is expected to take place. The trial was retrospectively registered at Clinicaltrials.gov NCT04004650 on July 2, 2019.


Combination therapy with Gamma Knife radiosurgery and antisense EGFR for malignant glioma in vitro and orthotopic xenografts.
Accumulating evidence has indicated that epidermal growth factor receptor (EGFR) signaling pathway plays a potentially important role in mediating radiation resistance in human gliomas. In this study, we aimed to evaluate the effect of combination therapy with Gamma Knife radiosurgery (GKR) and antisense EGFR for malignant glioma in vitro and orthotopic xenografts. GKR and down-regulation of EGFR expression by antisense EGFR resulted in significant suppression of cell proliferation and induction of cell apoptosis in vitro. Moreover, the growth of the C6 glioma in orthotopic xenografts was significantly inhibited by this combination treatment. Thus, our results indicate that down-regulation of EGFR expression enhanced the radiosensitivity of glioma and GKR in combination with antisense EGFR is a potential strategy for glioma therapy.


Long non-coding RNAs discriminate the stages and gene regulatory states of human humoral immune response.
lncRNAs make up a majority of the human transcriptome and have key regulatory functions. Here we perform unbiased de novo annotation of transcripts expressed during the human humoral immune response to find 30% of the human genome transcribed during this process, yet 58% of these transcripts manifest striking differential expression, indicating an lncRNA phylogenetic relationship among cell types that is more robust than that of coding genes. We provide an atlas of lncRNAs in naive and GC B-cells that indicates their partition into ten functionally categories based on chromatin features, DNase hypersensitivity and transcription factor localization, defining lncRNAs classes such as enhancer-RNAs (eRNA), bivalent-lncRNAs, and CTCF-associated, among others. Specifically, eRNAs are transcribed in 8.6% of regular enhancers and 36.5% of super enhancers, and are associated with coding genes that participate in critical immune regulatory pathways, while plasma cells have uniquely high levels of circular-RNAs accounted for by and reflecting the combinatorial clonal state of the Immunoglobulin loci.


Large Kerr nonlinearities on cavity-atom polaritons.
I analyze a scheme that is capable of producing large Kerr nonlinearities on cavity-atom polaritons in a cavity quantum electrodynamics system consisting of multiple three-level atoms confined in a cavity mode. A weak control laser coupled to the atoms from free space induces destructive quantum interference in the polariton excitation of the coupled cavity-atom system and creates large Kerr nonlinearities on the intra-cavity light field. The scheme can be used for optical switching or cross-phase modulation of the cavity-atom polariton at ultralow light levels.


Retraining automatic action-tendencies to approach alcohol in hazardous drinkers.
The main aim of this study was to test whether automatic action-tendencies to approach alcohol can be modified, and whether this affects drinking behaviour. Forty-two hazardous drinkers were assigned randomly to a condition in which they were implicitly trained to avoid or to approach alcohol, using a training variety of the alcohol Approach Avoidance Test (AAT). Participants pushed or pulled a joystick in response to picture-format (landscape or portrait). The pictures depicted alcoholic or non-alcoholic drinks. Participants in the avoid-alcohol condition pushed most alcoholic and pulled most non-alcoholic drinks. For participants in the approach-alcohol condition these contingencies were reversed. After the implicit training, participants performed a taste test, including beers and soft drinks. Automatic action tendencies at post-test were assessed with the AAT, including both trained and untrained pictures, and with a different test (Implicit Association Test, IAT). We further tested effects on subjective craving. Action tendencies for alcohol changed in accordance with training condition, with the largest effects in the clinically relevant avoid-alcohol condition. These effects occurred outside subjective awareness and generalized to new pictures in the AAT and to an entirely different test using words, rather than pictures (IAT). In relatively heavy drinking participants who demonstrated changed action tendencies in accordance with their training condition, effects were found on drinking behaviour, with participants in the approach-alcohol condition drinking more alcohol than participants in the avoid-alcohol condition. No effect was found on subjective craving. Retraining automatic processes may help to regain control over addictive impulses, which points to new treatment possibilities.


Problems getting back in the swing after breast cancer: gaps in rehabilitative care.
For more than 50 years, Cancer has explored every facet of malignant disease, including morphology, therapy, epidemiology, biology, historical perspective, and basic science. However, the Editors of Cancer believe that the human beings who bear the burden of this illness have much to teach us, and we now solicit essays from patients and family members about their experience.


