Enrollment Challenges in Critical Care Nursing Research.
Enrollment challenges for critical care research are common. Contributing factors include short enrollment windows, the crisis nature of critical illness, lack of research staff, unavailable legal proxy, family dynamics, and language barriers. To describe enrollment statistics for an ongoing critical care nursing trial, barriers to recruitment, and strategies to enhance enrollment. Two years' worth of recruitment and enrollment data from an oral care intervention trial in critically ill adults receiving mechanical ventilation at 1 hospital were analyzed. Recruitment logs include number of patients screened, eligible, enrolled, and declined and patients' sex, race, and ethnicity. Target enrollment (15.5 patients per month) was based on experience and historical data. Strategies implemented to promote enrollment included providing study personnel at least 18 hours per day for 7 days per week, regular rounds, communication with direct care staff, and Spanish consent processes. In 2 years, 6963 patients were screened; 1551 (22%) were eligible. Consent was sought from 366 (24% of eligible patients). Enrollment averaged 13.3 patients per month (86% of projected target). The main factor impeding enrollment was unavailability of a legal proxy to provide consent (88%). The refusal rates of white (11%), black (13%), and Hispanic (16%) patients did not differ significantly. However, those classified as Asian or as more than 1 race declined significantly more often (35%) than did white or black patients (P = .02). Unavailability of a legal proxy within a short enrollment window was the major challenge to enrollment. Various factors influenced consent decisions. Clinical study design requires more conservative estimates.


CodeMapper: semiautomatic coding of case definitions. A contribution from the ADVANCE project.
Assessment of drug and vaccine effects by combining information from different healthcare databases in the European Union requires extensive efforts in the harmonization of codes as different vocabularies are being used across countries. In this paper, we present a web application called CodeMapper, which assists in the mapping of case definitions to codes from different vocabularies, while keeping a transparent record of the complete mapping process. CodeMapper builds upon coding vocabularies contained in the Metathesaurus of the Unified Medical Language System. The mapping approach consists of three phases. First, medical concepts are automatically identified in a free-text case definition. Second, the user revises the set of medical concepts by adding or removing concepts, or expanding them to related concepts that are more general or more specific. Finally, the selected concepts are projected to codes from the targeted coding vocabularies. We evaluated the application by comparing codes that were automatically generated from case definitions by applying CodeMapper's concept identification and successive concept expansion, with reference codes that were manually created in a previous epidemiological study. Automated concept identification alone had a sensitivity of 0.246 and positive predictive value (PPV) of 0.420 for reproducing the reference codes. Three successive steps of concept expansion increased sensitivity to 0.953 and PPV to 0.616. Automatic concept identification in the case definition alone was insufficient to reproduce the reference codes, but CodeMapper's operations for concept expansion provide an effective, efficient, and transparent way for reproducing the reference codes.


Nanoparticle sensor for label free detection of swine DNA in mixed biological samples.
We used 40 ± 5 nm gold nanoparticles (GNPs) as colorimetric sensor to visually detect swine-specific conserved sequence and nucleotide mismatch in PCR-amplified and non-amplified mitochondrial DNA mixtures to authenticate species. Colloidal GNPs changed color from pinkish-red to gray-purple in 2 mM PBS. Visually observed results were clearly reflected by the dramatic reduction of surface plasmon resonance peak at 530 nm and the appearance of new features in the 620-800 nm regions in their absorption spectra. The particles were stabilized against salt-induced aggregation upon the adsorption of single-stranded DNA. The PCR products, without any additional processing, were hybridized with a 17-base probe prior to exposure to GNPs. At a critical annealing temperature (55 °C) that differentiated matched and mismatched base pairing, the probe was hybridized to pig PCR product and dehybridized from the deer product. The dehybridized probe stuck to GNPs to prevent them from salt-induced aggregation and retained their characteristic red color. Hybridization of a 27-nucleotide probe to swine mitochondrial DNA identified them in pork-venison, pork-shad and venison-shad binary admixtures, eliminating the need of PCR amplification. Thus the assay was applied to authenticate species both in PCR-amplified and non-amplified heterogeneous biological samples. The results were determined visually and validated by absorption spectroscopy. The entire assay (hybridization plus visual detection) was performed in less than 10 min. The LOD (for genomic DNA) of the assay was 6 µg ml(-1) swine DNA in mixed meat samples. We believe the assay can be applied for species assignment in food analysis, mismatch detection in genetic screening and homology studies between closely related species.


Noise reduction in spectral CT: reducing dose and breaking the trade-off between image noise and energy bin selection.
Our purpose was to reduce image noise in spectral CT by exploiting data redundancies in the energy domain to allow flexible selection of the number, width, and location of the energy bins. Using a variety of spectral CT imaging methods, conventional filtered backprojection (FBP) reconstructions were performed and resulting images were compared to those processed using a Local HighlY constrained backPRojection Reconstruction (HYPR-LR) algorithm. The mean and standard deviation of CT numbers were measured within regions of interest (ROIs), and results were compared between FBP and HYPR-LR. For these comparisons, the following spectral CT imaging methods were used:(i) numerical simulations based on a photon-counting, detector-based CT system, (ii) a photon-counting, detector-based micro CT system using rubidium and potassium chloride solutions, (iii) a commercial CT system equipped with integrating detectors utilizing tube potentials of 80, 100, 120, and 140 kV, and (iv) a clinical dual-energy CT examination. The effects of tube energy and energy bin width were evaluated appropriate to each CT system. The mean CT number in each ROI was unchanged between FBP and HYPR-LR images for each of the spectral CT imaging scenarios, irrespective of bin width or tube potential. However, image noise, as represented by the standard deviation of CT numbers in each ROI, was reduced by 36%-76%. In all scenarios, image noise after HYPR-LR algorithm was similar to that of composite images, which used all available photons. No difference in spatial resolution was observed between HYPR-LR processing and FBP. Dual energy patient data processed using HYPR-LR demonstrated reduced noise in the individual, low- and high-energy images, as well as in the material-specific basis images. Noise reduction can be accomplished for spectral CT by exploiting data redundancies in the energy domain. HYPR-LR is a robust method for reducing image noise in a variety of spectral CT imaging systems without losing spatial resolution or CT number accuracy. This method improves the flexibility to select energy bins in the manner that optimizes material identification and separation without paying the penalty of increased image noise or its corollary, increased patient dose.


National monitoring of Ascaris suum related liver pathologies in English abattoirs: a time-series analysis, 2005-2010.
Ascaris suum is the most important internal parasite in farmed pigs world-wide. In England, the BPEX Pig Health Scheme (BPHS) monitors the prevalence of ascariosis in slaughtered finished pigs by identifying milk spots - the healing lesions caused by A. suum larvae migration through the liver. This study investigates the trend of milk spot lesions from July 2005 to December 2010 to identify the progress made by the industry in controlling this parasitic disease. For visual explorations, the monthly prevalence for milk spots was modelled using "STL", a seasonal-trend decomposition method based on locally weighted regression. Random effects binomial modelling accounting for clustering at batch level was used to test the significance of the trend and seasonality. Additionally, the differences in the milk spot prevalence trends for BPHS members (those that joined the scheme) and non-members were investigated and tested. A mean of 12,442 pigs was assessed per month (in 290 batches) across 12 pig abattoirs over the study period, from which a monthly mean of 7102 pigs (159 batches) came from BPHS members. A mild overall decrease in prevalence of milk spots over the monitored period was identified as well as a seasonal variation which showed peaks in summer and at the beginning of autumn. BPHS members maintained a lower prevalence than non-members. The results from this work illustrate ascariosis as a persistent problem in current farm production.


Patient-Specific Robot-Assisted Stroke Rehabilitation Guided by EEG - A Feasibility Study.
Multi-session robot-assisted stroke rehabilitation program requires patients to perform repetitive tasks. It is challenging for the patient to maintain concentration during training sessions. A novel intervention strategy using Electroencephalography (EEG) signals is proposed to maintain concentration during training by enhancing the engagement of stroke patients using robot-assisted multi-session rehabilitation. The approach is illustrated by applying it to one stroke patient undergoing 12 training sessions of hand motor training on the AMADEO rehabilitation device. AMADEO offers four modes of training programs of increased intensity comprising passive training, passive training with biofeedback, assistive training as well as active 2D training games. The EEG signals are measured over eight electrode sites: FC4, C4, CP4, FC3, C3, CP3, Cz, and CPz during each training day to extract movement-related cortical potential (MRCP) signals. Moreover, functional hand recovery parameters are determined using the AMADEO assessment tool. The patient's level of engagement is determined by the negative amplitude of the MRCP signal. The rehabilitation program is switched to a more intense training mode when a consistent decrease is observed in the negative amplitude of MRCP signals from the monitored electrodes. Using this approach, the rehabilitation program becomes patient-specific and adaptive. In addition, it is shown that each training mode exhibits a different recovery level of the affected hand and maximum recovery is achieved when MRCP signals indicate that the patient is actively participating in the training.


