New and Improved? 21st Century Cures Act Revisions to Certificates of Confidentiality.
Certificates of Confidentiality ("Certificates") are a federal legal tool designed to protect sensitive, identifiable research data from compelled disclosure. Congress first authorized their use in 1970 to facilitate research on illegal drug use. The scope of their use was later expanded to cover mental health research and then again to apply broadly to identifiable, sensitive research data, regardless of topic. Certificates can be critical to enabling conduct of essential research on sensitive topics, such as effective interventions to curb the opioid epidemic or reduce HIV transmission among minority youth. Nevertheless, there have been criticisms about Certificates and their use on several grounds. For example, researchers and institutional review boards ("IRBs") may lack sufficient knowledge about them and, therefore, may not consider using them in studies for which they would be appropriate. In contrast to other protections, such as Department of Justice Privacy Certificates, Certificate protections were not automatically extended to these studies, but instead required an application. In addition, the concept of identifiable data had not kept up with technological changes that may allow for reidentification of data previously considered unidentifiable. Although a researcher who obtained a Certificate could use it to resist a legal demand for identifiable data, little was known about the actual effectiveness of the protection provided. The 21st Century Cures Act substantially revises the Certificates authorizing statute, and many of the changes are directly responsive to the criticisms that have been raised. Significantly, the Secretary of the Department of Health and Human Services ("HHS") must issue Certificate protection to federally funded research involving identifiable, sensitive research data, and the National Institutes of Health ("NIH") will automatically include such protections to research it funds. Non-federally funded researchers can continue to apply for Certificate protection. The definition of identifiable has been expanded to include data "for which there is at least a very small risk" of identification. Certificates will now not only protect against compelled disclosure, but also render protected data inadmissible in legal proceedings without participant consent. In addition, voluntary disclosure is no longer authorized, but there is now a broad exception for disclosure as required by federal, state, and local laws. In this paper, based on our previous research on Certificates, we critically evaluate the 21st Century Cures Act's Certificates revisions and their positive and negative impact on the dual goals of facilitating important, sensitive research while maximally protecting individual research participants.


Characterization of Class IIa Bacteriocin Resistance in Enterococcus faecium.
Vancomycin-resistant enterococci, particularly resistant Enterococcus faecium, pose an escalating threat in nosocomial environments because of their innate resistance to many antibiotics, including vancomycin, a treatment of last resort. Many class IIa bacteriocins strongly target these enterococci and may offer a potential alternative for the management of this pathogen. However, E. faecium's resistance to these peptides remains relatively uncharacterized. Here, we explored the development of resistance of E. faecium to a cocktail of three class IIa bacteriocins: enterocin A, enterocin P, and hiracin JM79. We started by quantifying the frequency of resistance to these peptides in four clinical isolates of E. faecium We then investigated the levels of resistance of E. faecium 6E6 mutants as well as their fitness in different carbon sources. In order to elucidate the mechanism of resistance of E. faecium to class IIa bacteriocins, we completed whole-genome sequencing of resistant mutants and performed reverse transcription-quantitative PCR (qRT-PCR) of a suspected target mannose phosphotransferase (ManPTS). We then verified this ManPTS's role in bacteriocin susceptibility by showing that expression of the ManPTS in Lactococcus lactis results in susceptibility to the peptide cocktail. Based on the evidence found from these studies, we conclude that, in accord with other studies in E. faecalis and Listeria monocytogenes, resistance to class IIa bacteriocins in E. faecium 6E6 is likely caused by the disruption of a particular ManPTS, which we believe we have identified.


The biology of white adipocyte proliferation.
Expanded adipose tissue mass increases the risk for many clinical conditions including diabetes, hypertension, coronary atherosclerotic heart disease, and some forms of cancer. Therefore, it is imperative that we understand the mechanisms by which fat pads expand. The enlargement of fat cells during the development of obesity has been previously hypothesized to be a triggering factor for the proliferation of new fat cells. There is now a preponderance of evidence that adipose tissue is a source of growth factors such as IGF-I, IGF binding proteins, TNF alpha, angiotensin II, and MCSF that are capable of stimulating proliferation. The relative importance of these autocrine/paracrine factors in the normal control of preadipocyte proliferation is unknown. In addition, the proliferative response of preadipocytes to the paracrine milieu is undoubtedly modulated by neural inputs to fat tissue and/or serum factors. Together, these multiple regulatory controls orchestrate overall and region-specific adipose tissue cellularity responses associated with the development of hyperplastic obesity. Both in vivo and in vitro studies are needed to understand the complex, interacting physiological mechanisms by which growth of this important organ is regulated.