Cyclophilin A differentially activates monocytes and endothelial cells: role of purity, activity, and endotoxin contamination in commercial preparations.
Cyclophilin A (CyPA) is a cytoplasmic protein secreted under inflammatory conditions. Extracellular CyPA is detected in atherosclerotic plaques and has been observed to activate endothelial cells as well as monocytes. Commercially available recombinant CyPA-induced expression of tissue factor (TF) and vascular cell adhesion molecule-1 (VCAM-1) in human aortic endothelial cells (HAEC). However, CyPA from commercial sources contained lipopolysaccharide at concentrations up to 18.9 ng/ml; moreover, it exhibited low purity as determined by protein spectrum analysis and low activity as assessed by peptidyl prolyl cis-trans isomerase (PPIase) assay. An in-house preparation of pure, active, and uncontaminated CyPA failed to induce endothelial TF or VCAM-1 expression; moreover, it was not chemotactic for HAEC. In contrast, such CyPA exhibited potent chemotactic activity on monocytic THP-1 cells, with a maximal effect on migration occurring at a concentration of 5.5 x 10(-9)mol/l. Pretreatment of CyPA with cyclosporine A prevented its effect on THP-1 cell migration; similarly, PPIase-deficient mutant CyPA protein did not induce migration of these cells. In-house prepared CyPA induced the release of Il-6, but not TNF-alpha, from THP-1 cells. Commercially available CyPA exhibits low purity and activity and may be contaminated by endotoxin. Pure, active, and uncontaminated CyPA does not induce endothelial TF or VCAM-1 expression; instead, it acts as a potent monocyte chemoattractant and induces monocyte Il-6 release, implying a role for extracellular CyPA in the pathogenesis of atherosclerosis via activation of monocytes rather than endothelial cells.


Loss of glial neurofascin155 delays developmental synapse elimination at the neuromuscular junction.
Postnatal synapse elimination plays a critical role in sculpting and refining neural connectivity throughout the central and peripheral nervous systems, including the removal of supernumerary axonal inputs from neuromuscular junctions (NMJs). Here, we reveal a novel and important role for myelinating glia in regulating synapse elimination at the mouse NMJ, where loss of a single glial cell protein, the glial isoform of neurofascin (Nfasc155), was sufficient to disrupt postnatal remodeling of synaptic circuitry. Neuromuscular synapses were formed normally in mice lacking Nfasc155, including the establishment of robust neuromuscular synaptic transmission. However, loss of Nfasc155 was sufficient to cause a robust delay in postnatal synapse elimination at the NMJ across all muscle groups examined. Nfasc155 regulated neuronal remodeling independently of its canonical role in forming paranodal axo-glial junctions, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Rather, high-resolution proteomic screens revealed that loss of Nfasc155 from glial cells was sufficient to disrupt neuronal cytoskeletal organization and trafficking pathways, resulting in reduced levels of neurofilament light (NF-L) protein in distal axons and motor nerve terminals. Mice lacking NF-L recapitulated the delayed synapse elimination phenotype observed in mice lacking Nfasc155, suggesting that glial cells regulate synapse elimination, at least in part, through modulation of the axonal cytoskeleton. Together, our study reveals a glial cell-dependent pathway regulating the sculpting of neuronal connectivity and synaptic circuitry in the peripheral nervous system.


Multiscale analysis of information correlations in an infinite-range, ferromagnetic Ising system.
The scale-specific information content of the infinite-range, ferromagnetic Ising model is examined by means of information-theoretic measures of high-order correlations in finite-sized systems. The order-disorder transition region can be identified through the appearance of collective order in the ferromagnetic phase. In addition, it is found that near the transition, the ferromagnetic phase is marked by characteristic information oscillations at scales comparable to the system size. The amplitude of these oscillations increases with the total number of spins, so that large-scale information measures of correlations are nonanalytic in the thermodynamic limit. In contrast, correlations at scales small relative to the system size have a monotonic behavior both above and below the transition point, and a well-defined thermodynamic limit.


Measurements of wavelength dependent scattering and backscattering coefficients by low-coherence spectroscopy.
Quantitative measurements of scattering properties are invaluable for optical techniques in medicine. However, noninvasive, quantitative measurements of scattering properties over a large wavelength range remain challenging. We introduce low-coherence spectroscopy as a noninvasive method to locally and simultaneously measure scattering μ(s) and backscattering μ(b) coefficients from 480 to 700 nm with 8 nm spectral resolution. The method is tested on media with varying scattering properties (μ(s) = 1 to 34 mm(-1) and μ(b) = 2.10(-6) to 2.10(-3) mm(-1)), containing different sized polystyrene spheres. The results are in excellent agreement with Mie theory.


Molecular cloning and functional expression of glutamate receptor subunit genes.
Three closely related genes, GluR1, GluR2, and GluR3, encode receptor subunits for the excitatory neurotransmitter glutamate. The proteins encoded by the individual genes form homomeric ion channels in Xenopus oocytes that are sensitive to glutamatergic agonists such as kainate and quisqualate but not to N-methyl-D-aspartate, indicating that binding sites for kainate and quisqualate exist on single receptor polypeptides. In addition, kainate-evoked conductances are potentiated in oocytes expressing two or more of the cloned receptor subunits. Electrophysiological responses obtained with certain subunit combinations show agonist profiles and current-voltage relations that are similar to those obtained in vivo. Finally, in situ hybridization histochemistry reveals that these genes are transcribed in shared neuroanatomical loci. Thus, as with gamma-aminobutyric acid, glycine, and nicotinic acetylcholine receptors, native kainate-quisqualate-sensitive glutamate receptors form a family of heteromeric proteins.


