Generation of tactile maps for artificial skin.
Prior research has shown that representations of retinal surfaces can be learned from the intrinsic structure of visual sensory data in neural simulations, in robots, as well as by animals. Furthermore, representations of cochlear (frequency) surfaces can be learned from auditory data in neural simulations. Advances in hardware technology have allowed the development of artificial skin for robots, realising a new sensory modality which differs in important respects from vision and audition in its sensorimotor characteristics. This provides an opportunity to further investigate ordered sensory map formation using computational tools. We show that it is possible to learn representations of non-trivial tactile surfaces, which require topologically and geometrically involved three-dimensional embeddings. Our method automatically constructs a somatotopic map corresponding to the configuration of tactile sensors on a rigid body, using only intrinsic properties of the tactile data. The additional complexities involved in processing the tactile modality require the development of a novel multi-dimensional scaling algorithm. This algorithm, ANISOMAP, extends previous methods and outperforms them, producing high-quality reconstructions of tactile surfaces in both simulation and hardware tests. In addition, the reconstruction turns out to be robust to unanticipated hardware failure.


A new EBSD based methodology for the quantitative characterisation of microstructures formed by displacive fcc-bcc transformations.
This work is concerned with a new methodology that can be used to quantify the degree to which grains in the microstructure are aligned in the form of packets. The methodology is based on a crystallographic definition of the term packet which is used to deduce the theoretically ideal misorientations of intra-packet grain boundaries. A misorientation distribution obtained from extensive EBSD mapping can thus be split into intra- and inter-packet misorientations and the corresponding fractions can be determined by integration. The theoretical framework of the methodology is explained and a step-by-step description of the procedure is given. Results from a trace analysis are provided to justify the assumptions made regarding habit plane and examples are included showing how the grain boundary network can be split into two separate parts, one for lath boundaries and the other for packet boundaries. Moreover, example weld metal microstructures along with the corresponding misorientation distributions as well as quantitative values of the microstructures are presented.


Meniscus induced self organization of multiple deep concave wells in a microchannel for embryoid bodies generation.
Embryonic stem cells (ESCs) have attracted great interest in the fields of tissue engineering, regenerative medicine, and organogenesis for their pluripotency and ability to self-renew. ESC aggregation, which produces an embryoid body (EB), has been widely utilized as a trigger of in vitro directed differentiation. In this paper, we propose a novel method for constructing large numbers of deep concave wells in PDMS microfluidic chips using the meniscus induced by the surface tension of a liquid PDMS prepolymer, and applied this chip for the mass production of uniform sized EBs. To investigate if the microenvironment in the deep concave well is suitable for ES cells, the oxygen diffusion to the deep concave well was analyzed by CFD simulation. Murine EBs were successfully formed in the deep concave wells without loss of cells and laborious careful intervention to refresh culture media. The size of the EBs was uniform, and retrieving of EBs was done just by flipping over the chip. All the processes including EB formation and harvest are easy and safe to cells, and their viability after completion of all processes was over 95%. The basic properties of the EBs were generated and their capacity to differentiate into 3 germ layers was investigated by analyzing the gene expression profile. The harvested EBs were found to differentiate into cardiac cells and neurons, and neurofilaments formed branches of elongated extensions more than 1.0 mm in length.


Polypharmacy in older people: lessons from 10 years of experience with the REPOSI register.
As a consequence of population aging, we have witnessed in internal medicine hospital wards a progressive shift from a population of in-patients relatively young and mainly affected by a single ailment to one of ever older and more and more complex patients with multiple chronic diseases, followed as out-patients by many different specialists with poor integration and inevitably treated with multiple medications. Polypharmacy (defined as the chronic intake of five or more drugs) is associated with increased risks of drug-drug interactions and related adverse effects, prescription and intake errors, poor compliance, re-hospitalization and mortality. With this background, the Italian Society of Internal Medicine chose to start in 2008 a prospective register called REPOSI (REgistro POliterapie SIMI, Società Italiana di Medicina Interna) in internal medicine and geriatric hospital wards. The country wide register is an ongoing observatory on multimorbidity and polypharmacy in the oldest old, with the goal to improve prescription appropriateness and, thus to avoid potentially inappropriate medications. The main findings of the register, that has accrued so far, 7005 older patients throughout a 10 year period, are summarized herewith, with special emphasis on the main patterns of poor prescription appropriateness and related risks of adverse events.


[Evaluation of the blood analyzer Beckman Coulter LH 750: analytic performance, decision rules].
We evaluated the new analyzer Beckman Coulter, an instrument dedicated to the cell blood count (CBC) and to the white blood cell (WBC) differential (including nucleated red blood cells (NRBCs)) over a global one month period, with three purposes: 1) evaluation of the analytical performance (precision, reproducibility, contamination, linearity); 2) accuracy of numerical results, by comparison to the laboratory instrument (CBC and WBC diff) or to the blood smear (NRBCs, low platelets); 3) evaluation, in terms of sensitivity and specificity, a set of abnormality messages built from the suspect flags and a few quantitative abnormalities. The analytical performances were found satisfactory. The WBC and platelet ranges of linearity were wider than in the GEN.S, as stated in the system specifications. However, the lack of adequate biological material made impossible the study of the whole mentioned linearity range. The accuracy of the CBC and differential parameters, as well as of reticulocytes, was studied with the Coulter GEN.S as reference instrument. The coefficients of correlation and the regression lines showed that the LH 750 results were similar to the GEN.S results. Furthermore, samples with thrombocytopenia and circulating NRBCs were evaluated and compared to the result obtained with microscopic lecture. The results showed a good relationship between platelets results given by the GEN.S and manual count leading to appropriate decision of transfusion. The correlation between GEN.S and manual count of NRBC was estimated as satisfactory. We used the LH 750 software to create conditional rules on the basis of qualitative and quantitative criteria, in order to define and enter a message system for detection of abnormalities. Our study showed that such a system flagged 95.7% of morphological abnormalities with a rate of unnecessary slide review (absence of any morphological abnormality on the blood smear) estimated at 8.3%. Furthermore, in 86% of the abnormalities studied, the relevant message was triggered. The Beckman Coulter LH 750 thus appeared as suitable in terms of validation efficiency.


The interaction of the B-ring of colchicine with alpha-tubulin: a novel footprinting approach.
Tubulin, the major structural component of the microtubules, participates actively in mitotic spindle formation and chromosomal organization during cell division. Tubulin is the major target for a variety of anti-mitotic drugs. Some of the drugs, such as Vinca alkaloids and taxol, are routinely used for cancer chemotherapy. It is unfortunate that our knowledge of the binding sites on tubulin of these drugs is limited because of lack of a useful and appropriate tool. The photoaffinity labeling approach is the major technique available at present to detect the binding sites of drugs on tubulin. This method, however, has several limitations. First, only part of the binding site can be identified, namely, the residues which react with the photoaffinity label. Second, there are regions of tubulin which are not at the binding site but are affected by the binding of the drug; these regions can not be detected by the photoaffinity labeling approach. The third, and perhaps most serious, limitation is that the traditional approach can detect areas which have nothing to do with the binding of the ligand but which are within a certain distance of the binding site, that distance being less than the length of the photoreactive moiety attached to the ligand. There has been a great deal of controversy on the localization of the binding site of colchicine on tubulin, with some reports suggesting that the binding site is on alpha and some supporting a binding site on beta. Colchicine also has significant effects on tubulin conformation, but the regions which are affected have not been identified. We have attempted here to address these questions by a novel "footprinting" method by which the drug-binding sites and as well as the domain of tubulin affected by drug-induced conformational changes could be determined. Here, we report for the first time that the interaction of the B-ring of colchicine with the alpha-subunit affects a domain of tubulin which appears to be far from its binding site. This domain includes the cysteine residues at positions 295, 305, 315 and 316 on alpha-tubulin; these residues are located well away from the alpha/beta interface where colchicine appears to bind. This is correlated with the stabilizing effect of colchicine on the tubulin molecule. Furthermore, we also found that the B-ring of colchicine plays a major role in the stability of tubulin while the A and the C-rings have little effect on it. Our results therefore, support a model whereby colchicine binds at the alpha/beta interface of tubulin with the B-ring on the alpha-subunit and the A and the C-rings on the beta-subunit.


Grapheme-color synesthesia influences overt visual attention.
For individuals with grapheme-color synesthesia, achromatic letters and digits elicit vivid perceptual experiences of color. We report two experiments that evaluate whether synesthesia influences overt visual attention. In these experiments, two grapheme-color synesthetes viewed colored letters while their eye movements were monitored. Letters were presented in colors that were either congruent or incongruent with the synesthetes' colors. Eye tracking analysis showed that synesthetes exhibited a color congruity bias-a propensity to fixate congruently colored letters more often and for longer durations than incongruently colored letters-in a naturalistic free-viewing task. In a more structured visual search task, this congruity bias caused synesthetes to rapidly fixate and identify congruently colored target letters, but led to problems in identifying incongruently colored target letters. The results are discussed in terms of their implications for perception in synesthesia.