Depressive symptoms among immigrant and Canadian born mothers of preterm infants at neonatal intensive care discharge: a cross sectional study.
Mothers of preterm infants are considered at higher risk for depressive symptoms, higher than for mothers of healthy term infants. Predictors of depressive symptoms in mothers of preterm infants are not yet well established. Immigrant mothers of term infants have higher prevalence of depressive symptoms than Canadian born mothers but the relative prevalence for immigrant mothers of preterm infants is unknown. This study had two aims: (i) to investigate the prevalence of depressive symptoms in immigrant as compared to Canadian born mothers of preterm infants, and (ii) to determine what factors are associated with depressive symptoms in mothers of preterm infants. This is a multi-site, cross sectional study of mothers whose preterm infants required hospitalization in neonatal intensive care unit (NICU). Consecutive eligible mothers (N = 291) were recruited during the week prior to their infant's NICU discharge. Mothers completed a self-administered questionnaire booklet of validated psychosocial/cultural measures including the Center for Epidemiological Studies Depression Scale (CES-D), Parental Stressor Scale:NICU, General Functioning Subscale of the McMaster Family Assessment Device, Social Support Index, and Vancouver Index of Acculturation; and demographic characteristics questions. Infant characteristics included gestational age, birth weight, sex, singleton/multiple birth, and Score for Neonatal Acute Physiology-II. Immigrant mothers (N = 107), when compared to Canadian born mothers (N = 184), reported more depressive symptoms, poorer family functioning, less social support, and less mainstream acculturation. Hierarchical regression for a subsample of 271 mothers indicated that single parent status, high stress, poorer family functioning, and less social support were associated with increased depressive symptoms and accounted for 39% of the variance on the CES-D. Immigrant status did not contribute significantly to the final regression model. Immigrant mothers of preterm infants are at increased risk for depressive symptoms. For immigrant and Canadian born mothers of preterm infants hospitalized in NICU and particularly for single mothers, interventions to reduce stress and increase family functioning and social support may reduce depressive symptoms. Given the effects of depression on maternal health and functioning, such an intervention may improve child outcomes.


Unification of speaker and meaning in language comprehension: an FMRI study.
When interpreting a message, a listener takes into account several sources of linguistic and extralinguistic information. Here we focused on one particular form of extralinguistic information, certain speaker characteristics as conveyed by the voice. Using functional magnetic resonance imaging, we examined the neural structures involved in the unification of sentence meaning and voice-based inferences about the speaker's age, sex, or social background. We found enhanced activation in the inferior frontal gyrus bilaterally (BA 45/47) during listening to sentences whose meaning was incongruent with inferred speaker characteristics. Furthermore, our results showed an overlap in brain regions involved in unification of speaker-related information and those used for the unification of semantic and world knowledge information [inferior frontal gyrus bilaterally (BA 45/47) and left middle temporal gyrus (BA 21)]. These findings provide evidence for a shared neural unification system for linguistic and extralinguistic sources of information and extend the existing knowledge about the role of inferior frontal cortex as a crucial component for unification during language comprehension.


The stability of amoxicillin trihydrate and potassium clavulanate combination in aqueous solutions.
The effect of various environmental factors on the stability of aqueous solutions of amoxicillin-clavulanic acid combination in a veterinary water-soluble powder product was investigated. In the swine industry, the combination is administered via the drinking water, where both substances are quickly decomposed depending on several environmental factors. The degradation rate of the substances was determined in solutions of different water hardness levels (German hardness of 2, 6 and 10) and pH values (3.0, 7.0 and 10.0), and in troughs made of different materials (metal or plastic). Increasing the water hardness decreased the stability of both substances, amoxicillin being more stable at each hardness value than clavulanate. Amoxicillin trihydrate proved to be most stable at an acidic pH, while increasing the pH decreased its stability (P < 0.05). Maximum stability of potassium clavulanate was experienced at neutral pH, while its decomposition rate was significantly higher at acidic and alkaline pH values (P < 0.01). The stability of the amoxicillin-clavulanic acid combination depends mainly on the less stable clavulanate, although the effect of metallic ions significantly increased the decomposition rate of amoxicillin, rendering it less stable in metal troughs than clavulanate (P < 0.05). Therefore, the amoxicillin-clavulanic acid combination should be administered to the animals in soft water, at neutral pH and in plastic troughs.


Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse.
The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Japan (JSTP), Europe (ESTP), Great Britain (BSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The primary purpose of this publication is to provide a standardized nomenclature for characterizing lesions observed in the cardiovascular (CV) system of rats and mice commonly used in drug or chemical safety assessment. The standardized nomenclature presented in this document is also available electronically for society members on the internet (http://goreni.org). Accurate and precise morphologic descriptions of changes in the CV system are important for understanding the mechanisms and pathogenesis of those changes, differentiation of natural and induced injuries and their ultimate functional consequence. Challenges in nomenclature are associated with lesions or pathologic processes that may present as a temporal or pathogenic spectrum or when natural and induced injuries share indistinguishable features. Specific nomenclature recommendations are offered to provide a consistent approach.


Identifying Dysfunctional Cortex: Dissociable Effects of Stroke and Aging on Resting State Dynamics in MEG and fMRI.
Spontaneous signals in neuroimaging data may provide information on cortical health in disease and aging, but the relative sensitivity of different approaches is unknown. In the present study, we compared different but complementary indicators of neural dynamics in resting-state MEG and BOLD fMRI, and their relationship with blood flow. Participants included patients with post-stroke aphasia, age-matched controls, and young adults. The complexity of brain activity at rest was quantified in MEG using spectral analysis and multiscale entropy (MSE) measures, whereas BOLD variability was quantified as the standard deviation (SDBOLD), mean squared successive difference (MSSD), and sample entropy of the BOLD time series. We sought to assess the utility of signal variability and complexity measures as markers of age-related changes in healthy adults and perilesional dysfunction in chronic stroke. The results indicate that reduced BOLD variability is a robust finding in aging, whereas MEG measures are more sensitive to the cortical abnormalities associated with stroke. Furthermore, reduced complexity of MEG signals in perilesional tissue were correlated with hypoperfusion as assessed with arterial spin labeling (ASL), while no such relationship was apparent with BOLD variability. These findings suggest that MEG signal complexity offers a sensitive index of neural dysfunction in perilesional tissue in chronic stroke, and that these effects are clearly distinguishable from those associated with healthy aging.


Metastatic neuroendocrine tumor of the esophagus with features of medullary thyroid carcinoma.
A 41-year-old female presented with a pedunculated mass in the upper esophagus and bilateral lymphadenopathy. Biopsies suggested a neuroendocrine tumor, possibly carcinoid, and ensuing imaging revealed cervical lymph node metastases. The esophageal mass was removed endoscopically and discovered by pathologists to closely resemble medullary thyroid carcinoma (MTC) on immunohistochemistry staining. Following surgery, further work up demonstrated very high serum calcitonin levels, suggestive of medullary thyroid carcinoma, however the thyroid gland was normal on ultrasound. The patient underwent a neck dissection to remove the lymph node metastases and subsequently her calcitonin levels dropped to 0 ng/mL, indicating remission. It appears that the primary tumor was not in the thyroid, but in the cervical esophagus. The thyroid has appeared normal on multiple ultrasounds without any detectable nodules or masses. This is quite a unique case because this patient presented with a tumor resembling medullary carcinoma of the thyroid that presented as a pedunculated mass in the cervical esophagus. The actual final diagnosis of this mass in the cervical esophagus was neuroendocrine tumor (NET), consistent with a carcinoid tumor, not ectopic MTC. This case report highlights that calcitonin-secreting tumors outside the thyroid should not lead to erroneous recommendations for thyroidectomy.


Hybrid, silica-coated, Janus-like plasmonic-magnetic nanoparticles.
Hybrid plasmonic-magnetic nanoparticles possess properties that are attractive in bioimaging, targeted drug delivery, in vivo diagnosis and therapy. The stability and toxicity, however, of such nanoparticles challenge their safe use today. Here, biocompatible, SiO2-coated, Janus-like Ag/Fe2O3 nanoparticles are prepared by one-step, scalable flame aerosol technology. A nanothin SiO2 shell around these multifunctional nanoparticles leaves intact their morphology, magnetic and plasmonic properties but minimizes the release of toxic Ag+ ions from the nanosilver surface and its direct contact with live cells. Furthermore, this silica shell hinders flocculation and allows for easy dispersion of such nanoparticles in aqueous and biological buffer (PBS) solutions without any extra functionalization step. As a result, these hybrid particles exhibited no cytotoxicity during bioimaging and remained stable in suspension with no signs of agglomeration and sedimentation or settling. Their performance as biomarkers was explored by selectively binding them with live tagged Raji and HeLa cells enabling their detection under dark-filed illumination. Therefore, these SiO2-coated Ag/Fe2O3 nanoparticles do not exhibit the limiting physical properties of each individual component but retain their desired functionalities facilitating thus, the safe use of such hybrid nanoparticles in bio-applications.


The factor structure and psychometric properties of the Spanish version of the Mayer-Salovey-Caruso Emotional Intelligence Test.
This research examined evidence regarding the reliability and validity of scores on the Spanish version of the Mayer-Salovey-Caruso Emotional Intelligence Test, Version 2.0 (MSCEIT; Mayer, Salovey, & Caruso, 2002). In Study 1, we found a close convergence of the Spanish consensus scores and the general and expert consensus scores determined with Mayer, Salovey, Caruso, and Sitarenios (2003) data. The MSCEIT also demonstrated adequate evidence of reliability of test scores as estimated by internal consistency and test-retest correlation after 12 weeks. Confirmatory factor analysis supported a 3-level higher factor model with 8 manifest variables (task scores), 4 first-level factors (corresponding to the 4-branch model of Mayer & Salovey [1997], with 2 tasks for each branch), 2 second-level factors (experiential and strategic areas, with 2 branches for each area), and 1 third-level factor (overall emotional intelligence [EI]), and multigroup analyses supported MSCEIT cross-gender invariance. Study 2 found evidence for the discriminant validity of scores on the MSCEIT subscales, which were differentially related to personality and self-reported EI. Study 3 provided evidence of the incremental validity of scores on the MSCEIT, which added significant variance to the prospective prediction of psychological well-being after controlling for personality traits. The psychometric properties of the Spanish MSCEIT are similar to those of the original English version, supporting its use for assessing emotional abilities in the Spanish population. (PsycINFO Database Record


Administration of docosahexaenoic acid influences behavior and plasma catecholamine levels at times of psychological stress.
The purpose of the present research was to clarify the effect of docosahexaenoic acid (DHA) intake on behavior and plasma catecholamines (CA). In Study 1, 42 students took either DHA-rich oil capsules containing 1.5-1.8 g DHA/d or control oil capsules containing 97% soybean oil plus 3% of another fish oil for 3 mon in a double-blind fashion. They took a psychological test (PF Study) at the start and end of the study. This study started at the end of summer vacation and ended just before the final exams. In the control group, external aggression (aggression against others) in PF Study was significantly increased at the end of the study as compared with that measured at the start (+8.9%), whereas it was not significantly changed in the DHA group (-1.0%). In a similar double-blind study (Study 2), we measured external aggression under nonstressful conditions. External aggression slightly decreased in the control group, whereas there were no significant changes in the DHA group. In Study 3 with 14 students, plasma CA were measured at the start and end of capsule administration period of 2 mon. Subjects were under continuous stress of the final exams that lasted throughout the whole study period. The ratio of plasma epinephrine to norepinephrine concentrations was significantly increased in the DHA group (78%), whereas it stayed at the same level in the control group. In Study 4, mice were fed either DHA-deficient diet or -sufficient diet for 4 wk, and their rearing frequency (an anxiety index) was measured. In the DHA-sufficient group, the rearing frequency was significantly less than in the other group. These effects of DHA intake may be applied to people in an attempt to ameliorate stress-related diseases.