Laser treatment of onychomycosis using a novel 0.65-millisecond pulsed Nd:YAG 1064-nm laser.
Onychomycosis is a common disorder of the nails. Treatment modalities include oral and topical antifungals, surgical treatment or a combination of these therapies. Cure rates remain low with relatively high relapse rates seen after successful treatment. The purpose of this study was to evaluate the treatment of onychomycosis using a novel 0.65-millisecond (ms) pulsed 1064-nm laser. Eight subjects were treated over two to three sessions spaced at least 3 weeks apart. Of the eight subjects evaluated, seven had negative post-treatment cultures after the second or third session. Treatments were well tolerated by all subjects. These data suggest that treatment of onychomycosis with a 0.65-ms pulsed Nd:YAG 1064-nm laser should be studied further to determine the long-term clinical and microbiologic effect. The optimal number of treatment sessions for each patient needs to be determined.


The Ensembl genome database project.
The Ensembl (http://www.ensembl.org/) database project provides a bioinformatics framework to organise biology around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of the human genome sequence, with confirmed gene predictions that have been integrated with external data sources, and is available as either an interactive web site or as flat files. It is also an open source software engineering project to develop a portable system able to handle very large genomes and associated requirements from sequence analysis to data storage and visualisation. The Ensembl site is one of the leading sources of human genome sequence annotation and provided much of the analysis for publication by the international human genome project of the draft genome. The Ensembl system is being installed around the world in both companies and academic sites on machines ranging from supercomputers to laptops.


Kv1.1 and Kv1.3 channels contribute to the delayed-rectifying K+ conductance in rat choroid plexus epithelial cells.
The choroid plexuses secrete, and maintain the composition of, the cerebrospinal fluid. K+ channels play an important role in these processes. In this study the molecular identity and properties of the delayed-rectifying K+ (Kv) conductance in rat choroid plexus epithelial cells were investigated. Whole cell K+ currents were significantly reduced by 10 nM dendrotoxin-K and 1 nM margatoxin, which are specific inhibitors of Kv1.1 and Kv1.3 channels, respectively. A combination of dendrotoxin-K and margatoxin caused a depolarization of the membrane potential in current-clamp experiments. Western blot analysis indicated the presence of Kv1.1 and Kv1.3 proteins in the choroid plexus. Furthermore, the Kv1.3 and Kv1.1 proteins appear to be expressed in the apical membrane of the epithelial cells in immunocytochemical studies. The Kv conductance was inhibited by 1 microM serotonin (5-HT), with maximum inhibition to 48% of control occurring in 8 min (P < 0.05 by Student's t-test for paired data). Channel inhibition by 5-HT was prevented by the 5-HT2C antagonist mesulergine (300 nM). It was also attenuated in the presence of calphostin C (a protein kinase C inhibitor). The conductance was partially inhibited by 1,2-dioctanoyl-sn-glycerol and phorbol 12-myristate 13-acetate, both of which activate protein kinase C. These data suggest that 5-HT acts at 5-HT2C receptors to activate protein kinase C, which inhibits the Kv channels. In conclusion, Kv1.1 and Kv1.3 channels make a significant contribution to K+ efflux at the apical membrane of the choroid plexus.


Dietician-delivered intensive nutritional support is associated with a decrease in severe postoperative complications after surgery in patients with esophageal cancer.
The aim of this study was to evaluate the effect of dietician-delivered intensive nutritional support (INS) on postoperative outcome in patients with esophageal cancer. Approximately 50-80% of patients with esophageal cancer are malnourished at the time of diagnosis. Malnutrition enhances the risk of postoperative complications, resulting in delay of postoperative recovery and impairment of quality of life. Sixty-five patients with esophageal cancer were included. All patients who received surgery (n = 28) in the time frame between March 2009 and April 2010, the first year after the start of INS, were included in the INS intervention group. The control group (n = 37) consisted of patients who received surgery during the 3 years before the start of INS. Logistic regression analysis was used to compare differences in severity of postoperative complications using the Dindo classification. Linear regression was applied to evaluate differences in preoperative weight change. The adjusted odds ratio for developing serious complications after surgery of INS compared with the control group was 0.23 (95% confidence interval: 0.053-0.97; P = 0.045). Benefit was mainly observed in patients who received neoadjuvant therapy before esophagectomy (n = 35). The INS program furthermore resulted in a relative preoperative weight gain in comparison with the control group of +4.8% (P = 0.009, adjusted) in these neoadjuvant-treated patients. This study shows that dietician-delivered INS preserves preoperative weight and decreases severe postoperative complications in patients with esophageal cancer.