Studies on the Metabolism of Nitrogen Compounds by Prof J. W. Gorrod.
The scientific research papers by Professor John William Gorrod who died in December 2015 are reviewed. He was one of the most important scientists in the area and investigated mainly the biological oxidation of nitrogen containing drugs and xenobiotics. In this review, more than 200 papers belong to him are evaluated, most of which involved the results from in vitro microsomal oxidative metabolism of nitrogen containing xenobiotics. These studies include the carcinogenicity of tobacco smoke constituents, aromatic amines, aminophenols, rubber and aminobiphenyls, the assay for ferriheamoglobinemia forming compounds, metabolism of aralkyl azo compounds, aromatic amines, aromatic azaheterocycles, synthesis of N-oxidative metabolites i.e. N-oxides, nitrones and hydroxylamines, mutagenicity of amines, metabolism of adenine derivatives, alicyclic amines and aromatic heterocyclic amines, in vivo and in vitro metabolism of nicotine and related tobacco alkaloids, effects of various substrates on MAO enzyme and reviews related to nicotine and N-oxidation of other nitrogen containing compounds. In the major part of these studies, the spectroscopic and chromatographic methods were developed to evaluate and determine the investigated compounds.


Expert-Augmented Computational Drug Repurposing Identified Baricitinib as a Treatment for COVID-19.
The onset of the 2019 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitated the identification of approved drugs to treat the disease, before the development, approval and widespread administration of suitable vaccines. To identify such a drug, we used a visual analytics workflow where computational tools applied over an AI-enhanced biomedical knowledge graph were combined with human expertise. The workflow comprised rapid augmentation of knowledge graph information from recent literature using machine learning (ML) based extraction, with human-guided iterative queries of the graph. Using this workflow, we identified the rheumatoid arthritis drug baricitinib as both an antiviral and anti-inflammatory therapy. The effectiveness of baricitinib was substantiated by the recent publication of the data from the ACTT-2 randomised Phase 3 trial, followed by emergency approval for use by the FDA, and a report from the CoV-BARRIER trial confirming significant reductions in mortality with baricitinib compared to standard of care. Such methods that iteratively combine computational tools with human expertise hold promise for the identification of treatments for rare and neglected diseases and, beyond drug repurposing, in areas of biological research where relevant data may be lacking or hidden in the mass of available biomedical literature.


Elevated infant cortisol is necessary but not sufficient for transmission of environmental risk to infant social development: Cross-species evidence of mother-infant physiological social transmission.
Environmental adversity increases child susceptibility to disrupted developmental outcomes, but the mechanisms by which adversity can shape development remain unclear. A translational cross-species approach was used to examine stress-mediated pathways by which poverty-related adversity can influence infant social development. Findings from a longitudinal sample of low-income mother-infant dyads indicated that infant cortisol (CORT) on its own did not mediate relations between early-life scarcity-adversity exposure and later infant behavior in a mother-child interaction task. However, maternal CORT through infant CORT served as a mediating pathway, even when controlling for parenting behavior. Findings using a rodent "scarcity-adversity" model indicated that pharmacologically blocking pup corticosterone (CORT, rodent equivalent to cortisol) in the presence of a stressed mother causally prevented social transmission of scarcity-adversity effects on pup social behavior. Furthermore, pharmacologically increasing pup CORT without the mother present was not sufficient to disrupt pup social behavior. Integration of our cross-species results suggests that elevated infant CORT may be necessary, but without elevated caregiver CORT, may not be sufficient in mediating the effects of environmental adversity on development. These findings underscore the importance of considering infant stress physiology in relation to the broader social context, including caregiver stress physiology, in research and interventional efforts.


Veterinary students' perceptions of their learning environment as measured by the Dundee Ready Education Environment Measure.
The Dundee Ready Education Environment Measure (DREEM) has been widely used to evaluate the learning environment within health sciences education, however, this tool has not been applied in veterinary medical education. The aim of this study was to evaluate the reliability and validity of the DREEM tool in a veterinary medical program and to determine veterinary students' perceptions of their learning environment. The DREEM is a survey tool which quantitatively measures students' perceptions of their learning environment. The survey consists of 50 items, each scored 0-4 on a Likert Scale. The 50 items are subsequently analysed within five subscales related to students' perceptions of learning, faculty (teachers), academic atmosphere, and self-perceptions (academic and social). An overall score is obtained by summing the mean score for each subscale, with an overall possible score of 200. All students in the program were asked to complete the DREEM. Means and standard deviations were calculated for the 50 items, the five subscale scores and the overall score. Cronbach's alpha was determined for the five subscales and overall score to evaluate reliability. Confirmatory factor analysis was used to evaluate construct validity. 224 responses (53%) were received. The Cronbach's alpha for the overall score was 0.93 and for the five subscales were; perceptions of learning 0.85, perceptions of faculty 0.79, perceptions of atmosphere 0.81, academic self-perceptions 0.68, and social self-perceptions 0.72. Construct validity was determined to be acceptable (p < 0.001) and all items contributed to the overall validity of the DREEM. The overall DREEM score was 128.9/200, which is a positive result based on the developers' descriptors and comparable to other health science education programs. Four individual items of concern were identified by students. In this setting the DREEM was a reliable and valid tool to measure veterinary students' perceptions of their learning environment. The four items identified as concerning originated from four of the five subscales, but all related to workload. Negative perceptions regarding workload is a common concern of students in health education programs. If not addressed, this perception may have an unfavourable impact on veterinary students' learning environment.


Evidence for HL-A-linked genes in "juvenile" diabetes mellitus.
HL-A typing of 150 patients who had developed diabetes mellitus by the age of 30 years showed a significant association with HL-A 8 and W 15. The HL-A genotypes were determined in 17 families in which two or more siblings had this type of diabetes. The zygotic assortment of HL-A haplotypes was found to be significantly disturbed from the expected random pattern, with a reduction in the number of siblings showing no identical haplotypes and an appreciable increase in the number with both haplotypes identical. This appears to be most consistent with the presence of a gene or genes pre-disposing to this type of diabetes at a locus closely linked to the HL-A chromosomal loci. This locus appears to have a fundamental role in the susceptibility to juvenile diabetes.


Randomized clinical trial of 3 types of physical exercise for patients with Parkinson disease.
To compare the efficacy of treadmill exercises and stretching and resistance exercises in improving gait speed, strength, and fitness for patients with Parkinson disease. A comparative, prospective, randomized, single-blinded clinical trial of 3 types of physical exercise. The Parkinson's Disease and Movement Disorders Center at the University of Maryland and the Baltimore Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center. A total of 67 patients with Parkinson disease who had gait impairment were randomly assigned to 1 of 3 arms of the trial. INTERVENTIONS; (1) A higher-intensity treadmill exercise (30 minutes at 70%-80% of heart rate reserve), (2) a lower-intensity treadmill exercise (50 minutes at 40%-50% of heart rate reserve), and (3) stretching and resistance exercises (2 sets of 10 repetitions on each leg on 3 resistance machines [leg press, leg extension, and curl]). These exercises were performed 3 times a week for 3 months. The primary outcome measures were gait speed (6-minute walk), cardiovascular fitness (peak oxygen consumption per unit time [$$ VO2], and muscle strength (1-repetition maximum strength). All 3 types of physical exercise improved distance on the 6-minute walk: lower-intensity treadmill exercise (12% increase; P=.001), stretching and resistance exercises (9% increase; P<.02), and higher-intensity treadmill exercise (6% increase; P=.07), with no between-group differences. Both treadmill exercises improved peak $$ VO2 (7%-8% increase; P<.05) more than did the stretching and resistance exercises. Only stretching and resistance improved muscle strength (16% increase; P<.001). The effects of exercise were seen across all 3 exercise groups. The lower-intensity treadmill exercise resulted in the greatest improvement in gait speed. Both the higher- and lower-intensity treadmill exercises improved cardiovascular fitness. Only the stretching and resistance exercises improved muscle strength. Therefore, exercise can improve gait speed, muscle strength, and fitness for patients with Parkinson disease. The combination of treadmill and resistance exercises may result in greater benefit and requires further investigation.


[The construction of nephrology nurse's core competencies between problems and safety].
Background: Nephrology, dialysis and kidney transplant facilities welcome patients with such different characteristics that they push the nurse into the sphere of care complexity, often generating criticality for the client and the professional. The purpose of the study is to understand the perception nephrological area nurses have about safety and the main difficulties encountered during the training course. Methods: The research was carried out through the questionnaries methodology and involved 104 nurses who work or have worked in the nephrological area in Italy. 58% of participants have an age of service over 16 years. Results: The data show how much the study path is judged to be lacking in the ability to provide adequate basic knowledge to deal with insertion in a context of Nephrology and dialysis. The study shows that those who have worked for less than 5 years consider the training methods unsatisfactory, generating insecurity at the end of the course. The main technical-professional difficulties encountered are the conduct of the hemodialysis and the management of the arteriovenous fistula. Conclusions: The research demonstrates how the construction of core competencies in the new hire is an issue widely experienced by the professional but not always shared nationwide.