Comparative transcriptome profiling of two Tibetan wild barley genotypes in responses to low potassium.
Potassium (K) deficiency is one of the major factors affecting crop growth and productivity. Development of low-K tolerant crops is an effective approach to solve the nutritional deficiency in agricultural production. Tibetan annual wild barley is rich in genetic diversity and can grow normally under poor soils, including low-K supply. However, the molecular mechanism about low K tolerance is still poorly understood. In this study, Illumina RNA-Sequencing was performed using two Tibetan wild barley genotypes differing in low K tolerance (XZ153, tolerant and XZ141, sensitive), to determine the genotypic difference in transcriptome profiling. We identified a total of 692 differentially expressed genes (DEGs) in two genotypes at 6 h and 48 h after low-K treatment, including transcription factors, transporters and kinases, oxidative stress and hormone signaling related genes. Meanwhile, 294 low-K tolerant associated DEGs were assigned to transporter and antioxidant activities, stimulus response, and other gene ontology (GO), which were mainly involved in starch and sucrose metabolism, lipid metabolism and ethylene biosynthesis. Finally, a hypothetical model of low-K tolerance mechanism in XZ153 was presented. It may be concluded that wild barley accession XZ153 has a higher capability of K absorption and use efficiency than XZ141 under low K stress. A rapid response to low K stress in XZ153 is attributed to its more K uptake and accumulation in plants, resulting in higher low K tolerance. The ethylene response pathway may account for the genotypic difference in low-K tolerance.


Mercury and Selenium - A Review on Aspects Related to the Health of Human Populations in the Amazon.
Mercury (Hg) toxicity is governed by cellular thiol compounds and its capacity to generate reactive oxygen radicals and oxidative stress. Selenium (Se) plays a key role in the prevention of the toxic effects of Hg by modulating the activity of several Se-dependent enzymes, including glutathione peroxidase (GSH-Px). In addition, dietary Se can reduce Hg toxicity by directly interacting with either Hg(II) or methylmercury (MeHg) to form inert products, such as HgSe complexes.. Although experimental and environmental data have indicated a protective role for selenium against Hg toxicity, human data are more limited and somewhat conroversial In the Amazon Region of Brazil, Hg pollution is rampant as a result of gold (Au) mining and other anthropogenic factors, leading to pervasive release of large quantities of metallic Hg0 into the environment. Exposure to Hg in this region is associated with direct occupational exposure in the gold mining industry, as well as consumption by in inhabitants of riverside communities of a diet rich in MeHg-contaminated fish. Human exposure to MeHg in the Amazon through the diet has been monitored by measuring Hg and MeHg in hair samples. In this paper, we review the environmental contamination of Hg in the Amazon and detail human exposures in populations of this region. We conclude with a brief synopsis on Se levels in the Amazon population and provide a brief review of data available on the interaction between Hg and Se in this region. Overall, the literature supports the notion that low environmental Se is linked to susceptibility to Hg toxicity and that Se levels could be used as a bioindicator to monitor the health of Hg exposed subjects. However, in light of the limited human data on this subject, further epidemiological studies are needed to clarify how changes in Se levels modify the toxicity of environmental Hg.


Phosphorylation of presenilin-2 regulates its cleavage by caspases and retards progression of apoptosis.
Mutations within the Presenilin-2 (PS-2) gene are associated with early onset familial Alzheimer's disease. The gene encodes a polytopic transmembrane protein that undergoes endoproteolytic processing resulting in the generation of N-terminal and C-terminal fragments (CTFs). PS-2 is also cleaved by proteases of the caspase family during apoptotic cell death. CTFs of PS-2 were shown to inhibit apoptosis, suggesting an important role in the regulation of programmed cell death. Recently, we found that the CTF of PS-2 is phosphorylated in vivo. We mapped the in vivo phosphorylation sites of PS-2 to serine residues 327 and 330, which are localized immediately adjacent to the cleavage sites of caspases after aspartate residues 326 and 329. Phosphorylation of PS-2 inhibits its cleavage by caspase-3. This effect can be mimicked by substitutions of serines 327 and 330 by aspartate or glutamate. In addition, the uncleavable form of PS-2 CTF was found to enhance its antiapoptotic properties, leading to a slower progression of apoptosis. These results demonstrate that PS-2 cleavage as well as its function in apoptosis can be regulated by protein phosphorylation. Alterations in the phosphorylation of PS-2 may therefore promote the pathogenesis of AD by affecting the susceptibility of neurons to apoptotic stimuli.


Personality psychology: lexical approaches, assessment methods, and trait concepts reveal only half of the story--why it is time for a paradigm shift.
This article develops a comprehensive philosophy-of-science for personality psychology that goes far beyond the scope of the lexical approaches, assessment methods, and trait concepts that currently prevail. One of the field's most important guiding scientific assumptions, the lexical hypothesis, is analysed from meta-theoretical viewpoints to reveal that it explicitly describes two sets of phenomena that must be clearly differentiated: 1) lexical repertoires and the representations that they encode and 2) the kinds of phenomena that are represented. Thus far, personality psychologists largely explored only the former, but have seriously neglected studying the latter. Meta-theoretical analyses of these different kinds of phenomena and their distinct natures, commonalities, differences, and interrelations reveal that personality psychology's focus on lexical approaches, assessment methods, and trait concepts entails a) erroneous meta-theoretical assumptions about what the phenomena being studied actually are, and thus how they can be analysed and interpreted, b) that contemporary personality psychology is largely based on everyday psychological knowledge, and c) a fundamental circularity in the scientific explanations used in trait psychology. These findings seriously challenge the widespread assumptions about the causal and universal status of the phenomena described by prominent personality models. The current state of knowledge about the lexical hypothesis is reviewed, and implications for personality psychology are discussed. Ten desiderata for future research are outlined to overcome the current paradigmatic fixations that are substantially hampering intellectual innovation and progress in the field.


Proprioception and muscle torque deficits in children with hypermobility syndrome.
Sensorimotor deficits such as impaired joint proprioception and muscle weakness have been found in association with hypermobility syndrome (HMS) in adults. HMS is more common in children than adults, yet such deficits have not been adequately investigated in paediatric populations. It is therefore uncertain as to what sensorimotor deficits are present in children with HMS. This study investigated knee joint proprioception and muscle torque in healthy children and those with HMS. Thirty-seven healthy children (mean age +/- s.d. = 11.5 +/- 2.6 yrs) and 29 children with HMS (mean age +/- s.d. = 11.9 +/- 1.8 yrs) participated in this study. Knee joint kinaesthesia (JK) and joint position sense (JPS) were measured, with the absolute angular error (AAE) calculated as the absolute difference between the target and perceived angles. Knee extensor and flexor muscle torque was assessed and normalized to body mass. Mann-Whitney U-tests were performed to compare JK, JPS and muscle torque between the two groups. Children with HMS had significantly poorer JK and JPS compared with the controls (both P < 0.001). Knee extensor and flexor muscle torque was also significantly reduced (both P < 0.001) in children with HMS compared with their healthy counterparts. The findings of this study demonstrated that knee joint proprioception was impaired in children with HMS. They also had weaker knee extensor and flexor muscles than healthy controls. Clinicians should be aware of these identified deficits in children with HMS, and a programme of proprioceptive training and muscle strengthening may be indicated.


Online and offline effects of cerebellar transcranial direct current stimulation on motor learning in healthy older adults: a randomized double-blind sham-controlled study.
The aim of this randomized double blinded sham-controlled study was to determine the effect of cerebellar anodal transcranial direct current stimulation (a-tDCS) on online and offline motor learning in healthy older individuals. Thirty participants were randomly assigned in experimental (n = 15) or sham tDCS (n = 15) groups. Participants in experimental group received 2 mA cerebellar a-tDCS for 20 min. However, the tDCS was turned off after 30 seconds in sham group. Response time (RT) and error rate (ER) in serial RT test were assessed before, during 35 minutes and 48 h after the intervention. Reduction of RT and ER following the intervention session was considered as short-term (35 min post intervention) and long-term offline learning (48 h post intervention), respectively. Online RT and ER reduction were similar in both groups (P > 0.05). RT was significantly reduced 48 hours post intervention in cerebellar a-tDCS group (P = 0.03). Moreover, RT was significantly increased after 35 minutes and 48 hours in sham tDCS group (P = 0.03, P = 0.007), which indicates a lack of short-term and long-term offline learning in older adults. A-tDCS on cerebellar region produced more short-term and long-term offline improvement in RT (P = 0.014, P = 0.01) compared to sham tDCS. In addition, online, short-term and long-term (48 h) offline error reduced in cerebellar a-tDCS as compared to sham-control group, although this reduction was not significant (P > 0.05). A deficit suggests that a direct comparison to a younger group was made. The findings suggested that cerebellar a-tDCS might be useful for improvement of offline motor learning in older individuals.