Pediatric intensive care unit family conferences: one mode of communication for discussing end-of-life care decisions.
To examine clinicians' and parents' reflections on pediatric intensive care unit family conferences in the context of discussion about end-of-life care decision making. Retrospective qualitative study. A university-based hospital. Eighteen parents of children who died in the pediatric intensive care unit and 48 pediatric intensive care unit clinicians (physicians, nurses, social workers, child-life specialists, chaplains, and case managers). In-depth, semistructured focus groups and one-on-one interviews designed to explore experiences in end-of-life care decision making. We identified comments about family conferences in all clinician focus groups/interviews, except one individual nurse interview, and in 13 of the 18 parent interviews. Comments from parents were sparse compared with those from clinicians. Four topics emerged: purpose, structural aspects, challenges, and suggestions for improvement. We identified three purposes for family conferences: communication between clinicians and parents; communication among clinicians; and support of families. Described structural aspects of family conferences included: preconference planning, communication during conferences, and postconference processing. Challenges noted involved communicating with parents during family conferences, such as: difficulties associated with having multiple services involved; balancing messages of hope and realism; using understandable language; and communicating with non-English-speakers. Participants described additional challenges related to the logistics of organizing family conferences. Suggestions focused on methods to improve communication in, organization of, and preparation for family conferences. Pediatric intensive care unit clinicians in this study perceive family conferences as having an important role in end-of-life care decision making. The paucity of data from parents, an important finding itself, limits our ability to comment on parents' perceptions of family conferences. Prospective research of pediatric intensive care unit family conferences, with specific attention to parents' experiences and to all aspects of family conferences, including pre- and postconference events, should seek to understand the role and impact of this mode of communication on end-of-life care decision making and to determine the need for improvement to family conferences.


Comparative seasonal sterol profiles in edible parts of Mediterranean fish and shellfish species.
The effect of different seasons on sterol content of seafoods was investigated. There were four sterols (cholesterol, sitosterol, desmosterol and stigmasterol) identified, with cholesterol being the predominant sterol. Stigmasterol was a minor component in fish muscle, whilst sitosterol was one of the main phytosterols found in fish muscle. Cholesterol content of fish consisted of 38-100% of total sterols in fish and 54-80% of total sterols in shellfish. The highest cholesterol content of fish muscle was found in summer and the lowest in autumn, whereas season did not have any effect on cholesterol level of green tiger prawn and speckled shrimp. Total sterol content of fish muscle ranged from 49 to 110 mg/100 g, although the range of total sterols in shrimp muscle was between 62 and 91 mg/100 g. The result of the study showed that total sterols in fish were generally found at lower levels in winter compared with other seasons.


Artemisinin for treatment of uncomplicated falciparum malaria: is there a place for monotherapy?
The efficacy of artemisinin monotherapy was studied in 227 patients with uncomplicated falciparum malaria. They all received artemisinin at t = 0 hr, t = 8 hr, and thereafter once daily; treatment was extended at random until they had taken either 5 days of artemisinin followed by 2 days of placebo (A5), or 7 days (A7) of artemisinin. The adult artemisinin dose was 500 mg; children aged < 15 years received 10 mg/kg per dose. The median (range) parasite clearance time was 39 (8-112) hr for A5 and 43 (38-104) hr for A7 (P = 0.085). The recrudescence rates were similar between the groups. The lowest parasite count achieved during treatment (Pterm) was associated with the occurrence of recrudescence (P = 0.046, Cox regression model); it was lower for patients with a radical cure or late recrudescence than for early recrudescence (P = 0.034, t-test). Artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. Extending the duration of monotherapy from 5 days to 7 days does not reduce recrudescence.


Effect of radial shock wave on chronic pelvic pain syndrome/chronic prostatitis.
[Purpose] This study aimed to evaluate the effect of radial extracorporeal shock wave therapy (rESWT) on patients with chronic pelvic pain syndrome (CPPS). [Participants and Methods] Forty male CPPS patients were randomly assigned into either an rESWT group or a control group. The first group was treated with rESWT two times per week for four weeks with a protocol 3,000 pulse, 12 Hz at 3 to 5 bar. The control group was treated with the same protocol, but the device's probe had been turned off. The follow-up assessment was done using the National Institutes of Health-developed Chronic Prostatitis Symptom Index (NIH-CPSI) before treatment, as well as one week, four weeks, and 8 weeks after treatment. [Results] No significant difference was found in terms of age, sub-domain, or the total score of the NIH-CPSI between the rESWT group and the control group at the baseline. A statistically significant decrease was determined in the pain domain, urine score, quality of life, and the total NIH-CPSI score of the rESWT group at all post-treatment time points. All domains and the total score of the NIH-CPSI at all three follow-up time points decreased more significantly in the rESWT group as compared to the control group. [Conclusion] The findings of this study confirmed that rESWT is an effective method for treating CPPS.