Membrane potential oscillations in reticulospinal and spinobulbar neurons during locomotor activity.
Feedback from the spinal locomotor networks provides rhythmic modulation of the membrane potential of reticulospinal (RS) neurons during locomotor activity. To further understand the origins of this rhythmic activity, the timings of the oscillations in spinobulbar (SB) neurons of the spinal cord and in RS neurons of the posterior and middle rhombencephalic reticular nuclei were measured using intracellular microelectrode recordings in the isolated brain stem-spinal cord preparation of the lamprey. A diffusion barrier constructed just caudal to the obex allowed induction of locomotor activity in the spinal cord by bath application of an excitatory amino acid to the spinal bath. All of the ipsilaterally projecting SB neurons recorded had oscillatory membrane potentials with peak depolarizations in phase with the ipsilateral ventral root bursts, whereas the contralaterally projecting SB neurons were about evenly divided between those in phase with the ipsilateral ventral root bursts and those in phase with the contralateral bursts. In the brain stem under these conditions, 75% of RS neurons had peak depolarizations in phase with the ipsilateral ventral root bursts while the remainder had peak depolarizations during the contralateral bursts. Addition of a high-Ca2+, Mg2+ solution to the brain stem bath to reduce polysynaptic activity had little or no effect on oscillation timing in RS neurons, suggesting that direct inputs from SB neurons make a major contribution to RS neuron oscillations under these conditions. Under normal conditions when the brain is participating in the generation of locomotor activity, these spinal inputs will be integrated with other inputs to RS neurons.


A Systematic Review of U.S. Studies on the Prevalence of Intellectual or Developmental Disabilities Since 2000.
This systematic review examined 14 U.S. studies published since 2000 reporting prevalence estimates for intellectual disability (ID) or developmental disability (DD). Prevalence rates for children were between 11.0 and 13.4 per 1,000 for ID and between 45.8 and 69.9 per 1,000 for DD using data from 2010 or later. A 2015 Ohio study of adults yielded a prevalence estimate of 41.0 per 1,000 for DD. The only study of ID in adults and the only study incorporating DD Act definitions used the 1994/1995 NHIS-D yielding prevalence estimates for ID and/or DD of 38.2 per 1,000 for children birth to 5 years, 31.7 for children 6 to 18 years, and 7.9 per 1,000 for adults. Notable differences in prevalence estimates by age and operational definition have important implications for public policy and research. Serious surveillance gaps limit our understanding of service utilization rates, unmet needs, and health and other outcomes for adults with ID or DD.


Hepatitis B virus infection and risk of non-Hodgkin lymphoma in South Korea: a cohort study.
Hepatitis B virus (HBV) infection is common throughout Asia and Africa. Whether chronic HBV infection increases risk of non-Hodgkin lymphoma (NHL) is unclear. We aimed to assess the association between chronic HBV infection and subsequent development of NHL in a South Korean cohort. The Korean Cancer Prevention Study is a cohort study of South Korean workers and their dependants enrolled during 1992-95. From this cohort, we excluded individuals who died before Jan 1, 1993, who had cancer at or before the initial visit, who had missing information about weight, height, alanine aminotransferase or aspartate aminotransferase concentrations, or alcohol use, or who had evidence of HIV or HCV infection. Of 1,284,586 eligible participants, 603,585 had baseline data for serum hepatitis B surface antigen (HBsAg) status and were included in our study. We regarded HBsAg positivity at baseline as evidence of chronic HBV infection. Participants were followed up from baseline until Dec 31, 2006. We used national databases of inpatient and outpatient diagnoses and mortality records to ascertain occurrence of haematological malignancies. We assessed incidence of NHL overall and of NHL subtypes, malignant immunoproliferation, Hodgkin's lymphoma, multiple myeloma, and various leukaemias. We used Cox regression to evaluate associations with HBsAg status, adjusting for sex, age, and enrolment year. 53,045 (9%) of 603,585 participants tested positive for HBsAg at baseline. Subsequently, 133 HBsAg-positive and 905 HBsAg-negative individuals developed NHL. HBsAg-positive participants had an increased risk of NHL overall compared with those who were HBsAg-negative (incidence 19.4 vs 12.3 per 100,000 person-years; hazard ratio [HR] 1.74, 95% CI 1.45-2.09, adjusted for sex, age at baseline, and enrolment year). Among NHL subtypes, HBsAg positivity was associated with increased risk of diffuse large B-cell lymphoma (n=325, incidence 6.86 vs 3.79 per 100,000 person-years; adjusted HR 2.01, 1.48-2.75) and other or unknown subtypes (n=591, incidence 10.5 vs 7.07 per 100,000 person-years; adjusted HR 1.65, 1.29-2.11), compared with HBsAg negativity. Increased risk was also recorded for malignant immunoproliferation (n=14, incidence 0.44 vs 0.15 per 100,000 person-years; adjusted HR 3.79, 1.05-13.7). Risk of these malignancies was consistently raised in HBsAg-positive participants throughout 14 years of follow-up. HBsAg positivity was not associated with follicular or T-cell NHL, Hodgkin's lymphoma, multiple myeloma, or various leukaemias. During extended follow-up, HBsAg-positive individuals had an increased risk of NHL, suggesting that chronic HBV infection promotes lymphomagenesis. Korean Seoul City Research and the National Research and Development Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea; US National Cancer Institute.


Human late memory CD8+ T cells have a distinct cytokine signature characterized by CC chemokine production without IL-2 production.
Late memory T cell skewing is observed in the setting of immune recovery after cord blood transplantation, and may be associated with inferior control of viral reactivation and cancers. Therefore, we sought to understand how late memory cells differ functionally from earlier stage memory T cells, and whether surface phenotypes associated with differentiation stages were predictably associated with functional signatures. Higher order cytokine flow cytometry allows characterization of human T cells based on complex phenotypic markers and their differential capacity to simultaneously secrete effector proteins, including cytokines and chemokines. We used 8-color, 10-parameter cytokine flow cytometry to characterize the functional activation of human late memory CD8(+) T cells defined by CD45RA and CD27 expression (CD27(-)CD45RA(+)). We assessed the 15 possible functional signatures of cells defined by production of IL-2, IFN-gamma, TNF-alpha, and MIP-1beta alone or in combination, following activation with Ags stimulating bypassing surface proteins (PMA:ionomycin) or through the TCR (e.g., viral Ags). Late memory CD8(+) T cells produced abundant amounts of CC chemokines (MIP-1beta, MIP-1alpha, and RANTES) but not IL-2. IL-2/IFN-gamma coproduction, characteristic of protective immune responses to viral infections, was absent in late memory CD8(+) T cells. These data demonstrate that functional cytokine signatures are predictably associated with CD8(+) maturation stages, and that the polarization of late memory CD8(+) T cells toward CC chemokine production and away from IL-2 production suggests a unique functional role for this subset.


Refugee children have fewer contacts to psychiatric healthcare services: an analysis of a subset of refugee children compared to Danish-born peers.
Studies show a high level of mental health problems among refugee children. This study examined whether a subset of refugee children living in Denmark accessed psychiatric healthcare services more than those born in the country. This study compared 24,427 refugee children from Asia, The Middle East, Sub-Saharan Africa and former Yugoslavia, who obtained residency in Denmark between 1 January 1993 and 31 December 2010 with 146,562 Danish-born children, matched 1:6 on age and sex. The study looked at contacts with psychiatric hospitals as well as psychologists and psychiatrists in private practice. Between 1 January 1996 and 30 June 2012, 3.5 % of the refugee children accessed psychiatric healthcare services compared to 7.7 % of the Danish-born children. The rate ratio of having any first-time psychiatric contact was 0.42 (95 % CI 0.40-0.45) among refugee boys and 0.35 (95 % CI 0.33-0.37) among refugee girls, compared to Danish-born children. Figures were similar for those accessing private psychologists or psychiatrists, emergency room, inpatient and outpatient services. Refugee children used fewer psychiatric healthcare services than Danish-born children. This may indicate that refugee children experience barriers in accessing psychiatric healthcare systems and do not receive adequate assessment of their mental health and subsequent referral to specialist services.


Can a single-reference approach provide a balanced description of ground and excited states? A comparison of the completely renormalized equation-of-motion coupled-cluster method with multireference quasidegenerate perturbation theory near a conical intersection and along a photodissociation coordinate in ammonia.
We calculated the two lowest electronically adiabatic potential energy surfaces of ammonia in the region of the conical intersection and at a sequence of geometries along which one of the N-H bonds is broken. We employed both a multireference (MR) method and a single-reference (SR) method. The MR calculations are based on multiconfiguration quasidegenerate perturbation theory (MC-QDPT) with a 6-311+G(3df,3pd) basis set. The SR calculations, carried out with the same basis, employ the completely renormalized equation-of-motion coupled-cluster method with singles and doubles, and a noniterative treatment of triples, denoted CR-EOMCCSD(T). At 91 geometries used for comparison, including geometries near a conical intersection, the surfaces agree to 7% on average.


Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection.
Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.