Skin temperature, sleep, and vigilance.
A large number of studies have shown a close association between the 24-hour rhythms in core body temperature and sleep propensity. More recently, studies have have begun to elucidate an intriguing association of sleep with skin temperature as well. The present chapter addresses the association of sleep and alertness with skin temperature. It discusses whether the association could reflect common underlying drivers of both sleep propensity and skin vasodilation; whether it could reflect efferents of sleep-regulating brain circuits to thermoregulatory circuits; and whether skin temperature could provide afferent input to sleep-regulating brain circuits. Sleep regulation and concomitant changes in skin temperature are systematically discussed and three parallel factors suggested: a circadian clock mechanism, a homeostatic hourglass mechanism, and a third set of sleep-permissive and wake-promoting factors that gate the effectiveness of signals from the clock and hourglass in the actual induction of sleep or maintenance of alert wakefulness. The chapter moreover discusses how the association between skin temperature and arousal can change with sleep deprivation and insomnia. Finally it addresses whether the promising laboratory findings on the effects of skin temperature manipulations on vigilance can be applied to improve sleep in everyday life.


Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2.
Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor-positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone. Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion. Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P < .0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only). These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor-positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy.


Analysis of orientations of collagen fibers by novel fiber-tracking software.
Recent evidence supports the notion that biological functions of extracellular matrix (ECM) are highly correlated to not only its composition but also its structure. This article integrates confocal microscopy imaging and image-processing techniques to analyze the microstructural properties of ECM. This report describes a two- and three-dimensional fiber middle-line tracing algorithm that may be used to quantify collagen fibril organization. We utilized computer simulation and statistical analysis to validate the developed algorithm. These algorithms were applied to confocal images of collagen gels made with reconstituted bovine collagen type I, to demonstrate the computation of orientations of individual fibers.


Ultralow-resolution ab initio phasing of filamentous proteins: crystals from a six-Ig fragment of titin as a case study.
Low-resolution diffraction data (resolution below 12 angstroms) from crystals of a filamentous six-Ig fragment of titin, I65-I70, were used in ab initio phasing with the aim of calculating its lattice packing and molecular envelope. Filamentous molecules, characterized by marked anisometry and idiosyncratic crystal lattices, have not been addressed before using this methodology. In this study, low-resolution phasing (19-122 angstroms) successfully identified the region of the unit cell occupied by the molecule. Phase extension to a higher resolution (12 angstroms) yielded regions of high density that corresponded either to the positions of individual Ig domains or to zones of dense intermolecular contacts, hindering the identification of individual domains and the interpretation of electron-density maps in terms of a molecular model. This problem resulted from the acutely uneven packing of the molecules in the crystal and it was further accentuated by the presence of partially disordered regions in the molecule. Addition of low-resolution reflections with phases computed ab initio to those obtained experimentally using MIRAS improved the initial electron-density maps of the atomic model, demonstrating the generic utility of low-resolution phases for the structure-elucidation process, even when individual molecules cannot be resolved in the lattice.


Structural similarity among Escherichia coli FtsW and RodA proteins and Bacillus subtilis SpoVE protein, which function in cell division, cell elongation, and spore formation, respectively.
The Escherichia coli cell division gene ftsW (2 min) was cloned and sequenced. It encodes a hydrophobic protein(s) with 414 and/or 384 amino acid residues. The deduced amino acid sequence and the hydropathy profile of the protein showed high homology with those of the E. coli RodA protein functioning in determination of the cell shape and the Bacillus subtilis SpoVE protein functioning in spore formation. Probably similar functional membrane proteins are involved in these three cell cycle process.


Self-reported weight at birth predicts measures of femoral size but not volumetric BMD in eldery men: MrOS.
The mechanism whereby poor intrauterine growth increases risk of adult hip fracture is unclear. We report the association between birth weight and proximal femoral geometry and density in community-dwelling elderly men. We used self-reported birth weight, measured adult height and weight and proximal femoral quantitative computed tomography (QCT) measurements of femoral neck axis length, cross-sectional area, and volumetric BMD (vBMD) among the participants in the Osteoporotic Fractures in Men (MrOS), a cohort study of community-dwelling US men aged 65 and older. We compared men with birth weight <7 pounds (lower birth weight [LBW]; n = 501) and ≥ 9 pounds (higher birth weight [HBW]; n = 262) with those weighing 7-8.9 pounds (medium birth weight [MBW], referent group; n = 1068) using linear regression adjusting for current age, height, and BMI. The mean age of the 1831 men who had both birth weight and QCT measurements was 73 years (SD 5.9). Compared with the referent MBW, HBW men had concordantly longer femoral neck (+0.16 SD; p = .028) and cross-sectional area (+0.24 SD, p = .001). LBW men had a smaller cross-sectional (-0.26 SD, p < .001) but longer femoral neck for their height (+0.11 SD, p = .05). Neither cortical nor trabecular vBMD at the femoral neck was associated with birth weight. These findings support the hypothesis that the skeletal envelope, but not density, is set, in part, at birth. Further research exploring the association between early developmental factors and lifetime fracture risk is needed and may inform primary preventative strategies for fracture prevention.


The ITP syndrome: pathogenic and clinical diversity.
Immune thrombocytopenia (ITP) is mediated by platelet autoantibodies that accelerate platelet destruction and inhibit their production. Most cases are considered idiopathic, whereas others are secondary to coexisting conditions. Insights from secondary forms suggest that the proclivity to develop platelet-reactive antibodies arises through diverse mechanisms. Variability in natural history and response to therapy suggests that primary ITP is also heterogeneous. Certain cases may be secondary to persistent, sometimes inapparent, infections, accompanied by coexisting antibodies that influence outcome. Alternatively, underlying immune deficiencies may emerge. In addition, environmental and genetic factors may impact platelet turnover, propensity to bleed, and response to ITP-directed therapy. We review the pathophysiology of several common secondary forms of ITP. We suggest that primary ITP is also best thought of as an autoimmune syndrome. Better understanding of pathogenesis and tolerance checkpoint defects leading to autoantibody formation may facilitate patient-specific approaches to diagnosis and management.


Adiponectin aggravates bone erosion by promoting osteopontin production in synovial tissue of rheumatoid arthritis.
We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). The exact mechanism of AD in promoting joint destruction remains unclear. Osteopontin (OPN) is required for osteoclast recruitment. We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. This study aimed to evaluate a novel role for AD in RA. The serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA). AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue. Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively. Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co-culture system. Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing. The expression levels of OPN and integrin αvβ3 in the ankle joint tissues of the mice were examined by double immunofluorescence. Our results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum. The AD distribution was coincident with that of OPN in the RA synovial tissue. AD stimulation of RASFs increased OPN production in a dose-dependent manner. AD-treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN. Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice. When bound to integrin αvβ3, OPN functions as a mediator of AD and osteoclasts. Our study provides new evidence of AD involvement in bone erosion. AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion. These data highlight AD as a novel target for RA treatment.


Baseline Sensitivity of Pyraclostrobin and Toxicity of SHAM to Sclerotinia sclerotiorum.
Sclerotinia sclerotiorum is a cosmopolitan plant pathogen notable for its wide host range. The quinone outside inhibitor (QoI) fungicide pyraclostrobin has not been registered for control of S. sclerotiorum in China. In this study, baseline sensitivity of pyraclostrobin was established based on effective concentration for 50% inhibition of mycelial growth (EC50) values of 153 isolates of S. sclerotiorum collected from five provinces of China and toxicity of alternative oxidase inhibitor salicylhydroxamic acid (SHAM) to S. sclerotiorum was determined. Results showed that the frequency distribution of EC50 values of the 153 isolates was unimodal but with a right-hand tail. The mean EC50 value was 0.1027 μg/ml and the range of EC50 values was 0.0124 to 0.6324 μg/ml. Applied as a preventive fungicide in pot experiments, pyraclostrobin at 5, 15, and 45 μg/ml provided control efficacies of 61, 77, and 100%, respectively. There was no positive cross-resistance between pyraclostrobin and carbendazim or dimethachlon. EC50 values for SHAM against four isolates of S. sclerotiorum were 44.4, 51.8, 54.4, and 68.7 μg/ml. SHAM at 20 μg/ml could significantly increase not only the inhibitory effect of pyraclostrobin on mycelial growth on potato dextrose agar media but also the control efficacy in planta. These results indicated that SHAM should not be added into artificial media in in vitro assay of S. sclerotiorum sensitivity to pyraclostrobin. This has broad implications for assay of sensitivity of fungal pathogen to QoI fungicides.