HotSwap for bioinformatics: a STRAP tutorial.
Bioinformatics applications are now routinely used to analyze large amounts of data. Application development often requires many cycles of optimization, compiling, and testing. Repeatedly loading large datasets can significantly slow down the development process. We have incorporated HotSwap functionality into the protein workbench STRAP, allowing developers to create plugins using the Java HotSwap technique. Users can load multiple protein sequences or structures into the main STRAP user interface, and simultaneously develop plugins using an editor of their choice such as Emacs. Saving changes to the Java file causes STRAP to recompile the plugin and automatically update its user interface without requiring recompilation of STRAP or reloading of protein data. This article presents a tutorial on how to develop HotSwap plugins. STRAP is available at http://strapjava.de and http://www.charite.de/bioinf/strap. HotSwap is a useful and time-saving technique for bioinformatics developers. HotSwap can be used to efficiently develop bioinformatics applications that require loading large amounts of data into memory.


Interweaving spins with their environment: novel inorganic nanohybrids with controllable magnetic properties.
We discuss current developments in the synthesis and characterization of magnetic nanohybrids made of molecular magnets and nanostructured materials. We first review several novel approaches that have recently been attempted to combine magnetic coordination complexes with differently-obtained inorganic systems. Special focus is placed on how the altered environment can affect the magnetic properties of single molecules, providing new routes to multifunctional devices based on hybrid magnetic nanosystems. We then show how this approach is opening new outlooks towards the control of nanomagnets using external stimuli (e.g. photons, electrons, etc.) and for the creation of ultra-sensitive devices. Eventually we provide a unified vision of the area, with a personal perspective on the main goals currently at stake and of possible future developments.


In defence of model-based inference in phylogeography.
Recent papers have promoted the view that model-based methods in general, and those based on Approximate Bayesian Computation (ABC) in particular, are flawed in a number of ways, and are therefore inappropriate for the analysis of phylogeographic data. These papers further argue that Nested Clade Phylogeographic Analysis (NCPA) offers the best approach in statistical phylogeography. In order to remove the confusion and misconceptions introduced by these papers, we justify and explain the reasoning behind model-based inference. We argue that ABC is a statistically valid approach, alongside other computational statistical techniques that have been successfully used to infer parameters and compare models in population genetics. We also examine the NCPA method and highlight numerous deficiencies, either when used with single or multiple loci. We further show that the ages of clades are carelessly used to infer ages of demographic events, that these ages are estimated under a simple model of panmixia and population stationarity but are then used under different and unspecified models to test hypotheses, a usage the invalidates these testing procedures. We conclude by encouraging researchers to study and use model-based inference in population genetics.


A system for sharing routine surgical pathology specimens across institutions: the Shared Pathology Informatics Network.
This report presents an overview for pathologists of the development and potential applications of a novel Web enabled system allowing indexing and retrieval of pathology specimens across multiple institutions. The system was developed through the National Cancer Institute's Shared Pathology Informatics Network program with the goal of creating a prototype system to find existing pathology specimens derived from routine surgical and autopsy procedures ("paraffin blocks") that may be relevant to cancer research. To reach this goal, a number of challenges needed to be met. A central aspect was the development of an informatics system that supported Web-based searching while retaining local control of data. Additional aspects included the development of an eXtensible Markup Language schema, representation of tissue specimen annotation, methods for deidentifying pathology reports, tools for autocoding critical data from these reports using the Unified Medical Language System, and hierarchies of confidentiality and consent that met or exceeded federal requirements. The prototype system supported Web-based querying of millions of pathology reports from 6 participating institutions across the country in a matter of seconds to minutes and the ability of bona fide researchers to identify and potentially to request specific paraffin blocks from the participating institutions. With the addition of associated clinical and outcome information, this system could vastly expand the pool of annotated tissues available for cancer research as well as other diseases.