Identification and evaluation of a core microsatellite panel for use in white-tailed deer (Odocoileus virginianus).
Microsatellite loci have been used extensively over the past two decades to study the genetic characteristics of non-model species. The ease of microsatellite development and ability to adapt markers from related species has led to the proliferation of available markers for many commonly studied species. Because it is often infeasible to genotype individuals across all available loci, researchers generally rely on subsets of markers. Marker choice can bias inferences made using disparate suites of loci. This has been a primary motivation for efforts to identify uniform marker panels. Here, we use the geographic distribution of previous studies to identify microsatellite loci for white-tailed deer (Odocoileus virginianus) with the potential for widespread use, and we evaluate the effectiveness of this panel in a portion of the range where few previous studies have been conducted. The purpose was to consolidate the numerous genetic resources for this species into a manageable panel and to provide a uniform methodology that improves comparisons between past and future studies. We reviewed microsatellite panels from 58 previous or ongoing projects and identified 106 candidate loci. We developed a multiplex protocol and evaluated the efficacy of 17 of the most commonly used loci using 720 DNA samples collected from the Mid-Atlantic region of the United States of America. Amplification errors were detected in six of these loci. The 11 remaining loci were highly polymorphic, exhibited low frequencies of null alleles, and were easy to interpret with the aid of allele binning software. The development of broadly-applicable, core microsatellite panels has the potential to improve repeatability and comparative ability for commonly studied species. The properties of the consolidated 11 microsatellite panel suggest that they are applicable for many common research objectives for white-tailed deer. The geographic distribution of previous studies using these markers provides a greater degree of confidence regarding the robustness to common sources of error related to amplification anomalies, such as null alleles, relative to loci with more limited use. While this does not replace further evaluation of genotyping errors, it does provide a common platform that benefits future research studies.


A short guide to insect oviposition: when, where and how to lay an egg.
Egg-laying behavior is one of the most important aspects of female behavior, and has a profound impact on the fitness of a species. As such, it is controlled by several layers of regulation. Here, we review recent advances in our understanding of insect neural circuits that control when, where and how to lay an egg. We also outline outstanding open questions about the control of egg-laying decisions, and speculate on the possible neural underpinnings that can drive the diversification of oviposition behaviors through evolution.


Differential regulation of cytokine and receptor transcript expression in human corneal and limbal fibroblasts by epidermal growth factor, transforming growth factor-alpha, platelet-derived growth factor B, and interleukin-1 beta.
To explore further the significance of three patterns of cytokine dialogues that have been characterized between human corneal and limbal epithelial cells and fibroblasts. Northern hybridization of the transcript expression of type I cytokine receptors (EGFR, IL-1R, and PDGFR-beta), type II cytokines (bFGF, LIF, and TGF-beta 1), and type III cytokines (HGF and KGF) by human corneal and limbal fibroblasts was conducted under the modulation of TGF-alpha, PDGF-BB, IL-1 beta, and EGF (type I cytokines). The mechanism of upregulation by IL-1 beta was studied further with respect to proto-oncogene expression and under the treatment of cycloheximide and actinomycin D. Results showed that EGF upregulated LIF and HGF but downregulated KGF and M-CSF. Unlike EGF, TGF-alpha upregulated additional EGFR, PDGFR-beta, bFGF, and TGF-beta 1, suggesting that although they share the same EGFR, TGF-alpha, which is produced by epithelium, is more effective in activating fibroblasts than EGF, which is present in tears. The upregulation of PDGF-BB was similar to that of TGF-alpha, except that it further stimulated IL-8, supporting their synergistic roles in promoting wound healing. Uniquely, IL-1 beta upregulated KGF expression by limbal fibroblasts more than corneal fibroblasts and IL-8 and M-CSF expression, but it downregulated PDGFR-beta. In IL-1 beta, the upregulation of cytokines and receptors was preceded by the upregulation of c-fos, c-jun, and c-myc, and it was inhibited by actinomycin D. Its upregulation of LIF was superinduced, but the upregulation of bFGF and KGF was inhibited, and that of the rest was not affected by cycloheximide. These findings suggest that epithelial cells under stress or injury (producing IL-1) might preferentially activate limbal epithelial stem cells indirectly by fibroblasts and simultaneously might promote inflammation during wound healing.


A role for human mitochondrial complex II in the production of reactive oxygen species in human skin.
The mitochondrial respiratory chain is a major generator of cellular oxidative stress, thought to be an underlying cause of the carcinogenic and ageing process in many tissues including skin. Previous studies of the relative contributions of the respiratory chain (RC) complexes I, II and III towards production of reactive oxygen species (ROS) have focussed on rat tissues and certainly not on human skin which is surprising as this tissue is regularly exposed to UVA in sunlight, a potent generator of cellular oxidative stress. In a novel approach we have used an array of established specific metabolic inhibitors and DHR123 fluorescence to study the relative roles of the mitochondrial RC complexes in cellular ROS production in 2 types of human skin cells. These include additional enhancement of ROS production by exposure to physiological levels of UVA. The effects within epidermal and dermal derived skin cells are compared to other tissue cell types as well as those harbouring a compromised mitochondrial status (Rho-zero A549). The results show that the complex II inhibitor, TTFA, was the only RC inhibitor to significantly increase UVA-induced ROS production in both skin cell types (P<0.05) suggesting that the role of human skin complex II in terms of influencing ROS production is more important than previously thought particularly in comparison to liver cells. Interestingly, two-fold greater maximal activity of complex II enzyme was observed in both skin cell types compared to liver (P<0.001). The activities of RC enzymes appear to decrease with increasing age and telomere length is correlated with ageing. Our study showed that the level of maximal complex II activity was higher in the MRC5/hTERT (human lung fibroblasts transfected with telomerase) cells than the corresponding wild type cells (P=0.0012) which can be considered (in terms of telomerase activity) as models of younger and older cells respectively.


GroEL/GroES promote dissociation/reassociation cycles of a heterodimeric intermediate during alpha(2)beta(2) protein assembly. Iterative annealing at the quaternary structure level.
Whereas the mechanism of GroEL/GroES-mediated protein folding has been extensively studied, the role of these chaperonins in oligomeric protein assembly remains poorly understood. In the present study, we investigated the interaction of the chaperonins with an alphabeta heterodimeric intermediate during the alpha(2)beta(2) assembly of human mitochondrial branched-chain alpha-ketoacid dehydrogenase/decarboxylase (BCKD). Incubation of the recombinant His(6)-tagged BCKD in 400 mM KSCN for 45 min at 23 degrees C caused a complete dissociation of the alpha(2)beta(2) heterotetramers into inactive alphabeta heterodimers. Dilution of the denaturant resulted in a rapid recovery of BCKD independent of the chaperonins GroEL/GroES. Prolonged incubation of BCKD in 400 mM KSCN resulted in the generation of nonproductive or "bad" heterodimers, which were unable to undergo spontaneous reactivation but capable of binding to GroEL to form a stable GroEL-alphabeta complex. Incubation of this complex with GroES and Mg-ATP led to the slow reactivation of BCKD with a second-order rate constant k = 480 M(-1) s(-1). Mixing experiments with radiolabeled and unlabeled protein substrates provided direct evidence that GroEL/GroES promote dissociation and subunit exchange between bad heterodimers. This was accompanied by the transformation of bad heterodimers to their "good" or productive counterparts. The good heterodimers were capable of spontaneous dimerization to initially form an inactive heterotetrameric species, followed by conversion to active heterotetramers. However, a large fraction of bad heterodimers were regenerated and rebound to GroEL. The cycle was perpetuated until the reconstitution of active BCKD was complete. Our data support the thesis that chaperonins GroEL/GroES mediate iterative annealing of nonproductive assembly intermediates at the quaternary structure level. This step is essential for an efficient subsequent higher order oligomerization.


Oral mucositis.
Oral mucositis is one of the most common complications of cancer therapy. It is a nonhematologic complication of cytotoxic chemotherapy and radiotherapy and reduces the quality of life. It is estimated that 40% the cases on standard chemotherapy may develop oral mucositis. Patients receiving radiation, especially in the cases of head and neck cancer, have 30%-60% chances of developing mucositis. Chemotherapy and radiotherapy interfere with the normal turnover of epithelial cells, leading to mucosal injuries. These injuries can also occur due to indirect invasion of Gram negative bacteria and fungi as most of the chemo-therapeutic agents will cause neutropenia and will give a favorable environment for the development of mucositis. The patient-related factors are also responsible for developing mucositis in chemo-induced and radiation-induced mucositis. Poor oral hygiene may also be responsible for bacterial super infection followed by chemotherapy. Mucositis is of two kinds: direct and indirect mucositis. Direct mucositis - The epithelial cells of the oral mucosa undergo rapid turnover in usually 7-14 days due to which these cells are more susceptible to the effect of the cytotoxic therapy which results in oral mucositis. Indirect mucositis - it can develop due to the infection caused by Gram-negative bacteria and fungal infection. There will be a greater risk for oral infection due to neutropenia. The onset of mucositis secondary to mylo-suppression varies depending upon the timing of the neutrophil count associated with chemotherapy agents but they typically develop around 10-21 days after chemotherapy administration.