Wolf (Canis lupus) hybrids highlight the importance of human-directed play behavior during domestication of dogs (Canis familiaris).
The domestication of animals and plants offers an exceptional opportunity to study evolutionary adaptations. In particular, domesticated animals display several behavioral alterations, including increased sociability and decreased fearfulness and aggression, when compared with their wild ancestors. However, studies quantifying simultaneous changes in multiple behaviors during domestication are lacking. Moreover, the role of human-directed play behavior has been largely neglected when studying the domestication process. Here we address these issues by examining behavioral changes during the domestication of the dog (Canis familiaris) from the gray wolf (Canis lupus) using a standardized behavioral test applied to wolf hybrids and several dog breeds. Contrary to expectations, our study provides little support for collective behavioral alterations. Specifically, although we found that wolf hybrids were less playful and overall more fearful than dogs, we did not detect any differences in sociability or aggression between wolf hybrids and dog breeds. Instead, our results suggest that behavioral alterations during domestication do not necessarily occur in concert and point to an important, but previously overlooked, role of selection on play behavior directed at humans during the domestication of dogs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Second-order moments of an electromagnetic Gaussian Schell-model beam in a uniaxial crystal.
We derive the analytical expressions for the second-order moments of an electromagnetic Gaussian Schell-model (EGSM) beam propagating in a uniaxial crystal. With the help of the derived formulas, we study the evolution properties of the propagation factor, the effective radius of curvature and the Rayleigh range of an EGSM beam in a uniaxial crystal. It is found that the evolution properties of an EGSM beam in a uniaxial crystal are much different from its evolution properties in free space and are closely determined by the initial beam parameters and the parameters of the uniaxial crystal. The uniaxial crystal provides one way for modulating the properties of an EGSM beam.


A comparative study of lactic acid 10% and ammonium lactate 12% lotion in the treatment of foot xerosis.
Xerotic skin is a pattern of reaction to a variety of disorders that have abnormalities of desquamation in common. This double-blind, randomized clinical trial investigated the effect of Lactinol (Pedinol Pharmaceuticals, Farmingdale, New York) versus Lac-Hydrin 12% (Bristol-Myers Squibb, Princeton, New Jersey) lotion in mild to moderate foot xerosis. Clinical assessment of xerosis was performed at baseline visit, and the designated sites were evaluated at 2 and 4 weeks after treatment began. Of the 53 patients enrolled, 18 were excluded from analysis. Although both treatment groups had significantly improved xerosis scores after 2 and 4 weeks of treatment, no statistically significant difference was observed. Of the 44% of patients who did express a preference, 72% preferred Lactinol, which may account for the 20% increase in its overall use in the study.


Effect of a new desensitizing material on human dentin permeability.
Resin-modified glass ionomers (RMGI) have demonstrated clinical success providing immediate and long-term relief from root sensitivity. RMGIs have been recently introduced as paste-liquid systems for convenience of clinical usage. The objective of this study was to measure the ability of a new paste-liquid RMGI to reduce fluid flow through human dentin, compared to an established single-bottle nanofilled total etch resin adhesive indicated for root desensitization. Dentin permeability was measured on human crown sections on etched dentin, presenting a model for the exposed tubules typical of root sensitivity, and permitting measurement of the maximum permeability. In the first two groups, the etched dentin was coated with either the RMGI or adhesive, and permeability measured on the coated dentin. In a third group, a smear layer was created on the dentin with sandpaper, then the specimens were coated with the RMGI; permeability was measured on the smeared and coated dentin. Specimens from each group were sectioned and examined via scanning electron microscopy (SEM). Both the resin adhesive and the new paste-liquid RMGI protective material significantly reduced fluid flow through dentin, and exhibited excellent seal on dentin with either open tubules or smear-layer occluded tubules. The RMGI infiltrated the smear layer with resin during placement, penetrated dentin tubules, and formed resin tags. The RMGI was equivalent to the adhesive in its ability to reduce fluid flow and seal dentin. It is therefore concluded that the new RMGI and the adhesive show the potential to offer excellent sensitivity relief on exposed root dentin.


Frames of reference for the light-from-above prior in visual search and shape judgements.
Faced with highly complex and ambiguous visual input, human observers must rely on prior knowledge and assumptions to efficiently determine the structure of their surroundings. One of these assumptions is the 'light-from-above' prior. In the absence of explicit light-source information, the visual system assumes that the light-source is roughly overhead. A simple, low-cost strategy would place this 'light-from-above' prior in a retinal frame of reference. A more complex, but optimal strategy would be to assume that the light-source is gravitationally up, and compensate for observer orientation. Evidence to support one or other strategy from psychophysics and neurophysiology has been mixed. This paper pits the gravitational and retinal frames against each other in two different visual tasks that relate to the light-from-above prior. In the first task, observers had to report the presence or absence of a target where distractors and target were defined purely by shading. In the second task, observers made explicit shape judgements of similar stimuli. The orientation of the stimuli varied across trials and the observer's head was fixed at 0, +/-45 or +/-60 degrees . In both tasks the retinal frame of reference dominated. Visual search behaviour with shape-from-shading stimuli (SFS) was modulated purely by stimulus orientation relative to the retina. However, the gravitational frame of reference had a significant effect on shape judgements, with a 30% correction for observer orientation. In other words, shading information is processed quite differently depending on the demands of the current task. When a 'quick and dirty' representation is required to drive fast, efficient search, that is what the visual system provides. In contrast, when the task is to explicitly estimate shape, extra processing to compensate for head orientation precedes the perceptual judgment. These results are consistent with current neurophysiological data on SFS if we re-frame compensation for observer orientation as a cue-combination problem.


EPICO PROJECT. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non- neutropenic critically ill adult patients.
Although there has been an improved management of Invasive Candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches. We sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with Invasive Candidiasis. Prospective Spanish survey reaching consensus by the Delphi technique, anonymously conducted by electronic e-mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including Intensivists, Anesthesiologists, Microbiologists, Pharmacologists and Infectious Disease Specialists, responding to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations. In the first term, 20 recommendations were preselected (Epidemiology 4, Scores 3, Diagnostic tools 4, TREATMENT 6 and De-escalation approaches 3). After the second round, the following 12 were validated: Think about Candidiasis in your ICU and do not forget that non-albicans species also exist. DIAGNOSTIC TOOLS: Blood cultures should be performed under suspicion every 2-3 days and, if positive, every 3 days until obtaining the first negative result. Obtain sterile fluid and tissue, if possible (direct examination of the sample is important). Use nonculture based methods of microbiological tools, whenever possible. Determination of antifungal susceptibility is mandatory. SCORES: As screening tool, use the Candida Score and determine multicolonization in high risk patients. Start early. Choose Echinocandins. Withdraw the catheter. Fundoscopy is needed. DE-ESCALATION: Only applied when knowing susceptibility determinations and after 3 days of clinical stability. The higher rate of agreement was achieved in the optimization of microbiological tools and the withdrawal of the catheter, whereas the lower rate corresponded to de-escalation therapy and the use of scores. The management of invasive candidiasis in ICU patients requires the application of a broad range of knowledge and skills that our summarized in our recommendations. These recommendations may help to identify the potential patients, standardize their global management and improve their outcomes, based on the DELPHI methodology.


How Do Ancestral Traits Shape Family Trees Over Generations?
Whether and how does the structure of family trees differ by ancestral traits over generations? This is a fundamental question regarding the structural heterogeneity of family trees for the multi-generational transmission research. However, previous work mostly focuses on parent-child scenarios due to the lack of proper tools to handle the complexity of extending the research to multi-generational processes. Through an iterative design study with social scientists and historians, we develop TreeEvo that assists users to generate and test empirical hypotheses for multi-generational research. TreeEvo summarizes and organizes family trees by structural features in a dynamic manner based on a traditional Sankey diagram. A pixel-based technique is further proposed to compactly encode trees with complex structures in each Sankey Node. Detailed information of trees is accessible through a space-efficient visualization with semantic zooming. Moreover, TreeEvo embeds Multinomial Logit Model (MLM) to examine statistical associations between tree structure and ancestral traits. We demonstrate the effectiveness and usefulness of TreeEvo through an in-depth case-study with domain experts using a real-world dataset (containing 54,128 family trees of 126,196 individuals).


Expressed sequence tags from the flower pathogen Claviceps purpurea.
SUMMARY The ascomycete Claviceps purpurea (ergot) is a biotrophic flower pathogen of rye and other grasses. The deleterious toxic effects of infected rye seeds on humans and grazing animals have been known since the Middle Ages. To gain further insight into the molecular basis of this disease, we generated about 10 000 expressed sequence tags (ESTs)-about 25% originating from axenic fungal culture and about 75% from tissues collected 6-20 days after infection of rye spikes. The pattern of axenic vs. in planta gene expression was compared. About 200 putative plant genes were identified within the in planta library. A high percentage of these were predicted to function in plant defence against the ergot fungus and other pathogens, for example pathogenesis-related proteins. Potential fungal pathogenicity and virulence genes were found via comparison with the pathogen-host interaction database (PHI-base; http://www.phi-base.org) and with genes known to be highly expressed in the haustoria of the bean rust fungus. Comparative analysis of Claviceps and two other fungal flower pathogens (necrotrophic Fusarium graminearum and biotrophic Ustilago maydis) highlighted similarities and differences in their lifestyles, for example all three fungi have signalling components and cell wall-degrading enzymes in their arsenal. In summary, the analysis of axenic and in planta ESTs yielded a collection of candidate genes to be evaluated for functional roles in this plant-microbe interaction.


A pilot evaluation of whole blood finger-prick sampling for point-of-care HIV viral load measurement: the UNICORN study.
There is a global need for HIV viral load point-of-care (PoC) assays to monitor patients receiving antiretroviral therapy. UNICORN was the first study of an off-label protocol using whole blood finger-prick samples tested with and without a simple three minute spin using a clinic-room microcentrifuge. Two PoC assays were evaluated in 40 HIV-positive participants, 20 with detectable and 20 with undetectable plasma viral load (pVL) (<20 copies/ml). Using 100 µl finger-prick blood samples, the Cepheid Xpert HIV-1 Viral Load and HIV-1 Qual cartridges were compared with laboratory pVL assessment (TaqMan, Roche). For participants with undetectable viraemia by TaqMan, there was poor concordance without centrifugation with the TaqMan platform with only 40% 'undetectable' using Xpert VL and 25% 'not detected' using the Qual assay. After a 3 minute spin, 100% of samples were undetectable using either assay, showing full concordance with the TaqMan assay. Defining a lower limit of detection of 1000 copies/ml when including a spin, there was 100% concordance with the TaqMan platform with strong correlation (rho 0.95 and 0.94; p < 0.0001 for both assays). When including a simple microcentrifugation step, finger-prick PoC testing was a quick and accurate approach for assessing HIV viraemia, with excellent concordance with validated laboratory approaches.