Retinal effects of 6 months of daily use of tadalafil or sildenafil.
To assess changes in electroretinography (ERG) and other retinal function parameters during 6 months of daily use of tadalafil, sildenafil citrate, or placebo. Subjects were randomized to use of a placebo (n=82), 5 mg of tadalafil (n=85), or 50 mg of sildenafil (n=77) daily for 6 months. Electroretinographs were recorded using the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol and standardized ERG equipment at all 15 study sites. Other tests of ocular anatomy and visual function were performed at each assessment. The primary outcome was the average mean change for both eyes from baseline to endpoint in ERG b-wave amplitude using dark-adapted combined standard response to a bright ISCEV standard flash. Secondary endpoints were other ERG parameter changes, visual acuity, number of errors in color discrimination testing, mean deviation in automated visual field testing, and intraocular pressure (IOP). No significant differences were found between treatment/placebo groups for the primary outcome, most other ERG variables, visual function, IOP, or anatomic assessments. The medications were well tolerated. No abnormalities in ERG or visual function and no treatment-related findings suggestive of drug toxicity are associated with daily administration of tadalafil or sildenafil for 6 months. Assessed visual safety of tadalafil/sildenafil administered daily over a prolonged period. clinicaltrials.gov Identifier: NCT00333281.


Construction of Sierpiński Triangles up to the Fifth Order.
Self-similar fractal structures are of fundamental importance in science, mathematics, and aesthetics. A series of molecular defect-free Sierpiński triangle fractals have been constructed on surfaces recently. However, the highest order of the fractals is only 4 because of the limitation of kinetic growth. Here complete fifth-order Sierpiński triangles with a lateral length of 0.05 μm were successfully prepared in ultrahigh vacuum by a combination of templating and coassembly methods. Fe atoms, 4,4″-dicyano-1,1':3',1″-terphenyl, and 1,3-bis(4-pyridyl)benzene molecules were used to build fractals on the reconstructed Au(100)-(hex) surface. The new strategy may be applied to construct various Sierpiński triangles of higher orders.


Zinc-chelated poly(1-vinylimidazole) and a carbohydrate ligand polycation form DNA ternary complexes for gene delivery.
Zinc-chelated poly(1-vinylimidazole) (PVIm-Zn) and a carbohydrate ligand polycation, a poly(l-lysine) conjugated with lactose molecules (PLL-Lac), have formed DNA ternary complexes for gene delivery. The particle size of the PVIm-Zn/DNA complexes with negative zeta potential was decreased by the addition of the PLL-Lac. The resulting PLL-Lac/PVIm-Zn/DNA ternary complexes, which exhibited the pH-dependent dissociation of the PLL-Lac, mediated more gene expression than the PVIm/DNA binary complexes. The PLL-Lac/PVIm-Zn/DNA complexes with the specific recognition of cell surface receptors mediated the highest gene expression without cytotoxicity at a relatively lower charge ratio (positive/negative = 2.5). These results suggest that the pH-dependent dissociation of the carbohydrate ligands after the recognition of cell surface receptors, including the physicochemical and biochemical function of PVIm-Zn, played an important role in gene expression.


Evolving blood pressure dynamics for extremely preterm infants.
To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants. Prospective observational study of infants 23(0/7) to 26(6/7) weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 h. A cohort of 367 infants had 18 709 ABP measurements recorded. ABP decreased for the first 3 h, reached a nadir at 4 to 5 h and then increased at an average rate of 0.2 mm Hg h(-1). The rise in ABP from hour 4 to 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135) or dopamine (n=92). GA-specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA. ABP increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.