Effect of weight loss on urinary incontinence in overweight and obese women: results at 12 and 18 months.
Initial weight loss improves urinary incontinence in overweight and obese women. In this study we examined the longer term effects of a weight loss intervention on urinary incontinence. Overweight and obese women (mean +/- SD age 53 +/- 10 years) with 10 or more urinary incontinence episodes weekly were randomized to an 18-month behavioral weight loss intervention (226) or control group (112). Outcome measures were collected at 12 and 18 months. At baseline women had a mean body mass index of 36 +/- 6 kg/m(2) and reported a mean of 24 +/- 18 incontinence episodes weekly. Of the patients 86% completed 18-month measurements. The percent weight loss in the intervention group averaged 8.0%, 7.5% and 5.5% at 6, 12 and 18 months, respectively, vs approximately 1.5% in the control group (all values p <0.001). Compared with controls at 12 months the intervention group reported a greater percent reduction in weekly stress urinary incontinence episodes (65% vs 47%, p <0.001), and a greater proportion achieved at least a 70% decrease in weekly total and stress urinary incontinence episodes. At 18 months a greater proportion of women in the weight loss intervention group had more than 70% improvement in urge incontinence episodes but there were no significant differences between the groups for stress or total urinary incontinence. The intervention group also reported greater satisfaction with changes in urinary incontinence than the control group at 6, 12 and 18 months. Weight loss intervention reduced the frequency of stress incontinence episodes through 12 months and improved patient satisfaction with changes in incontinence through 18 months. Improving weight loss maintenance may provide longer term benefits for urinary incontinence.


Two newborns of heroin-addicted mothers suffering neonatal withdrawal syndrome.
Neonatal withdrawal syndrome is characterized by non-specific signs and symptoms that occur in infants following in-utero drug exposure. The incidence of neonatal withdrawal syndrome is 16-90% in infants of mothers abusing heroin. Clinical signs of withdrawal syndrome usually occur within the first 48-72 hours after birth. Central nervous system and gastrointestinal system symptoms are the main symptoms. In this case report, two newborns born to the mothers addicted to heroin who suffered neonatal withdrawal syndrome are presented. They were successfully treated with phenobarbital and morphine infusion.


Gender differences in the relationships between sleep disturbances and academic performance among nursing students: A cross-sectional study.
Sleep disturbances, such as insomnia, excessive daytime sleepiness, and poor-quality sleep, are common among nursing students and are closely linked with academic performance. To examine the prevalence of sleep disturbances and academic performances in male and female nursing students and to determine gender-specific effects on the relationship between sleep disturbances and academic performance. A cross-sectional study design was adopted. This study was conducted in a school of nursing in Indonesia. A total of 492 undergraduate students (103 males and 389 females) were included. Data pertaining to the biosociodemographic characteristics, Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale, Morningness-Eveningness Questionnaire, and Beck Depression Inventory were collected from July 1, 2018 to September 30, 2018. Academic performance was measured using grade point average of the academic year 2017-2018. A multivariate logistic regression model was used for data analyses. The prevalence of poor sleep quality, insomnia, and daytime sleepiness was 66.0%, 45.6%, and 24.3%, respectively, in male nursing students and 71.5%, 52.4%, and 28.8%, respectively, in female nursing students. For circadian rhythm preferences, 66% male and 51.7% female nursing students were categorized as intermediate- and morning-type people, respectively. Insomnia was the only variable among sleep disturbances that significantly correlated with the risk of poor academic performance in female nursing students even after adjustment of covariates. Sleep disturbances were highly prevalent among female and male nursing students, and insomnia was substantially associated with poor academic performance in female nursing students. Identifying sleep disturbances among nursing students and designing effective interventions to specifically target them are required to improve academic performance of female nursing students.


Cleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosis.
Stress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker. IPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects. cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome. cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.


Risk prediction for estrogen receptor-specific breast cancers in two large prospective cohorts.
Few published breast cancer (BC) risk prediction models consider the heterogeneity of predictor variables between estrogen-receptor positive (ER+) and negative (ER-) tumors. Using data from two large cohorts, we examined whether modeling this heterogeneity could improve prediction. We built two models, for ER+ (ModelER+) and ER- tumors (ModelER-), respectively, in 281,330 women (51% postmenopausal at recruitment) from the European Prospective Investigation into Cancer and Nutrition cohort. Discrimination (C-statistic) and calibration (the agreement between predicted and observed tumor risks) were assessed both internally and externally in 82,319 postmenopausal women from the Women's Health Initiative study. We performed decision curve analysis to compare ModelER+ and the Gail model (ModelGail) regarding their applicability in risk assessment for chemoprevention. Parity, number of full-term pregnancies, age at first full-term pregnancy and body height were only associated with ER+ tumors. Menopausal status, age at menarche and at menopause, hormone replacement therapy, postmenopausal body mass index, and alcohol intake were homogeneously associated with ER+ and ER- tumors. Internal validation yielded a C-statistic of 0.64 for ModelER+ and 0.59 for ModelER-. External validation reduced the C-statistic of ModelER+ (0.59) and ModelGail (0.57). In external evaluation of calibration, ModelER+ outperformed the ModelGail: the former led to a 9% overestimation of the risk of ER+ tumors, while the latter yielded a 22% underestimation of the overall BC risk. Compared with the treat-all strategy, ModelER+ produced equal or higher net benefits irrespective of the benefit-to-harm ratio of chemoprevention, while ModelGail did not produce higher net benefits unless the benefit-to-harm ratio was below 50. The clinical applicability, i.e. the area defined by the net benefit curve and the treat-all and treat-none strategies, was 12.7 × 10- 6 for ModelER+ and 3.0 × 10- 6 for ModelGail. Modeling heterogeneous epidemiological risk factors might yield little improvement in BC risk prediction. Nevertheless, a model specifically predictive of ER+ tumor risk could be more applicable than an omnibus model in risk assessment for chemoprevention.


Effect of protein and energy levels in sweet sorghum bagasse leaf residue-based diets on the performance of growing Deccani lambs.
Sweet sorghum bagasse with leaf residue (SSBLR) based complete diets with high or low protein and high- or low-energy levels were evaluated in a 60-day growth trial using growing sheep. Twenty-eight Deccani ram lambs were divided into four groups (16.0 ± 0.59 kg) of seven each and fed low-protein high-/low-energy and high-protein high-/low-energy diets ad lib. Average daily gain (g; P < 0.05) and feed efficiency (P < 0.01) were significantly higher in lambs fed high energy than those with low-energy diets, and cost per kg gain ($) was significantly lower (P < 0.05) in low protein than high-protein diets. Dry matter intake (DMI) (g/day) was not significantly affected either by protein or energy level in the diet, but dry matter (DM), organic matter (OM), protein, and neutral detergent fiber (NDF) digestibilities were higher significantly (P < 0.01) in high protein/energy diets than low protein/energy diets. Crude protein (CP) intake (g/day) was significantly (P < 0.001) higher in lambs fed high protein than low-protein diets. However, N balance (g/day) was significantly (P < 0.001) higher in lambs fed low protein than high-protein diets. It is concluded that feeding of SSBLR-based diet with low protein (CP 12.9 %) and high energy (9.4 MJ metabolizable energy (ME)/kg DM) was recommended for better performance, nitrogen retention, and returns from growing Deccani ram lambs.


Changes to the Human Serum Proteome in Response to High Intensity Interval Exercise: A Sequential Top-Down Proteomic Analysis.
Exercise has been shown to improve health status and prevent chronic diseases. In contrast, overtraining can lead to maladaptation and detrimental health outcomes. These outcomes appear to be mediated in part by released peptides and, potentially, alterations in protein abundances and their modified forms, termed proteoforms. Proteoform biomarkers that either predict the beneficial effects of exercise or indicate (mal)adaptation are yet to be elucidated. Thus, we assessed the influence of high-intensity interval exercise (HIIE) on the human serum proteome to identify novel exercise-regulated proteoforms. To this end, a top-down proteomics approach was used, whereby two-dimensional gel electrophoresis was used to resolve and differentially profile intact proteoforms, followed by protein identification via liquid chromatography-tandem mass spectrometry. Blood was collected from six young-adult healthy males, pre-exercise and 5 min and 1 h post-exercise. Exercise consisted of a maximal cycle ergometer test followed by 8 min × 1 min high-intensity intervals at 90% W max, with 1 min non-active recovery between intervals. Twenty resolved serum proteoforms changed significantly in abundance at 5 min and/or 1 h post-HIIE, including apolipoproteins, serpins (protease inhibitors), and immune system proteins, known to have broad anti-inflammatory and antioxidant effects, involvement in lipid clearance, and cardio-/neuro-protective effects. This initial screening for potential biomarkers indicates that a top-down analytical proteomic approach may prove useful in further characterizing the response to exercise and in understanding the molecular mechanisms that lead to health benefits, as well as identifying novel biomarkers for exercise (mal)adaptation.


Clinical management of drug-drug interactions in HCV therapy: challenges and solutions.
Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug-drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug-drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug-drug interaction studies and a list of contraindicated medications is not enough for the clinical management of these drug-drug interactions. Knowledge of pharmacokinetic profiles and concentration-effect relationships is key for the interpretation of these data, and insight into how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges.