Happens in the best of subfamilies: establishment and repeated replacements of co-obligate secondary endosymbionts within Lachninae aphids.
Virtually all aphids maintain an obligate mutualistic symbiosis with bacteria from the Buchnera genus, which produce essential nutrients for their aphid hosts. Most aphids from the Lachninae subfamily have been consistently found to house additional endosymbionts, mainly Serratia symbiotica. This apparent dependence on secondary endosymbionts was proposed to have been triggered by the loss of the riboflavin biosynthetic capability by Buchnera in the Lachninae last common ancestor. However, an integral large-scale analysis of secondary endosymbionts in the Lachninae is still missing, hampering the interpretation of the evolutionary and genomic analyses of these endosymbionts. Here, we analysed the endosymbionts of selected representatives from seven different Lachninae genera and nineteen species, spanning four tribes, both by FISH (exploring the symbionts' morphology and tissue tropism) and 16S rRNA gene sequencing. We demonstrate that all analysed aphids possess dual symbiotic systems, and while most harbour S. symbiotica, some have undergone symbiont replacement by other phylogenetically-distinct bacterial taxa. We found that these secondary associates display contrasting cell shapes and tissue tropism, and some appear to be lineage-specific. We propose a scenario for symbiont establishment in the Lachninae, followed by changes in the symbiont's tissue tropism and symbiont replacement events, thereby highlighting the extraordinary versatility of host-symbiont interactions.


Single-subject oscillatory γ responses in tinnitus.
This study used magnetoencephalography to record oscillatory activity in a group of 17 patients with chronic tinnitus. Two methods, residual inhibition and residual excitation, were used to bring about transient changes in spontaneous tinnitus intensity in order to measure dynamic tinnitus correlates in individual patients. In residual inhibition, a positive correlation was seen between tinnitus intensity and both delta/theta (6/14 patients) and gamma band (8/14 patients) oscillations in auditory cortex, suggesting an increased thalamocortical input and cortical gamma response, respectively, associated with higher tinnitus states. Conversely, 4/4 patients exhibiting residual excitation demonstrated an inverse correlation between perceived tinnitus intensity and auditory cortex gamma oscillations (with no delta/theta changes) that cannot be explained by existing models. Significant oscillatory power changes were also identified in a variety of cortical regions, most commonly midline lobar regions in the default mode network, cerebellum, insula and anterior temporal lobe. These were highly variable across patients in terms of areas and frequency bands involved, and in direction of power change. We suggest a model based on a local circuit function of cortical gamma-band oscillations as a process of mutual inhibition that might suppress abnormal cortical activity in tinnitus. The work implicates auditory cortex gamma-band oscillations as a fundamental intrinsic mechanism for attenuating phantom auditory perception.


Feature stabilized digital x-ray coronary angiograms improve human visual detection in JPEG compressed images.
We evaluate the effect on human visual detection of a display method that stabilizes the motion of the feature of interest in sequential JPEG compressed x-ray coronary angiogram images. At all levels of image compression the feature stabilized display significantly improved performance with respect to the standard display where the artery is moving. In addition, for both the moving artery and stabilized display, human performance with images compressed at 15:1 was not significantly different from performance with the uncompressed images.


Bacterial culture detection and identification in blood agar plates with an optoelectronic nose.
Clinical microbiology automation is currently limited by the lack of an in-plate culture identification system. Using an inexpensive, printed, disposable colorimetric sensor array (CSA) responsive to the volatiles emitted into plate headspace by microorganisms during growth, we report here that not only the presence but the species of bacteria growing in plate was identified before colonies are visible. In 1894 trials, 15 pathogenic bacterial species cultured on blood agar were identified with 91.0% sensitivity and 99.4% specificity within 3 hours of detection. The results indicate CSAs integrated into Petri dish lids present a novel paradigm to speciate microorganisms, well-suited to integration into automated plate handling systems.


Gender differences in Taiwan university students' attitudes toward Web-based learning.
This study explored gender differences on university students' attitudes toward Web-based learning in Taiwan. A Web-based Learning Attitude Survey (WLAS) was developed. The WLAS consisted of five scales, including access, social structure, content, pedagogy, and community relationship toward Web-based learning. By using an online survey, this study gathered the responses of 1,866 Taiwanese university students (940 males and 926 females) whose ages ranged from 18 to 23. The results showed significant gender differences in the aspects of social structure, content, and community relationship involved in Web-based learning. Interestingly, although females might consider the Internet a masculine-dominated technology, they displayed more favorable attitudes than males did regarding the impacts of socioeconomic status (the social structure scale) on students' performance of Web-based learning. Moreover, females possessed more positive attitudes than males toward the helpfulness and variety of the content for Web learning. However, they did not think the virtual interaction on the Internet could develop adequate teacher-student and peer relationships (the community relationship scale). Some follow-up interviews were also conducted with selected students, and the implications derived from this study were discussed.


Effects of accessory proteins on the bypass of a cis-syn thymine-thymine dimer by Saccharomyces cerevisiae DNA polymerase eta.
Among several hypotheses to explain how translesion synthesis (TLS) by DNA polymerase eta (pol eta) suppresses ultraviolet light-induced mutagenesis in vivo despite the fact that pol eta copies DNA with low fidelity, here we test whether replication accessory proteins enhance the fidelity of TLS by pol eta. We first show that the single-stranded DNA binding protein RPA, the sliding clamp PCNA, and the clamp loader RFC slightly increase the processivity of yeast pol eta and its ability to recycle to new template primers. However, these increases are small, and they are similar when copying an undamaged template and a template containing a cis-syn TT dimer. Consequently, the accessory proteins do not strongly stimulate the already robust TT dimer bypass efficiency of pol eta. We then perform a comprehensive analysis of yeast pol eta fidelity. We show that it is much less accurate than other yeast DNA polymerases and that the accessory proteins have little effect on fidelity when copying undamaged templates or when bypassing a TT dimer. Thus, although accessory proteins clearly participate in pol eta functions in vivo, they do not appear to help suppress UV mutagenesis by improving pol eta bypass fidelity per se.


Texturing fluids.
We present a novel technique for synthesizing textures over dynamically changing fluid surfaces. We use both image textures as well as bump maps as example inputs. Image textures can enhance the rendering of the fluid by either imparting realistic appearance to it or by stylizing it, whereas bump maps enable the generation of complex micro-structures on the surface of the fluid that may be very difficult to synthesize using simulation. To generate temporally coherent textures over a fluid sequence, we transport texture information, i.e. color and local orientation, between free surfaces of the fluid from one time step to the next. This is accomplished by extending the texture information from the first fluid surface to the 3D fluid domain, advecting this information within the fluid domain along the fluid velocity field for one time step, and interpolating it back onto the second surface -- this operation, in part, uses a novel vector advection technique for transporting orientation vectors. We then refine the transported texture by performing texture synthesis over the second surface using our "surface texture optimization" algorithm, which keeps the synthesized texture visually similar to the input texture and temporally coherent with the transported one. We demonstrate our novel algorithm for texture synthesis on dynamically evolving fluid surfaces in several challenging scenarios.


Microbial biofilm growth versus tissue integration on biomaterials with different wettabilities and a polymer-brush coating.
Biomaterials-associated infections (BAI) constitute a major clinical problem and often necessitate implant replacement. In this study, the race for the surface between Staphylococcus epidermidis ATCC 35983 and U2OS osteosarcoma cells is studied on biomaterials with different wettabilities and on a polymer-brush coating. S. epidermidis was deposited on the different surfaces in a parallel plate flow chamber and then U2OS cells were seeded. Subsequently, staphylococci and U2OS cells were allowed to grow simultaneously on the surfaces for 48 h under low flow conditions. The presence of staphylococci reduced cell growth on all surfaces, but adhering cells spread equally well in the absence and presence of staphylococci. A hydrophilic polymer-brush coating discouraged bacterial and cellular adhesion and growth. Thus, whereas the biomaterials evaluated support both biofilm formation and tissue integration, polymer-brush coatings support neither. Therewith, the outcome of the race for the surface on these surfaces remains uncertain, emphasizing the need for biofunctionalized surfaces that discourage biofilm formation and support tissue growth at the same time.