Fluoride mouthrinses for preventing dental caries in children and adolescents.
Fluoride mouthrinses have been used extensively as a caries-preventive intervention in school-based programmes and by individuals at home. This is an update of the Cochrane review of fluoride mouthrinses for preventing dental caries in children and adolescents that was first published in 2003. The primary objective is to determine the effectiveness and safety of fluoride mouthrinses in preventing dental caries in the child and adolescent population.The secondary objective is to examine whether the effect of fluoride rinses is influenced by:• initial level of caries severity;• background exposure to fluoride in water (or salt), toothpastes or reported fluoride sources other than the study option(s); or• fluoride concentration (ppm F) or frequency of use (times per year). We searched the following electronic databases: Cochrane Oral Health's Trials Register (whole database, to 22 April 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 3), MEDLINE Ovid (1946 to 22 April 2016), Embase Ovid (1980 to 22 April 2016), CINAHL EBSCO (the Cumulative Index to Nursing and Allied Health Literature, 1937 to 22 April 2016), LILACS BIREME (Latin American and Caribbean Health Science Information Database, 1982 to 22 April 2016), BBO BIREME (Bibliografia Brasileira de Odontologia; from 1986 to 22 April 2016), Proquest Dissertations and Theses (1861 to 22 April 2016) and Web of Science Conference Proceedings (1990 to 22 April 2016). We undertook a search for ongoing trials on the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform. We placed no restrictions on language or date of publication when searching electronic databases. We also searched reference lists of articles and contacted selected authors and manufacturers. Randomised or quasi-randomised controlled trials where blind outcome assessment was stated or indicated, comparing fluoride mouthrinse with placebo or no treatment in children up to 16 years of age. Study duration had to be at least one year. The main outcome was caries increment measured by the change in decayed, missing and filled tooth surfaces in permanent teeth (D(M)FS). At least two review authors independently performed study selection, data extraction and risk of bias assessment. We contacted study authors for additional information when required. The primary measure of effect was the prevented fraction (PF), that is, the difference in mean caries increments between treatment and control groups expressed as a percentage of the mean increment in the control group. We conducted random-effects meta-analyses where data could be pooled. We examined potential sources of heterogeneity in random-effects metaregression analyses. We collected adverse effects information from the included trials. In this review, we included 37 trials involving 15,813 children and adolescents. All trials tested supervised use of fluoride mouthrinse in schools, with two studies also including home use. Almost all children received a fluoride rinse formulated with sodium fluoride (NaF), mostly on either a daily or weekly/fortnightly basis and at two main strengths, 230 or 900 ppm F, respectively. Most studies (28) were at high risk of bias, and nine were at unclear risk of bias.From the 35 trials (15,305 participants) that contributed data on permanent tooth surface for meta-analysis, the D(M)FS pooled PF was 27% (95% confidence interval (CI), 23% to 30%; I(2) = 42%) (moderate quality evidence). We found no significant association between estimates of D(M)FS prevented fractions and baseline caries severity, background exposure to fluorides, rinsing frequency or fluoride concentration in metaregression analyses. A funnel plot of the 35 studies in the D(M)FS PF meta-analysis indicated no relationship between prevented fraction and study precision (no evidence of reporting bias). The pooled estimate of D(M)FT PF was 23% (95% CI, 18% to 29%; I² = 54%), from the 13 trials that contributed data for the permanent teeth meta-analysis (moderate quality evidence).We found limited information concerning possible adverse effects or acceptability of the treatment regimen in the included trials. Three trials incompletely reported data on tooth staining, and one trial incompletely reported information on mucosal irritation/allergic reaction. None of the trials reported on acute adverse symptoms during treatment. This review found that supervised regular use of fluoride mouthrinse by children and adolescents is associated with a large reduction in caries increment in permanent teeth. We are moderately certain of the size of the effect. Most of the evidence evaluated use of fluoride mouthrinse supervised in a school setting, but the findings may be applicable to children in other settings with supervised or unsupervised rinsing, although the size of the caries-preventive effect is less clear. Any future research on fluoride mouthrinses should focus on head-to-head comparisons between different fluoride rinse features or fluoride rinses against other preventive strategies, and should evaluate adverse effects and acceptability.


Screening and assessment for obstructive sleep apnea in primary care.
Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and contributes to increased morbidity and compromised cardiovascular outcomes. Sleep disorders are common but rarely reported and addressed by primary health providers. An American Academy of Sleep Medicine task force (2015) released quality measures for the care of adult patients with OSA; the first outcome is improved detection and categorization of OSA symptoms and severity to promote assessment and diagnosis of the disorder. This state of the science integrative review aimed to evaluate the screening and assessment for OSA in primary care settings including the psychometric properties of OSA screening measures. Studies that met inclusion criteria were fourteen non-experimental and three experimental designs. OSA screening measurements (Berlin questionnaire, Epworth sleepiness scale, STOP Bang) with extensive validation studies were examined. Conclusions are that the current practice model of screening and assessment for OSA in primary care is fragmented and ineffective. Primary care providers encounter patients with OSA symptoms but do not routinely screen, assess, or refer to a sleep specialist. More psychometric research is needed for the OSA screening measurements in primary care. The results of these studies can be translated into practice to increase detection of OSA.


Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I.
The classic form of Ehlers-Danlos syndrome (cEDS) is an inherited connective tissue disorder, where mutations in type V collagen-encoding genes result in abnormal collagen fibrils. Thus the cEDS patients have pathological connective tissue morphology and low stiffness, but the rate of connective tissue protein turnover is unknown. We investigated whether cEDS affected the protein synthesis rate in skin and tendon, and whether this could be stimulated in tendon tissue with insulin-like growth factor-I (IGF-I). Five patients with cEDS and 10 healthy, matched controls (CTRL) were included. One patellar tendon of each participant was injected with 0.1 ml IGF-I (Increlex, Ipsen, 10 mg/ml) and the contralateral tendon with 0.1 ml isotonic saline as control. The injections were performed at both 24 and 6 h prior to tissue sampling. The fractional synthesis rate (FSR) of proteins in skin and tendon was measured with the stable isotope technique using a flood-primed continuous infusion over 6 h. After the infusion one skin biopsy and two tendon biopsies (one from each patellar tendon) were obtained. We found similar baseline FSR values in skin and tendon in the cEDS patients and controls [skin: 0.005 ± 0.002 (cEDS) and 0.007 ± 0.002 (CTRL); tendon: 0.008 ± 0.001 (cEDS) and 0.009 ± 0.002 (CTRL) %/h, mean ± SE]. IGF-I injections significantly increased FSR values in cEDS patients but not in controls (delta values: cEDS 0.007 ± 0.002, CTRL 0.001 ± 0.001%/h). In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections.


Borderline Values of Troponin-T and High Sensitivity C-Reactive Protein Did Not Predict 2-Year Mortality in TnT Positive Chest-Pain Patients, Whereas Brain Natriuretic Peptide Did.
Troponin-T (TnT), high-sensitive C-reactive protein (hsCRP), and Brain Natriuretic Peptide (BNP) have been shown to be independent prognostic indicators of total and cardiac death during short- and long-term follow-up. We investigated prospectively the prognostic value of admission samples of TnT, hsCRP, and BNP in 871 chest-pain patients from South-Western Norway and 982 patients from Northern Argentina, based on a similar protocol and database setup. Follow-up was 2 years for the pooled population. The prognostic value of the selected biomarkers was investigated in quartiles of 239 patients with TnT values greater than 0.01 and up to and including 0.1 ng/mL, with continuous TnT as a potential confounder. After 24 months, 69 patients had died, of whom 38 died from cardiac causes. In the selected range of TnT, this biomarker was not significantly different between patients who died and survived (mean 0.0452 and 0.0457, p = 0.887). The BNP levels were significantly higher among patients dying than in long-term survivors [340 (142-656) versus 157 (58-367) pg/mL (median, 25 and 75% percentiles), p < 0.001]. In a multivariable Cox regression model for death within 2 years, the hazard ratio (HR) for BNP in the highest quartile (Q4) as compared to the lowest (Q1) was significantly related to total mortality [HR 2.84 (95% confidence interval (CI), 1.13-7.17)], p = 0.027, in addition to age (p ≤ 0.001) and hypercholesterolemia (p = 0.043). For cardiac death, the HR for BNP was 5.18 (95% CI, 1.06-25.3), p = 0.042. Several other variables (age, congestive heart failure, ST elevation myocardial infarction, and study country) were also significantly related to cardiac death. In a multivariable Cox regression model, hsCRP rendered no significant prognostic information for all-cause mortality (p = 0.089) or for cardiac mortality (p = 0.524). In patients with borderline TnT values (greater than 0.01 and up to and including 0.1 ng/mL), this biomarker as well as hsCRP did not render prognostic information, whereas BNP was found to be a strong prognostic indicator of 2-year total and cardiac mortality.


Inhibition of T cell differentiation into effectors by NKT cells requires cell contacts.
NKT cells are potent regulatory T cells that prevent the development of several autoimmune diseases. Analysis of NKT cell regulatory function in the NOD mouse has revealed that NKT cells inhibit the development of type 1 diabetes by impairing the differentiation of anti-islet T cells into Th1 effector cells. In the present study, we have performed in vitro and in vivo experiments to determine the respective role of cytokines and cell contacts in the blockade of T cell differentiation by NKT cells. These experiments reveal that cytokines such as IL-4, IL-10, IL-13, and TGF-beta, that have been involved in other functions of NKT cells, play only a minor role if any in the blockade of T cell differentiation by NKT cells. Diabetes is still prevented by NKT cells in the absence of functional IL-4, IL-10, IL-13, and TGF-beta. In contrast, we show for the first time that cell contacts are crucial for the immunoregulatory function of NKT cells.


Predicting future protection of respirator users: Statistical approaches and practical implications.
The purpose of this article is to describe a statistical approach for predicting a respirator user's fit factor in the future based upon results from initial tests. A statistical prediction model was developed based upon joint distribution of multiple fit factor measurements over time obtained from linear mixed effect models. The model accounts for within-subject correlation as well as short-term (within one day) and longer-term variability. As an example of applying this approach, model parameters were estimated from a research study in which volunteers were trained by three different modalities to use one of two types of respirators. They underwent two quantitative fit tests at the initial session and two on the same day approximately six months later. The fitted models demonstrated correlation and gave the estimated distribution of future fit test results conditional on past results for an individual worker. This approach can be applied to establishing a criterion value for passing an initial fit test to provide reasonable likelihood that a worker will be adequately protected in the future; and to optimizing the repeat fit factor test intervals individually for each user for cost-effective testing.