Exploring a self-help coping intervention for pregnant women with a miscarriage history.
Pregnant women with a history of miscarriages experience symptoms of anxiety and depression in a subsequent pregnancy and are in need of support in the period after miscarriage, when trying to get pregnant again and during the first phase of pregnancy. The aim of this study was to investigate whether a Positive Reappraisal Coping Intervention (PRCI) and Daily Record Keeping (DRK) chart, developed for use in assisted conception treatment, are also appropriate for use in pregnant women with a history of miscarriage(s). In this convergent parallel mixed method study, thirteen women visiting an Early Pregnancy Unit and/or Recurrent Miscarriage Clinic in a university medical center in the Netherlands were selected on the basis of the number of miscarriages and age. Exclusion criteria were not speaking the Dutch language, pregnancy after fertility treatment and having a medical cause identified for the miscarriages. Women used the PRCI and DRK for 3 weeks in a subsequent pregnancy. Quantitative data were obtained from the DRK and were analyzed by reporting frequencies and means for each case. Qualitative data were collected by semi-structured interviews and were analyzed by using thematic analysis. The majority of the women were able to use the PRCI and DRK for 3weeks. Women adapted the way in which they used the PRCI and DRK based on their judgment about the effect, the intensity of the emotions they experienced, or whether they felt the effort to use these instruments to be worthwhile or not.


Gestational immunosuppression is mediated by specific Lyt 2+ T cells.
Female BALB/c mice were tested during the first week of pregnancy for their lymphocyte-mediated cytotoxic response to paternal alloantigens. Spleen or uterine regional lymph node cells were not spontaneously cytotoxic against concanavalin A-activated paternal target lymphocytes. Female mice immunized i.p. with paternal H-2-matched or third-party allogeneic cells on the fifth day and tested on the 12th day of pregnancy demonstrated total suppression of cell-mediated cytotoxicity to paternal alloantigens and partial suppression to third-party alloantigens. A generalized non-specific immunosuppression to alloantigens seems to be associated with pregnancy, which may indicate that soluble factors were involved in mediating the suppressive effect. Cocultures of spleen cells from virgin mice and the whole population of spleen or regional lymph node cells from allogeneic pregnant female mice demonstrated specifically suppressed responses to alloantigens. Similar cocultures with Thy 1.2- and Lyt 2.2-depleted populations restored the cytotoxicity levels of activated spleen cells. We conclude that antigen-specific Lyt 2+ T cells were activated during pregnancy to regulate the female T-cell response to paternal alloantigens.


Design and activity of a murine and humanized anti-CEACAM6 single-chain variable fragment in the treatment of pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, with surgery being the only curative modality for localized disease, and gemcitabine with or without erlotinib remains the standard of therapy for unresectable or metastatic disease. CEACAM6 is overexpressed in human PDA independent of stage or grade and causes anoikis resistance when dysregulated. Because murine monoclonal antibody 13-1 possesses target-specific cytotoxicity in human PDA cell lines, we designed a humanized anti-CEACAM6 single-chain variable fragment (scFv) based on monoclonal antibody 13-1. PEGylation of the glycine-serine linker was used to enhance plasma half-life. These scFvs bound CEACAM6 with high affinity, exhibited cytotoxic activity, and induced dose-dependent poly(ADP-ribose) polymerase cleavage. Murine PDA xenograft models treated with humanized scFv alone elicited tumor growth inhibition, which was enhanced in combination with gemcitabine. Immunohistochemistry showed significant apoptosis, with inhibition of angiogenesis and proliferation, and preservation of the target. Collectively, our results have important implications for the development of novel antibody-based therapies against CEACAM6 in PDA.