Bibliographic study showed improving methodology of meta-analyses published in leading journals 1993-2002.
To assess the methodology of meta-analyses published in leading general and specialist medical journals over a 10-year period. Volumes 1993-2002 of four general medicine journals and four specialist journals were searched by hand for meta-analyses including at least five controlled trials. Characteristics were assessed using a standardized questionnaire. A total of 272 meta-analyses, which included a median of 11 trials (range 5-195), were assessed. Most (81%) were published in general medicine journals. The median (range) number of databases searched increased from 1 (1-9) in 1993/1994 to 3.5 (1-21) in 2001/2002, P<0.0001. The proportion of meta-analyses including searches by hand (10% in 1993/1994, 25% in 2001/2002, P=0.005), searches of the grey literature (29%, 51%, P=0.010 by chi-square test), and of trial registers (10%, 32%, P=0.025) also increased. Assessments of the quality of trials also became more common (45%, 70%, P=0.008), including whether allocation of patients to treatment groups had been concealed (24%, 60%, P=0.001). The methodological and reporting quality was consistently higher in general medicine compared to specialist journals. Many meta-analyses published in leading journals have important methodological limitations. The situation has improved in recent years but considerable room for further improvements remains.


s-cyclophilin is retained intracellularly via a unique COOH-terminal sequence and colocalizes with the calcium storage protein calreticulin.
Cyclophilins (cyclosporin A-binding proteins) are conserved, ubiquitous, and abundant proteins that accelerate the isomerization of XaaPro peptide bonds and the refolding of proteins in vitro. s-Cyclophilin is a member of the cyclophilin family with unique NH2- and COOH-terminal extensions, and with a signal sequence. We now report that s-cyclophilin is retained in the cell, and that the conserved s-cyclophilin-specific COOH-terminal extension VEKPFAIAKE is sufficient to direct a secretory protein to s-cyclophilin containing structures. Antibodies to s-cyclophilin-specific peptides were produced and the location of the protein was determined by an immunocytochemical study at the light microscopic level. s-Cyclophilin colocalized with the Ca(2+)-binding protein calreticulin and, to a lesser extent, with the microsomal Ca(2+)-ATPase in the myogenic cell line L6, and with the Ca(2+)-binding protein calsequestrin in skeletal muscle. In activated platelets, s-cyclophilin immunoreactivity was detected in a ring-like structure that might correspond to the Ca(2+)-storing and -releasing dense tubular network. In spreading cells, s-cyclophilin containing vesicular structures accumulated at actin-rich protrusion sites. While s-cyclophilin consistently codistributed with Ca2+ storage site markers, the distribution of s-cyclophilin immunoreactivity was not identical to that of ER markers. To determine whether the COOH-terminal extension of s-cyclophilin was involved in its intracellular transport we added this sequence to the COOH-terminus of the secretory protein glia-derived nexin. Appropriate constructs were expressed transiently in cultured cells and proteins were detected with specific antibodies. We found that glia-derived nexin with the COOH-terminal sequence VEKPFAIAKE (but not with the control sequence GLVVMNIT) colocalized with endogenous s-cyclophilin, indicating that the sequence contained retention information. These results indicate that s-cyclophilin is a retained component of an intracellular organelle and that it may accumulate in specialized portions of the ER, and possibly in calciosomes. Because of its conserved structure, widespread distribution, and abundance s-cyclophilin may be a useful marker to study the biogenesis and distribution of ER subcompartments.


Primary cystic peritoneal masses and mimickers: spectrum of diseases with pathologic correlation.
Cystic lesions within the peritoneum have been classified classically according to their lining on histology into four categories-endothelial, epithelial, mesothelial, and others (germ cell tumors, sex cord gonadal stromal tumors, cystic mesenchymal tumors, fibrous wall tumors, and infectious cystic peritoneal lesions). In this article, we will proceed to classify cystic peritoneal lesions focusing on the degree of radiological complexity into three categories-simple cystic, mildly complex, and cystic with solid component lesions. Many intra-abdominal collections within the peritoneal cavity such as abscess, seroma, biloma, urinoma, or lymphocele may mimic primary peritoneal cystic masses and need to be differentiated. Clinical history and imaging features may help differentiate intra-abdominal collections from primary peritoneal masses. Lymphangiomas are benign multilocular cystic masses that can virtually occur in any location within the abdomen and insinuate between structures. Ultrasound may help differentiate enteric duplication cysts from other mesenteric and omental cysts in the abdomen. Double-layered wall along the mesenteric side of bowel may suggest its diagnosis in the proper clinical setting. Characteristic imaging features of hydatid cysts are internal daughter cysts, floating membranes and matrix, peripheral calcifications, and collagenous pericyst. Non-pancreatic psuedocysts usually have a fibrotic thick wall and chylous content may lead to a fat-fluid level. Pseudomyxoma peritonei appears as loculated fluid collections in the peritoneal cavity, omentum, and mesentery and may scallop visceral surfaces. Many of the primary cystic peritoneal masses have specific imaging features which can help in accurate diagnosis and management of these entities. Knowledge of the imaging spectrum of cystic peritoneal masses is necessary to distinguish from other potential cystic abdominal mimicker masses.


Spatial and temporal variability across life's hierarchies in the terrestrial Antarctic.
Antarctica and its surrounding islands lie at one extreme of global variation in diversity. Typically, these regions are characterized as being species poor and having simple food webs. Here, we show that terrestrial systems in the region are nonetheless characterized by substantial spatial and temporal variations at virtually all of the levels of the genealogical and ecological hierarchies which have been thoroughly investigated. Spatial variation at the individual and population levels has been documented in a variety of genetic studies, and in mosses it appears that UV-B radiation might be responsible for within-clump mutagenesis. At the species level, modern molecular methods have revealed considerable endemism of the Antarctic biota, questioning ideas that small organisms are likely to be ubiquitous and the taxa to which they belong species poor. At the biogeographic level, much of the relatively small ice-free area of Antarctica remains unsurveyed making analyses difficult. Nonetheless, it is clear that a major biogeographic discontinuity separates the Antarctic Peninsula and continental Antarctica, here named the 'Gressitt Line'. Across the Southern Ocean islands, patterns are clearer, and energy availability is an important correlate of indigenous and exotic species richness, while human visitor numbers explain much of the variation in the latter too. Temporal variation at the individual level has much to do with phenotypic plasticity, and considerable life-history and physiological plasticity seems to be a characteristic of Antarctic terrestrial species. Environmental unpredictability is an important driver of this trait and has significantly influenced life histories across the region and probably throughout much of the temperate Southern Hemisphere. Rapid climate change-related alterations in the range and abundance of several Antarctic and sub-Antarctic populations have taken place over the past several decades. In many sub-Antarctic locations, these have been exacerbated by direct and indirect effects of invasive alien species. Interactions between climate change and invasion seem set to become one of the most significant conservation problems in the Antarctic. We conclude that despite the substantial body of work on the terrestrial biodiversity of the Antarctic, investigations of interactions between hierarchical levels remain scarce. Moreover, little of the available information is being integrated into terrestrial conservation planning, which lags far behind in this region by comparison with most others.


Small intestinal permeability in patients with eosinophilic oesophagitis during active phase and remission.
Eosinophilic oesophagitis (EoE) is presumed to be an isolated oesophageal disease; yet other allergic diseases associated with eosinophilic infiltration of target tissues, such as asthma and eczema, show perturbed functions of other sites that may be involved in the diathesis of allergy modulation. To analyse small intestinal permeability in patients with active EoE and in a separate group of patients in remission. Small bowel permeability was determined using a dual sugar method by calculating lactulose:mannitol (L:M) ratio in 17 patients who met consensus criteria for active EoE (>15 eos/HPF) and 8 patients in remission (<5 eos/HPF). Data from 28 healthy controls was used for comparison. Patients with active EoE had significantly higher L:M ratios when compared to controls (0.045 vs. 0.033, p<0.001) and to EoE in remission (0.041 vs. 0.027, p<.001). There was no significant difference in L:M between the group with EoEin remission and healthy controls. The current data show that L:M ratio of 0.033 also provides a reasonable cut-off that defined the active EoE group compared to patients in remission. The main component explaining the change in L:M ratio was increased absorption (and excretion) of lactulose ((1601 ± 106 ug) when compared to the EoE remission (969 ± 91 ug) and control (1043 ± 92 ug, p<.001) groups. Small bowel permeability is overall increased in patients with active EoE, and is normal in patients with EoE in remission when compared to healthy controls. The role of the small bowel in active EoE deserves further investigation.


Preferences for return of incidental findings from genome sequencing among women diagnosed with breast cancer at a young age.
While experts have made recommendations, information is needed regarding what genome sequencing results patients would want returned. We investigated what results women diagnosed with breast cancer at a young age would want returned and why. We conducted 60 semi-structured, in-person individual interviews with women diagnosed with breast cancer at age 40 or younger. We examined interest in six types of incidental findings and reasons for interest or disinterest in each type. Two coders independently coded interview transcripts; analysis was conducted using NVivo 10. Most participants were at least somewhat interested in all six result types, but strongest interest was in actionable results (i.e. variants affecting risk of a preventable or treatable disease and treatment response). Reasons for interest varied between different result types. Some participants were not interested or ambivalent about results not seen as currently actionable. Participants wanted to be able to choose what results are returned. Participants distinguished between types of individual genome sequencing results, with different reasons for wanting different types of information. The findings suggest that a focus on actionable results can be a common ground for all stakeholders in developing a policy for returning individual genome sequencing results.


Observations in particle physics from two neutrinos to the standard model.
The two-neutrino experiment established a relationship between particles, muon and muon neutrino, electron and electron neutrino, which evolved into the standard model of particle physics. The theme of this article is a personal one, which reviews a series of experiments at the Columbia Synchrocyclotron, the Brookhaven Cosmotron, the Alternating Gradient Synchrotron, the CERN intersecting storage rings, the Fermilab 400-gigavolt proton synchrotron, and the Cornell electron storage rings, all of which were important in the evolution of the standard model. In some cases the fermion particles were discovered (the second neutrino vmicro, b quark); in other cases fields of research were opened (muon spin resonance, neutral kaons and charge-parity violation, dimuons and the Drell-Yan process), which led to further development of the standard model. Finally, the current ignorance about the properties of now three neutrinos is reviewed.


Pharyngeal dysphagia in inflammatory muscle diseases resulting from impaired suprahyoid musculature.
Dysphagia has previously been reported in the inflammatory myopathies (IMs): inclusion body myositis (IBM), dermatomyositis (DM), and polymyositis (PM). Patients report coughing, choking, and bolus sticking in the pharynx. Myotomy has been the treatment of choice, with variable success reported. We sought to determine underlying causes of dysphagia in IM patients using instrumental evaluation. Eighteen subjects participated in the study: four with DM, six with PM, and eight with IBM. They underwent simultaneous videofluoroscopy and manometry, yielding 214 swallows for analysis regarding function of the upper esophageal sphincter (UES), swallow initiation, hyolaryngeal excursion, and pharyngeal residue. Penetration and aspiration were also recorded. UES failed to relax in two participants. High incidence of pharyngeal dysphagia was noted; 72% of participants demonstrated abnormalities, including delayed swallow initiation (24%), decreased hyolaryngeal excursion (22%), pyriform residue (17%), and penetration (22%). Dysphagia in IM patients appears to be more due to impaired muscle contraction and reduced hyolaryngeal excursion than the often held belief of failed UES relaxation. The distinction between mechanisms causing patients' dysphagia should be examined, particularly if CP myotomy is being considered as it may be contraindicated for patients with normal UES relaxation. More studies investigating IM patients pre- and post-myotomy are needed.