Freshwater dispersion stability of PAA-stabilised cerium oxide nanoparticles and toxicity towards Pseudokirchneriella subcapitata.
An aqueous dispersion of poly (acrylic acid)-stabilised cerium oxide (CeO₂) nanoparticles (PAA-CeO₂) was evaluated for its stability in a range of freshwater ecotoxicity media (MHRW, TG 201 and M7), with and without natural organic matter (NOM). In a 15 day dispersion stability study, PAA-CeO₂ did not undergo significant aggregation in any media type. Zeta potential varied between media types and was influenced by PAA-CeO₂ concentration, but remained constant over 15 days. NOM had no influence on PAA-CeO₂ aggregation or zeta potential. The ecotoxicity of the PAA-CeO₂ dispersion was investigated in 72 h algal growth inhibition tests using the freshwater microalgae Pseudokirchneriella subcapitata. PAA-CeO₂ EC₅₀ values for growth inhibition (GI; 0.024 mg/L) were 2-3 orders of magnitude lower than pristine CeO₂ EC₅₀ values reported in the literature. The concentration of dissolved cerium (Ce(3+)/Ce(4+)) in PAA-CeO₂ exposure suspensions was very low, ranging between 0.5 and 5.6 μg/L. Free PAA concentration in the exposure solutions (0.0096-0.0384 mg/L) was significantly lower than the EC10 growth inhibition (47.7 mg/L) value of pure PAA, indicating that free PAA did not contribute to the observed toxicity. Elemental analysis indicated that up to 38% of the total Cerium becomes directly associated with the algal cells during the 72 h exposure. TOF-SIMS analysis of algal cell wall compounds indicated three different modes of action, including a significant oxidative stress response to PAA-CeO₂ exposure. In contrast to pristine CeO₂ nanoparticles, which rapidly aggregate in standard ecotoxicity media, PAA-stabilised CeO₂ nanoparticles remain dispersed and available to water column species. Interaction of PAA with cell wall components, which could be responsible for the observed biomarker alterations, could not be excluded. This study indicates that the increased dispersion stability of PAA-CeO₂ leads to an increase in toxicity compared to pristine non-stabilised forms.


Relationship between outdoor temperature and cardiovascular disease risk factors in older people.
Background Previous studies demonstrated that lower outdoor temperatures increase the levels of established cardiovascular disease risk factors, such as blood pressure and lipids. Whether or not low temperatures increase novel cardiovascular disease risk factors levels is not well studied. The aim was to investigate associations of outdoor temperature with a comprehensive range of established and novel cardiovascular disease risk factors in two large Northern European studies of older adults, in whom cardiovascular disease risk is increased. Design and methods Data came from the British Regional Heart Study (4252 men aged 60-79 years) and the Prospective Study of Pravastatin in the Elderly at Risk (5804 men and women aged 70-82 years). Associations between outdoor temperature and cardiovascular disease risk factors were quantified in each study and then pooled using a random effects model. Results With a 5℃ lower mean temperature, total cholesterol was 0.04 mmol/l (95% confidence interval (CI) 0.02-0.07) higher, low density lipoprotein cholesterol was 0.02 mmol/l (95% CI 0.01-0.05) higher and SBP was 1.12 mm Hg (95% CI 0.60-1.64) higher. Among novel cardiovascular disease risk factors, C-reactive protein was 3.3% (95% CI 1.0-5.6%) higher, interleukin-6 was 2.7% (95% CI 1.1-4.3%) higher, and vitamin D was 11.2% (95% CI 1.0-20.4%) lower. Conclusions Lower outdoor temperature was associated with adverse effects on cholesterol, blood pressure, circulating inflammatory markers, and vitamin D in two older populations. Public health approaches to protect the elderly against low temperatures could help in reducing the levels of several cardiovascular disease risk factors.


Three-dimensional solution structure of human interleukin-4 by multidimensional heteronuclear magnetic resonance spectroscopy.
The three-dimensional solution structure of recombinant human interleukin-4, a protein of 133 residues and 15.4 kilodaltons that plays a key role in the immune and inflammatory systems, has been solved by multidimensional heteronuclear magnetic resonance spectroscopy. The structure is dominated by a left-handed four-helix bundle with an unusual topology comprising two overhand connections. The linker elements between the helices are formed by either long loops, small helical turns, or short strands. The overall topology is remarkably similar to that of growth hormone and granulocyte-macrophage colony stimulating factor, despite the absence of any sequence homology, and substantial differences in the relative lengths of the helices, the length and nature of the various connecting elements, and the pattern of disulfide bridges. These three proteins, however, bind to cell surface receptors belonging to the same hematopoietic superfamily, which suggests that interleukin-4 may interact with its receptor in an analogous manner to that observed in the crystal structure of the growth hormone-extracellular receptor complex.