Mediators of the stress-substance-use relationship in urban male adolescents.
Exposure to chronic or severe acute stressors throughout the lifespan has been linked with numerous negative behavioral, emotional, cognitive, and physical consequences. Adolescence is considered to be a particularly vulnerable period given that the brain is experiencing dramatic developmental change during this time. The present study examined a sample of adolescents (N=125) considered to be at high risk for stress exposures and drug use by virtue of their environment and low income levels to identify possible neurocognitive (i.e., impulsivity, delay of gratification, emotional perception, and risky decision-making) and social competency mechanisms that may mediate this relationship. Using Mplus, a mediational model was tested using full information maximum likelihood estimates. Risky decision-making and poor social competency skills were related to previous stressful experiences; however, only social competencies mediated the effect of stressors on reports of past year marijuana, alcohol, and polydrug use. As such, stress appears to exert its negative impact through alterations in abilities to generate and execute prosocial decisions and behaviors. Interventions that directly address the effects of stress on social competencies may be especially important for children who have experienced adversity including those exposed to parental divorce, parental psychopathology, neglect or abuse, parental death, and poverty.


The value of artefacts in stimulated-recall interviews.
To assess the use of artefacts in semi-structured, stimulated-recall interviews in a study exploring mentors' decisions regarding students' competence in practice. Few empirical studies have examined how mentors reach a decision when assessing students' performance in practice. Concerns have repeatedly been voiced that students may lack essential skills at the point of registration or that mentors may have failed or been reticent to judge students' performance as unsatisfactory. Student practice assessment documents (PADs) were used in stimulated-recall (SR) interviews with mentors to explore decision making. A review of the literature identified that artefacts can play a role in triggering a more comprehensive retrospective examination of decision making, thus helping to capture the essence of a mentor's decision over time and in context. Use of an artefact to stimulate recall can elicit evidence of thought processes, which may be difficult to obtain in a normal, semi-structured interview. PADs proved to be a valuable way to generate naturalistic decision making. In addition, discussion of artefacts created by participants can promote participant-driven enquiry, thereby reducing researcher bias. Identifying an approach that captures post hoc decision making based on sustained engagement and interaction between students and their mentors was a challenge. Artefacts can be used to address the difficulties associated with retrospective introspection about a unique decision. There is the potential to increase the use of artefacts in healthcare research. SR can also help novice mentors develop their skills in making decisions regarding assessments of students.


Replication of single-stranded porcine circovirus DNA by DNA polymerases alpha and delta.
Porcine circovirus is the only mammalian DNA virus so far known to contain a single-stranded circular genome (Tischer et al. (1982) Nature 295, 64-66). Replication of its small viral DNA (1.76 kb) appears to be dependent on cellular enzymes expressed during S-phase of the cell cycle (Tischer et al. (1987) Arch. Virol. 96, 39-57). In this paper we have exploited the porcine circovirus genome to probe for in vitro initiation and elongation of DNA replication by different preparations of calf thymus DNA polymerase alpha and delta as well as by a partially purified preparation from pig thymus. The results indicated that three different purification fractions of calf thymus DNA polymerase alpha and one from pig thymus initiate DNA synthesis at several sites on the porcine circovirus DNA. It appears that the sites at which DNA primase synthesizes primers are not entirely random. Subsequent DNA elongation by a highly purified DNA polymerase alpha holoenzyme which had been isolated by the criterion of replicating single-stranded M13 DNA (Ottiger et al. (1987) Nucleic Acids Res. 15, 4789-4807) is very efficient. Complete conversion to the double-stranded form is obtained in less than 1 min. When the DNA synthesis by DNA polymerase alpha is blocked with the DNA polymerase alpha specific monoclonal antibody SJK 132-20 after initiation by DNA primase, DNA polymerase delta can efficiently replicate from the primers. This in vitro DNA replication system may be used in analogy to the bacteriophage systems in E. coli to study initiation and elongation of DNA replication.


Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone.
Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.


Expression of calretinin in human ovary, testis, and ovarian sex cord-stromal tumors.
Calretinin, a calcium-binding protein, is primarily expressed in certain subtypes of neurons. It has also been found to be present in mesothelial cells and mesotheliomas but not in many types of carcinomas. Using a polyclonal anti-calretinin antibody, we investigated the expression of calretinin immunohistochemically in nonneoplastic human ovaries and testes and ovarian sex cord-stromal tumors (SCSTs). In ovaries, calretinin was expressed in theca interna cells, hilus cells, and scattered individual stromal cells. Oocytes, granulosa cells, theca externa cells, rete ovarii, and most stromal cells were negative. Expression of calretinin was also seen in the ovarian surface epithelium and in collapsed and flat epithelial inclusion glands (EIGs), but not in round, columnar, and ciliated EIGs. In some glands, a transition from calretinin-positive to calretinin-negative epithelium was observed. In postpubertal testes, calretinin was expressed in Leydig cells, but not in germ cells or most rete testes and Sertoli cells. In ovarian SCSTs, strong calretinin staining was seen in all hilus cell tumors (4/4) and the Leydig cell component of Sertoli-Leydig cell tumors (10/10). The Sertoli cell component showed focal weak positivity in 5/10. Fibrothecomas were completely negative (0/8). In granulosa cell tumors, the tumor cells were either completely negative (8/14) or weakly positive at the periphery of the tumor (6/14) while scattered stromal cell staining was seen in 9/14 cases. The expression of calretinin in normal Leydig cells, theca interna cells, the Leydig cell component of Sertoli-Leydig cell tumors, and hilus cell tumors suggests its functional relationship with androgen production. Its pattern of expression in ovarian SCSTs is useful in the differential diagnosis of these tumors. The presence of a transition from calretinin-positive, flat, nonciliated epithelium to calretinin-negative, columnar, ciliated epithelium in the same glands provides strong evidence for mullerian metaplasia.


Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy.
To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy. In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16. Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE. Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.


Surgical and medical second trimester abortion in South Africa: a cross-sectional study.
A high percentage of abortions performed in South Africa are in the second trimester. However, little research focuses on women's experiences seeking second trimester abortion or the efficacy and safety of these services.The objectives are to document clinical and acceptability outcomes of second trimester medical and surgical abortion as performed at public hospitals in the Western Cape Province. We performed a cross-sectional study of women undergoing abortion at 12.1-20.9 weeks at five hospitals in Western Cape Province, South Africa in 2008. Two hundred and twenty women underwent D&E with misoprostol cervical priming, and 84 underwent induction with misoprostol alone. Information was obtained about the procedure and immediate complications, and women were interviewed after recovery. Median gestational age at abortion was earlier for D&E clients compared to induction (16.0 weeks vs. 18.1 weeks, p < 0.001). D&E clients reported shorter intervals between first clinic visit and abortion (median 17 vs. 30 days, p < 0.001). D&E was more effective than induction (99.5% vs. 50.0% of cases completed on-site without unplanned surgical procedure, p < 0.001). Although immediate complications were similar (43.8% D&E vs. 52.4% induction), all three major complications occurred with induction. Early fetal expulsion occurred in 43.3% of D&E cases. While D&E clients reported higher pain levels and emotional discomfort, most women were satisfied with their experience. As currently performed in South Africa, second trimester abortions by D&E were more effective than induction procedures, required shorter hospital stay, had fewer major immediate complications and were associated with shorter delays accessing care. Both services can be improved by implementing evidence-based protocols.


Variations of high frequency parameter of heart rate variability following osteopathic manipulative treatment in healthy subjects compared to control group and sham therapy: randomized controlled trial.
Heart Rate Variability (HRV) indicates how heart rate changes in response to inner and external stimuli. HRV is linked to health status and it is an indirect marker of the autonomic nervous system (ANS) function. To investigate the influence of osteopathic manipulative treatment (OMT) on cardiac autonomic modulation in healthy subjects, compared with sham therapy and control group. Sixty-six healthy subjects, both male and female, were included in the present 3-armed randomized placebo controlled within subject cross-over single blinded study. Participants were asymptomatic adults (26.7 ± 8.4 y, 51% male, BMI 18.5 ± 4.8), both smokers and non-smokers and not on medications. At enrollment subjects were randomized in three groups: A, B, C. Standardized structural evaluation followed by a patient need-based osteopathic treatment was performed in the first session of group A and in the second session of group B. Standardized evaluation followed by a protocoled sham treatment was provided in the second session of group A and in the first session of group B. No intervention was performed in the two sessions of group C, acting as a time-control. The trial was registered on clinicaltrials.gov identifier: NCT01908920. HRV was calculated from electrocardiography before, during and after the intervention, for a total amount time of 25 min and considering frequency domain as well as linear and non-linear methods as outcome measures. OMT engendered a statistically significant increase of parasympathetic activity, as shown by High Frequency power (p < 0.001), expressed in normalized and absolute unit, and possibly decrease of sympathetic activity, as revealed by Low Frequency power (p < 0.01); results also showed a reduction of Low Frequency/High Frequency ratio (p < 0.001) and Detrended fluctuation scaling exponent (p < 0.05). Findings suggested that OMT can influence ANS activity increasing parasympathetic function and decreasing sympathetic activity, compared to sham therapy and control group.