Recurrent insular low-grade gliomas: factors guiding the decision to reoperate.
Reoperation has been established as an effective therapeutic strategy in recurrent diffuse low-grade gliomas (LGGs). Insular gliomas represent a specific surgical challenge because of the surrounding vascular and functional structures. The aim of this study was to investigate the main clinicoradiological factors guiding the decision to reoperate on recurrent insular LGGs (ILGGs). In this retrospective consecutive series, the authors screened all patients operated on for an ILGG in their institution who further presented with a tumor regrowth without the development of contrast enhancement. They compared patients who were subsequently offered a reoperation under awake mapping at recurrence or who underwent reoperation after adjuvant treatment had reduced the volume of the initial tumor recurrence (with a proven pathological diagnosis of LGG after the second surgery) to patients who were not selected for a reoperation. The first group (reoperated group; n = 20) included all recurrent ILGG patients who underwent second resection, and the second group (nonreoperated group; n = 60) included patients who did not undergo reoperation but underwent adjuvant oncological treatment. Factors significantly associated with reoperation were extent of resection (EOR) at first surgery (91.9% vs 89.7%, p = 0.014), residual tumor volume (9.5 ± 7.1 mL [range 0-30 mL] vs 6.3 ± 7.3 mL [range 0-30 mL], p = 0.02) at first surgery and left temporopolar infiltration at the time of tumor recurrence (Liebermeister statistical analysis, 4293 voxels survived false discovery rate correction with p < 0.05; maximal z-statistic = 6.50). Infiltration of the anterior perforated substance at tumor recurrence was significantly anticorrelated to reoperation (179 voxels survived false discovery rate correction with p < 0.05; minimal z-statistic = -4.33). The mean EOR was 83.7% at reoperation with a 90% survival rate at last follow-up (9.3 ± 3.8 years), low postsurgical morbidity (Karnofsky Performance Status score ≥ 80 in 95% of patients), a high rate of postoperative professional resumption (95%), and seizure control in 57.1% of patients. In selected patients with recurrent ILGG without radiographic evidence of malignant transformation, reoperation with intraoperative awake mapping is associated with favorable oncological outcomes and a low postsurgical morbidity. A greater EOR and a lower residual tumor volume at first surgery were significantly associated with reoperation. Patients who benefited from a second surgery typically had a recurrent pattern within cortical areas (such as the temporopolar region), while other patients typically presented with a deeper infiltrative pattern within the anterior perforated substance and the surrounding white matter pathways. Such original findings may be helpful to select the optimal indications of reoperation in recurrent ILGG.


Er:YAG laser treatment of verrucous epidermal nevi.
The term verrucous epidermal nevi refers to benign hyperplasia of the epidermis. Numerous treatment modalities have been tried, but no ideal treatment is yet available. We would like to present our experience with Er:YAG laser ablation in the treatment of verrucous epidermal nevi. The purpose of this study is to assess the long-term results of Er:YAG laser treatment of verrucous epidermal nevi. Twenty patients with verrucous epidermal nevi were treated with Er:YAG laser. Twelve patients were treated with the variable-pulsed Er:YAG laser, a 5-mm handpiece at the setting of 7.0 to 7.5 J/cm2, at a 500-micros pulse duration. The dual-mode Er:YAG laser, with a 2-mm handpiece at the setting of 6.3 J/cm2, at a 350-micros pulse duration (25 microns ablation), was used in eight patients. The laser was fired at 5 Hz until all epidermal nevi were removed. The results of treatment were evaluated for the changes of skin lesions, texture, and color by physicians over a 24-month period. After a single laser treatment, successful elimination of the verrucous epidermal nevi was observed in 15 patients. Five patients (25%) showed a relapse within 1 year after the treatment. Postoperative healing time was 7 to 10 days. Erythema occurred in all patients after the laser treatment and subsided in 2 months. Postinflammatory hyperpigmentation occurred in two patients (10%). One patient (5%) experienced transient hypopigmentation. Mild to moderate postoperative acne flare-up occurred in one patient (5%) with facial lesions. No other adverse effects, including scarring, were observed. The Er:YAG laser ablation is an effective, safe, and nonscarring method for the treatment of verrucous epidermal nevi.


Neurosphere assays: growth factors and hormone differences in tumor and nontumor studies.
The "no new neuron" dogma that the brain is quiescent throughout adult life has been challenged by the discovery of cells with stem cell-like qualities of self-renewal and multipotency in the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus in adults. This self-renewing capacity also makes these neural stem cells a possible source of brain tumors, which was supported by the discovery of self-sustaining brain tumor stem-like cells in cancers such as glioblastoma multiforme. Neurosphere assays are the standard for studying these stem-like cells in both normal and cancer tissues. Despite the importance of these assays, there is no standardized protocol to allow for a comparison of results because several studies use different growth factors and hormones at different concentrations. The primary objective of this study is to review the literature for both nontumor and tumor studies to assess their respective neurosphere assay components. We found significant variation in assay components, namely hormones and growth factors, as well as their respective concentrations. This illustrates the need for a standardized protocol to allow proper comparison among studies and a better assessment of the effects of different factors.


The protective effects of omega 3 fatty acids and sesame oil against cyclosporine A-induced nephrotoxicity.
Cyclosporine A (CsA) is a drug used in autoimmune disorders and organ transplantations. Omega 3 fatty acids (O-3) and sesame oil (SO) have antioxidant properties. We aimed to investigate and compare the protective effects of O-3 and SO against CsA-induced nephrotoxicity. Seven groups of male Wistar albino rats were included in the study. In group 1 (control), saline was administered, and in group 2, CsA (subcutaneously) was administered. In group 3, CsA+SO (orally; p.o.) was given; in group 4, CsA+O-3 (p.o.) was given; and in group 5, CsA+SO+O-3 was given. In group 6, SO was administered, and in group 7, O-3 was administered. After 15 days of treatment, kidneys were excised. Histopathological evaluation, apoptotic cell count, and renal/hepatic function tests were performed. In group 2, vacuolar degeneration and necrosis of tubular cells as well as hemorrhagic foci were observed; the apoptotic cell number was higher than in the control (P < 0.001). In groups 3, 4, and 5, tubular scores and apoptotic cell count were lower than in group 2 (P < 0.01 and P < 0.001, respectively). In groups 6 and 7, healthy renal histology and a few apoptotic cells were determined. In groups 2, 3, 4, and 5, blood urea nitrogen was higher and albumin was lower than in the control (P < 0.001). Liver enzymes were unchanged. O-3/SO showed similar protective effects against CsA-induced nephrotoxicity, as revealed by a remarkable decrease in histopathological changes and apoptotic cell count. However, impaired renal function tests were not improved with O-3/SO treatment. SO and O-3 can be used as chemoprotectants against CsA.


Adenylate cyclase of human articular chondrocytes. Responsiveness to prostaglandins and other hormones.
Adenylate cyclase [ATP pyrophosphate lyase (cyclizing), EC 220.127.116.11] was shown to be present in cultured human articular chondrocytes. Optimal conditions of incubation time, protein and substrate concentrations and pH were determined in whole cell lysates. Maximal activity occurred at pH 8.5 with no decrease in activity up to pH 10.0. Adenylate cyclase activity of particulate membrane preparations was enhanced by the addition of crude cytosol preparations. The prostaglandins E1, E2, F1 alpha, F2 alpha, D2, B1, B2, A1 and A2, as well as adrenaline and isoprenaline, stimulated adenylate cyclase derived from either adult or foetal chondrocytes. No significant stimulation was observed in the presence of human calcitonin or glucagon. Bovine parathyroid hormone always significantly stimulated the adenylate cyclase derived from foetal chondrocytes, but not from adult chondrocytes. Preincubation of the chondrocytes in culture with indomethacin and with or without supernatant medium from cultured mononuclear cells increased the responsiveness of the adenylate cyclase to prostaglandin E1.


The trisaccharide raffinose modulates epidermal differentiation through activation of liver X receptor.
The epidermal barrier function requires optimal keratinocyte differentiation and epidermal lipid synthesis. Liver X receptor (LXR) α and β, are important transcriptional regulators of the epidermal gene expression. Here, we show that raffinose, a ubiquitously present trisaccharide in plants, activated the transcriptional activity of LXRα/β, which led to the induction of genes required for keratinocyte differentiation such as involucrin and filaggrin, and genes involved in lipid metabolism and transport including SCD1 and ABCA1 in both HaCaT and normal human epidermal keratinocytes. Raffinose induced the expression of JunD and Fra1, and their DNA binding in the AP1 motif in the promoters of involucrin and loricrin. Interestingly, LXR bound the AP1 motif upon raffinose treatment, and conversely, JunD and Fra1 bound the LXR response element in promoters of LXR target genes, which indicates the presence of a postive cross-talk between LXR and AP1 in the regualtion of these genes. Finally, the effect of raffinose in epidermal barrier function was confirmed by applying raffinose in an ointment formulation to the skin of hairless mice. These findings suggest that raffinose could be examined as an ingredient in functional cosmetics and therapeutic agents for the treatment of cutaneous disorders associated with abnormal epidermal barrier function.