Longitudinal decline in lung function in patients with occupational asthma due to western red cedar.
There are few reports about longitudinal changes in lung function in asthmatic patients. Patients with asthma had a greater loss of lung function than normal healthy adults. To date, there have been no studies about the longitudinal changes in lung function in patients with occupational asthma. 280 male patients with red cedar asthma (RCA) who were followed up for at least one year were the study group. The exposed controls consisted of 399 male sawmill workers. Forced expiratory volume in one second (FEV1) was measured with a Collins water spirometer. Changes in FEV1 over time (FEV1 slope) were calculated by a two point method for each subject. Atopy was considered to be present if the subjects showed at least one positive response to three allergens by skin prick test. Multiple regression analysis was carried out to examine factors that might affect longitudinal decline in FEV1. Patients with RCA who were still exposed had a greater decline in FEV1 slope (-26 ml/y) than sawmill workers. Smokers also showed a greater rate of decline in FEV1 (-43 ml/y) than non-smokers. Patients with RCA who continued to be exposed had a greater rate of decline in FEV1 than sawmill workers. Early diagnosis of occupational asthma and removal of these patients from a specific sensitiser is important in the prevention of further deterioration of lung function and respiratory symptoms.


With a little help from my friends: The effect of social proximity on emotion regulation-related brain activity.
When experiencing negative emotions, individuals often reach out for social support to help regulate their emotions. In times of an acute crisis, however, close friends might not be available, and physical closeness might be impossible. This functional magnetic resonance imaging (fMRI) study investigated the effect of social proximity on the effectiveness of social support for regulating emotions and the underlying neural mechanisms. Participants regulated their emotions in response to negative images either alone (intrapersonal regulation), or with help of a picture and supporting sentence provided by the best friend, or by a stranger (interpersonal regulation). Regulation success was enhanced for the support of friends compared to regulating alone or with the support of strangers. This effect was accompanied by the interplay of large-scale brain networks involved in processing emotions, social cognition, and cognitive control. Interpersonal regulation appeared to be implemented by lateral prefrontal regions. The amygdala showed increased activation for strangers. The activation profile of the social cognition network suggests a role in supporting empathic and mentalizing processes. The results highlight the power of social connectedness for boosting emotion regulation ability and the different neural networks that contribute to this effect.


A rare variant of the ulnar artery with important clinical implications: a case report.
Variations in the major arteries of the upper limb are estimated to be present in up to one fifth of people, and may have significant clinical implications. During routine cadaveric dissection of a 69-year-old fresh female cadaver, a superficial brachioulnar artery with an aberrant path was found bilaterally. The superficial brachioulnar artery originated at midarm level from the brachial artery, pierced the brachial fascia immediately proximal to the elbow, crossed superficial to the muscles that originated from the medial epicondyle, and ran over the pronator teres muscle in a doubling of the antebrachial fascia. It then dipped into the forearm fascia, in the gap between the flexor carpi radialis and the palmaris longus. Subsequently, it ran deep to the palmaris longus muscle belly, and superficially to the flexor digitorum superficialis muscle, reaching the gap between the latter and the flexor carpi ulnaris muscle, where it assumed is usual position lateral to the ulnar nerve. As far as the authors could determine, this variant of the superficial brachioulnar artery has only been described twice before in the literature. The existence of such a variant is of particular clinical significance, as these arteries are more susceptible to trauma, and can be easily confused with superficial veins during medical and surgical procedures, potentially leading to iatrogenic distal limb ischemia.


Self-assembly of MoO3 needles in gas current for cubic formation pathway.
Nucleation and subsequent rapid growth are enigmatic due to the unrevealed pathways. Despite the relatively simpler mechanism compared to nucleation and growth in solution, that in vapor has received little attention. The largest hindrance to unveiling this process may be observing the rapid and mesoscopic-scale phenomena. To overcome this hindrance, we combine an experimental approach with in situ spatial scanning Fourier-transform infrared spectroscopy, which reveals the nucleating and growing nanoparticles in vapor. The nanoparticles are then collected at different evolutionary stages and analyzed by ex situ transmission electron microscopy (TEM). Needle-shaped molybdenum oxide (MoO3) nanoparticles were formed within ∼0.1 s after homogeneous nucleation from a highly supersaturated vapor. Over one second, the needle particles gradually evolved into a cubic shape by fusion in a crystallographically favored orientation in a free-flying state in vapor. The similar sizes of the elongated axes of the needle and cubic structures suggest an additional growth stage, in which the needle particles become the growth units of the cubic particles. The morphology of a final crystal should reflect the formation environment of the particle because growing crystals are sensitive to the formation conditions such as temperature, concentration, and impurities. Although nucleation under very high supersaturation induces the anisotropic growth of the needle particles, this information of the initial nucleation environment is lost in the final cubic crystal. These findings enrich our understanding of pathways in the nucleation and growth of nanoparticles and provide new insights into the growth stages driven by oriented attachment.