Pathways to ethnic-racial identity development and psychological adjustment: The differential associations of cultural socialization by parents and peers.
Ethnic-racial identity (ERI) development is a central developmental process for youth of color. Although a great deal of research establishes the importance of cultural socialization by parents to the development of ERI, limited empirical work has examined peers' role in these processes. This study uses 4 cross-sectional data sets (N = 127, 312, 257, and 238, mean age = 17.96-18.24) followed by a meta-analytic summary to test a path model of ERI development and parent and peer cultural socialization and their associations with psychological adjustment in a diverse sample of emerging adults. The final sample size adjusted meta-analytic model indicated that parent ethnic socialization predicted both ERI exploration and commitment while only peer preparation for bias predicted ERI commitment. In turn, ERI commitment and exploration predicted more positive mental health. The findings of this study highlight the importance of both parents and peers to cultural socialization processes during emerging adulthood. In particular, this study suggests that the messages peers impart about prejudice play a unique role in the development of ERI. The findings have important implications about the unique role peers play in communicating messages about prejudice as well as for ERI and the psychological adjustment of youth of color at this developmental stage. Additionally, these cross-sectional findings provide a preliminary but robust model from which researchers can frame future longitudinal work in this area. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Advances in Sequencing Technologies for Understanding Hereditary Ataxias: A Review.
The hereditary progressive ataxias comprise genetic disorders that affect the cerebellum and its connections. Even though these diseases historically have been among the first familial disorders of the nervous system to have been recognized, progress in the field has been challenging because of the large number of ataxic genetic syndromes, many of which overlap in their clinical features. We have taken a historical approach to demonstrate how our knowledge of the genetic basis of ataxic disorders has come about by novel techniques in gene sequencing and bioinformatics. Furthermore, we show that the genes implicated in ataxia, although seemingly unrelated, appear to encode for proteins that interact with each other in connected functional modules. It has taken approximately 150 years for neurologists to comprehensively unravel the genetic diversity of ataxias. There has been an explosion in our understanding of their molecular basis with the arrival of next-generation sequencing and computer-driven bioinformatics; this in turn has made hereditary ataxias an especially well-developed model group of diseases for gaining insights at a systems level into genes and cellular pathways that result in neurodegeneration.


The DNA binding and catalytic domains of poly(ADP-ribose) polymerase 1 cooperate in the regulation of chromatin structure and transcription.
We explored the mechanisms of chromatin compaction and transcriptional regulation by poly(ADP-ribose) polymerase 1 (PARP-1), a nucleosome-binding protein with an NAD(+)-dependent enzymatic activity. By using atomic force microscopy and a complementary set of biochemical assays with reconstituted chromatin, we showed that PARP-1 promotes the localized compaction of chromatin into supranucleosomal structures in a manner independent of the amino-terminal tails of core histones. In addition, we defined the domains of PARP-1 required for nucleosome binding, chromatin compaction, and transcriptional repression. Our results indicate that the DNA binding domain (DBD) of PARP-1 is necessary and sufficient for binding to nucleosomes, yet the DBD alone is unable to promote chromatin compaction and only partially represses RNA polymerase II-dependent transcription in an in vitro assay with chromatin templates (approximately 50% of the repression observed with wild-type PARP-1). Furthermore, our results show that the catalytic domain of PARP-1, which does not bind nucleosomes on its own, cooperates with the DBD to promote chromatin compaction and efficient transcriptional repression in a manner independent of its enzymatic activity. Collectively, our results have revealed a novel function for the catalytic domain in chromatin compaction. In addition, they show that the DBD and catalytic domain cooperate to regulate chromatin structure and chromatin-dependent transcription, providing mechanistic insights into how these domains contribute to the chromatin-dependent functions of PARP-1.


European Society of Contact Dermatitis guideline for diagnostic patch testing - recommendations on best practice.
The present guideline summarizes all aspects of patch testing for the diagnosis of contact allergy in patients suspected of suffering, or having been suffering, from allergic contact dermatitis or other delayed-type hypersensitivity skin and mucosal conditions. Sections with brief descriptions and discussions of different pertinent topics are followed by a highlighted short practical recommendation. Topics comprise, after an introduction with important definitions, materials, technique, modifications of epicutaneous testing, individual factors influencing the patch test outcome or necessitating special considerations, children, patients with occupational contact dermatitis and drug eruptions as special groups, patch testing of materials brought in by the patient, adverse effects of patch testing, and the final evaluation and patient counselling based on this judgement. Finally, short reference is made to aspects of (continuing) medical education and to electronic collection of data for epidemiological surveillance.


Extracellular calcium transients and action potential configuration changes related to post-stimulatory potentiation in rabbit atrium.
Extracellular calcium transients were monitored with 2 mM tetramethylmurexide at low calcium (250 microM total, 130 microM free), and action potentials were monitored together with developed tension at normal calcium (1.3 mM) during the production and decay of post-stimulatory potentiation in rabbit left atrial strips. At normal calcium, the contractile potentiation produced by a brief burst of 4 Hz stimulation is lost in three to five post-stimulatory excitations, which correlate with a negative staircase of the late action potential. At low calcium, stimulation at 4 Hz for 3-8 s results in a net extracellular calcium depletion of 5-15 microM. At the subsequent potentiated contraction (1-45 s rest), total extracellular calcium increases by 4-8 microM. The contractile response at a second excitation is greatly suppressed and results in little or no further calcium shift; the sequence can be repeated immediately thereafter. Reducing external sodium to 60 mM (sucrose replacement) enhances post-rest contractions, suppresses the late action potential, nearly eliminates loss of contractility and net calcium efflux at post-rest excitations, and markedly reduces extracellular calcium depletion during rapid stimulation. 4-Aminopyridine (1 mM) markedly suppresses the rapid early repolarization of this preparation at post-rest excitations and the loss of contractility at post-rest stimulation from the rested state; during a post-stimulatory potentiation sequence at low calcium, replenishment of extracellular calcium takes several post-stimulatory excitations. Ryanodine (10 nM to 5 microM) abolishes the post-stimulatory contraction at rest periods of greater than 5 s. If the initial repolarization is rapid, ryanodine suppresses the late action potential, calcium efflux during quiescence is greatly accelerated, and subsequent excitations do not result in an accumulation of extracellular calcium. A positive staircase of the early action potential correlates with the magnitude of net extracellular calcium depletion. These findings demonstrate that negative contractile staircases at post-rest stimulation correspond closely to an accumulation of extracellular calcium at activation and a negative staircase of the late action potential; the correlation of these three events suggests that electrogenic sodium-calcium exchange is the common underlying mechanism.


Comet 67P/Churyumov-Gerasimenko sheds dust coat accumulated over the past four years.
Comets are composed of dust and frozen gases. The ices are mixed with the refractory material either as an icy conglomerate, or as an aggregate of pre-solar grains (grains that existed prior to the formation of the Solar System), mantled by an ice layer. The presence of water-ice grains in periodic comets is now well established. Modelling of infrared spectra obtained about ten kilometres from the nucleus of comet Hartley 2 suggests that larger dust particles are being physically decoupled from fine-grained water-ice particles that may be aggregates, which supports the icy-conglomerate model. It is known that comets build up crusts of dust that are subsequently shed as they approach perihelion. Micrometre-sized interplanetary dust particles collected in the Earth's stratosphere and certain micrometeorites are assumed to be of cometary origin. Here we report that grains collected from the Jupiter-family comet 67P/Churyumov-Gerasimenko come from a dusty crust that quenches the material outflow activity at the comet surface. The larger grains (exceeding 50 micrometres across) are fluffy (with porosity over 50 per cent), and many shattered when collected on the target plate, suggesting that they are agglomerates of entities in the size range of interplanetary dust particles. Their surfaces are generally rich in sodium, which explains the high sodium abundance in cometary meteoroids. The particles collected to date therefore probably represent parent material of interplanetary dust particles. This argues against comet dust being composed of a silicate core mantled by organic refractory material and then by a mixture of water-dominated ices. At its previous recurrence (orbital period 6.5 years), the comet's dust production doubled when it was between 2.7 and 2.5 astronomical units from the Sun, indicating that this was when the nucleus shed its mantle. Once the mantle is shed, unprocessed material starts to supply the developing coma, radically changing its dust component, which then also contains icy grains, as detected during encounters with other comets closer to the Sun.


Skeletal muscle insulin signaling and whole-body glucose metabolism following acute sleep restriction in healthy males.
Sleep restriction is associated with impaired glucose metabolism and insulin resistance, however, the underlying mechanisms leading to this impairment are unknown. This study aimed to assess whether the decrease in insulin sensitivity observed after sleep restriction is accompanied by changes in skeletal muscle PKB activity. Ten healthy young males participated in this randomized crossover study which included two conditions separated by a 3-week washout period. Participants underwent two nights of habitual sleep (CON) and two nights of sleep which was restricted to 50% of habitual sleep duration (SR) in the home environment. Whole-body glucose tolerance and insulin sensitivity were assessed by an oral glucose tolerance test after the second night of each condition. Skeletal muscle tissue samples were obtained from the vastus lateralis to determine PKB activity. Findings displayed no effect of trial on plasma glucose concentrations (P = 0.222). Plasma insulin area under the curve was higher after sleep restriction compared to the control (P = 0.013). Matsuda index was 18.6% lower in the sleep restriction (P = 0.010). Fold change in PKB activity from baseline tended to be lower in the sleep restriction condition at 30 min (P = 0.098) and 120 min (P = 0.087). In conclusion, we demonstrated decreased whole-body insulin sensitivity in healthy young males following two nights of sleep restriction. Skeletal muscle insulin signaling findings are inconclusive and require further study to examine any potential changes.