Genome size is a strong predictor of cell size and stomatal density in angiosperms.
Across eukaryotes phenotypic correlations with genome size are thought to scale from genome size effects on cell size. However, for plants the genome/cell size link has only been thoroughly documented within ploidy series and small subsets of herbaceous species. Here, the first large-scale comparative analysis is made of the relationship between genome size and cell size across 101 species of angiosperms of varying growth forms. Guard cell length and epidermal cell area were used as two metrics of cell size and, in addition, stomatal density was measured. There was a significant positive relationship between genome size and both guard cell length and epidermal cell area and a negative relationship with stomatal density. Independent contrast analyses revealed that these traits are undergoing correlated evolution with genome size. However, the relationship was growth form dependent (nonsignificant results within trees/shrubs), although trees had the smallest genome/cell sizes and the highest stomatal density. These results confirm the generality of the genome size/cell size relationship. The results also suggest that changes in genome size, with concomitant influences on stomatal size and density, may influence physiology, and perhaps play an important genetic role in determining the ecological and life-history strategy of a species.


Treating subglottic haemangioma with methylprednisolone and interferonα-2a.
Subglottic haemangiomas are benign vascular malformations presenting in early infancy with respiratory distress due to progressive airway obstruction. The lesion, after undergoing proliferation during the first few months, naturally involutes by an age of 2-3 years. Due to high incidence of mortality, therapy should be initiated immediately. Multiple therapeutic options, such as steroids, interferon, surgery and laser ablation, are available but the best treatment is controversial. This report describes an infant presenting with respiratory distress and cutaneous haemangioma who was detected to have airway obstructive haemangioma from the subglottis to the carina. Due to the massive size, surgical and laser ablation could not be exercised. Also, the infant showed no response to dexamethasone, prednisolone or interferon. Following failure of these modalities, the infant was successfully managed with concurrent administration of daily interferon and pulse methylprednisolone. The regime resulted in rapid shrinkage of the haemangioma and resolution of symptoms, with no recurrence up to 24 months of age.


Current thinking regarding potential neurotoxicity of general anesthesia in infants.
Numerous preclinical studies have shown that general anesthetics adversely influence the development of young brains. These adverse effects are dose-dependent occurring in specific stages of brain development. Histologic examinations show increased apoptosis, pathological neurogenesis and dendritic formation after exposure in infant animals to virtually all general anesthetics at a clinically effective dose which are associated with memory and behavioral changes at adulthood. Clinical research into the long-term effects of anesthesia during early childhood on brain development is mainly limited to retrospective cohort studies, with conflicting results. Only recently, the interim analysis of a prospective randomized clinical trial examining the effects of general anesthesia has been published. In this GAS-study the influence up to 1 h of general anesthesia versus regional anesthesia in young infants has been assessed on the neurocognitive functioning at the age of 2 years. No differences were found between the two groups. However, the primary outcome analysis which is the 5-year outcomes will not be complete until 2018. Pending clear evidence, anesthesiologists should discuss the indication of anesthesia for surgery and diagnostic procedures with caregivers and parents taking into consideration the risks and benefits of the planned procedure.