Enhancement of anthracycline growth inhibition in parent and multidrug-resistant Chinese hamster ovary cells by cyclosporin A and its analogues.
Cyclosporins have been shown to sensitize multidrug-resistant cells to chemotherapeutic agents but, generally, have minimal effect on sensitive lines. We studied the effect of cyclosporin A (CsA) and two nonimmunosuppressive analogues, 11-methyl-leucine- (11-Me-Leu-CsA) and 6-methyl-alanine-cyclosporin A (6-Me-Ala-CsA), on the action of doxorubicin (DOX) and 4'-epidoxorubicin against parent (AuXB1) and multidrug-resistant (CHRC5) Chinese hamster ovary cells. CsA and its two analogues reduced the IC50 values for DOX in sensitive AuXB1 cells from 0.1 to 0.01-0.02 microM. Cyclosporins reduced the IC50 of DOX in resistant CHRC5 cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 microM (11-Me-Leu-CsA). Similar results were seen when cyclosporins were combined with 4'-epidoxorubicin. The cyclosporins alone had no effect at these concentrations (1-2.0 micrograms/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CHRC5 cells. The ability of the cyclosporins to enhance anthracycline growth inhibition in parent AuXB1 cells may be related to an increase in drug uptake and an increase in anthracycline-induced DNA damage. CsA increased DOX accumulation as well as DOX-associated DNA single-strand breaks in AuXB1 cells over those seen in cells exposed to DOX alone. The degree of increase in DNA breaks paralleled the degree of growth inhibition seen in cells exposed to the same concentrations of drugs. In contrast, CsA had no effect on DOX accumulation or DNA single-strand breaks in CHRC5 cells. These findings imply that, in the resistant cell line, the enhanced anthracycline growth inhibition in the presence of CsA is independent of DOX accumulation and single-strand DNA breaks. These studies demonstrate that CsA and two nonimmunosuppressive analogues can sensitize both sensitive and resistant Chinese hamster ovary cells to anthracyclines. Furthermore, the mechanisms underlying this effect may differ between sensitive and multidrug-resistant cells.


Should ribavirin be used to treat hepatitis C in dialysis patients?
Hepatitis C virus infection adversely affects outcomes in patients with chronic kidney disease undergoing maintenance dialysis. Pegylated interferon and ribavirin, the standard-of-care treatment in patients with intact renal function, is associated with severe side effects, toxicity, and high dropout rates in this population. Ribavirin has an important role in maintaining antiviral response following completion of therapy and increases sustained viral response (SVR) rates. However, the use of ribavirin in dialysis patients has been limited by the high frequency of severe hemolytic anemia and is currently reserved for study protocols and highly selected candidates treated at experienced centers. Encouraging data from small trials have shown a significant increase in SVR rates with the use of different dosing regimens of ribavirin in addition to interferon-based therapy and aggressive erythroid-stimulating agent support in dialysis patients. Use of ribavirin in selected dialysis patients, particularly renal transplant candidates, by experienced clinicians is appropriate.


Effects of Two Concussions on the Neuropsychological Functioning and Symptom Reporting of High School Athletes.
To assess the effects of two sports-related concussions on neuropsychological functioning and symptom reporting, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) was administered to 483 high school athletes. Three groups of athletes were determined based on the number of previous concussions: no concussion (n = 409), 1 concussion (n = 58), and 2 concussions (n = 16). The results showed that the three groups did not differ in terms of their ImPACT composite scores (Verbal Memory, Visual Memory, Reaction Time, and Processing Speed) and the Total Symptom Score. As there are only a few studies that have reported the sequelae of 2 concussions in high school athletes, it is premature to declare that a repeated concussion does not have persistent neurocognitive effects on high school athletes.


Graphene oxide hydration and solvation: an in situ neutron reflectivity study.
Graphene oxide membranes were recently suggested for applications in separation of ethanol from water using a vapor permeation method. Using isotope contrast, neutron reflectivity was applied to evaluate the amounts of solvents intercalated into a membrane from pure and binary vapors and to evaluate the selectivity of the membrane permeation. Particularly, the effect of D2O, ethanol and D2O-ethanol vapours on graphene oxide (GO) thin films (∼25 nm) was studied. The interlayer spacing of GO and the amount of intercalated solvents were evaluated simultaneously as a function of vapour exposure duration. The significant difference in neutron scattering length density between D2O and ethanol allows distinguishing insertion of each component of the binary mixture into the GO structure. The amount of intercalated solvent at saturation corresponds to 1.4 molecules per formula unit for pure D2O (∼1.4 monolayers) and 0.45 molecules per formula unit (one monolayer) for pure ethanol. This amount is in addition to H2O absorbed at ambient humidity. Exposure of the GO film to ethanol-D2O vapours results in intercalation of GO with both solvents even for high ethanol concentration. A mixed D2O-ethanol layer inserted into the GO structure is water enriched compared to the composition of vapours due to slower ethanol diffusion into GO interlayers.


The sense and nonsense of direct-to-consumer genetic testing for cardiovascular disease.
Expectations are high that increasing knowledge of the genetic basis of cardiovascular disease will eventually lead to personalised medicine-to preventive and therapeutic interventions that are targeted to at-risk individuals on the basis of their genetic profiles. Most cardiovascular diseases are caused by a complex interplay of many genetic variants interacting with many non-genetic risk factors such as diet, exercise, smoking and alcohol consumption. Since several years, genetic susceptibility testing for cardiovascular diseases is being offered via the internet directly to consumers. We discuss five reasons why these tests are not useful, namely: (1) the predictive ability is still limited; (2) the risk models used by the companies are based on assumptions that have not been verified; (3) the predicted risks keep changing when new variants are discovered and added to the test; (4) the tests do not consider non-genetic factors in the prediction of cardiovascular disease risk; and (5) the test results will not change recommendations of preventive interventions. Predictive genetic testing for multifactorial forms of cardiovascular disease clearly lacks benefits for the public. Prevention of disease should therefore remain focused on family history and on non-genetic risk factors as diet and physical activity that can have the strongest impact on disease risk, regardless of genetic susceptibility.


MR, CT, and plain film imaging of the developing skull base in fetal specimens.
The developing fetal skull base has previously been studied via dissection and low-resolution CT. Most of the central skull base develops from endochondral ossification through an intermediary chondrocranium. We traced the development of the normal fetal skull base by using plain radiography, MR imaging, and CT. Twenty-nine formalin-fixed fetal specimens ranging from 9 to 24 weeks' gestational age were examined with mammographic plain radiography, CT, and MR imaging. Skull base development and ossification were assessed. The postsphenoid cartilages enclose the pituitary and fuse to form the basisphenoid, from which the sella turcica and the posterior body of the sphenoid bone originate. The presphenoid cartilages will form the anterior body of the sphenoid bone. Portions of the presphenoid cartilage give rise to the mesethmoid cartilage, which forms the central portion of the anterior skull base. Ossification begins in the occipital bone (12 weeks) and progresses anteriorly. The postsphenoid (14 weeks) and then the presphenoid portion (17 weeks) of the sphenoid bone ossify. Ossification is seen laterally (16 weeks) in the orbitosphenoid, which contributes to the lesser wing of the sphenoid, and the alisphenoid (15 weeks), which forms the greater wing. MR imaging can show early progressive ossification of the cartilaginous skull base and its relation to intracranial structures. The study of fetal developmental anatomy may lead to a better understanding of abnormalities of the skull base.


Amino acid supplementation for reversing bed rest and steroid myopathies.
Muscular inactivity is inherent in many circumstances, including convalescence from serious illness or injury, spaceflight, and the progression of aging. Inactivity in a healthy individual leads to a decrease in whole-body protein turnover composed primarily of a decrease in muscle protein synthesis. The decrease in muscle protein synthesis leads to a substantial loss of lean body mass. We have demonstrated that this loss of lean mass is greater when inactivity is accompanied by stress, specifically hypercortisolemia. During convalescence from trauma or injury, the anabolic stimulus provided by nutrient ingestion represents a primary means of ameliorating the loss of muscle protein. We have previously demonstrated that ingestion of essential amino acids (EAAs), formulated to mimic the proportion of EAAs in muscle, provides a potent anabolic stimulus for muscle protein. Recently, we demonstrated that EAA supplementation throughout 28 d of bed rest stimulated net muscle protein synthesis. The repeated stimulation translated to maintenance of lean body mass and an amelioration of functional decrement compared to a placebo treatment. We have also demonstrated that this EAA supplement stimulates net protein synthesis during acute hypercortisolemia and are currently testing the effects during prolonged inactivity. Although EAAs promote muscle anabolism during hypercortisolemia, it is unlikely that a nutritional intervention alone would be effective in maintaining lean body mass during severe stress. It may be necessary to concomitantly reduce the catabolic influence of cortisol or provide another anabolic stimulus.