Making the Grade: The Impact of Low-Grade Toxicities on Patient Preference for Treatment With Novel Agents.
Targeted therapies have shown clinical benefit in the treatment of solid tumors. The toxicity profiles and treatment duration and schedule of these agents differ considerably from those of traditional chemotherapy. Many studies of targeted therapies report sizeable numbers of grade 1 or 2 toxicities. We sought to determine whether anticipation of low-grade toxicities and treatment logistics impact patient willingness to undergo therapy. A total of 209 patients with cancer (101 lung and 108 breast) were surveyed at the Vanderbilt-Ingram Cancer Center regarding willingness to comply with treatment based on anticipated efficacy, dosing convenience, and toxicity profiles. All toxicities were Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grade 1 and 2. Willingness to comply with treatment depending on toxicity, anticipated benefit, cancer type, and dosing convenience was compared. A substantial number of patients (2.9%-48.8%, depending on the toxicity described) professed unwillingness to undergo treatment because of anticipated grade 1 and 2 toxicities. Gastrointestinal and constitutional toxicities had a stronger negative impact on patient willingness to undergo therapy than dermatologic toxicity. Patients with lung cancer were significantly more likely to accept dermatologic and gastrointestinal toxicities than those with breast cancer. Willingness to tolerate toxicities correlated with expected benefit in terms of life expectancy and chance of cure. Lengthy travel distance for treatment negatively impacted willingness to undergo treatment. Anticipation of low-grade toxicities and dosing inconvenience negatively impacts patient willingness to be treated, which may affect adherence and therapeutic outcomes from therapy. Long-term tolerability should be considered when developing and assessing the impact of novel agents.


Mechanism of insect resistance to the microbial insecticide Bacillus thuringiensis.
Receptor binding studies show that resistance of a laboratory-selected Plodia interpunctella strain to a Bacillus thuringiensis insecticidal crystal protein (ICP) is correlated with a 50-fold reduction in affinity of the membrane receptor for this protein. The strain is sensitive to a second type of ICP that apparently recognizes a different receptor. Understanding the mechanism of resistance will provide strategies to prevent or delay resistance and hence prolong the usefulness of B. thuringiensis ICPs as environmentally safe insecticides.


Response: Reading between the lines of cancer screening trials: using modeling to understand the evidence.
In our article about limitations of basing screening policy on screening trials, we offered several examples of ways in which modeling, using data from large screening trials and population trends, provided insights that differed somewhat from those based only on empirical trial results. In this editorial, we take a step back and consider the general question of whether randomized screening trials provide the strongest evidence for clinical guidelines concerning population screening programs. We argue that randomized trials provide a process that is designed to protect against certain biases but that this process does not guarantee that inferences based on empirical results from screening trials will be unbiased. Appropriate quantitative methods are key to obtaining unbiased inferences from screening trials. We highlight several studies in the statistical literature demonstrating that conventional survival analyses of screening trials can be misleading and list a number of key questions concerning screening harms and benefits that cannot be answered without modeling. Although we acknowledge the centrality of screening trials in the policy process, we maintain that modeling constitutes a powerful tool for screening trial interpretation and screening policy development.


The TRPv1 receptor is a mediator of the exercise pressor reflex in rats.
The skeletal muscle exercise pressor reflex (EPR) induces increases in heart rate (HR) and mean arterial pressure (MAP) during physical activity. This reflex is activated during contraction by stimulation of afferent fibres responsive to mechanical distortion and/or the metabolic by-products of skeletal muscle work. The molecular mechanisms responsible for activating these afferent neurons have yet to be identified. It has been reported that activation of the transient receptor potential vanilloid 1 (TRPv1) receptor within skeletal muscle (localized to unmyelinated afferent fibres) elicits increases in MAP and HR similar to those generated by the EPR. Thus, we hypothesized that stimulation of the TRPv1 receptor during muscle contraction contributes to the activation of the EPR. The EPR was activated by electrically induced static muscle contraction of the hindlimb in decerebrate Sprague-Dawley rats (n = 61) before and after the administration of the TRPv1 receptor antagonists, capsazepine (Capz; 100 microg/100 microl), iodoresinaferatoxin (IRTX; 1 microg/100 microl), or Ruthenium Red (RR; 100 microg/100 microl). Static muscle contraction alone induced increases in both HR (8 +/- 2 bpm) and MAP (21 +/- 3 mmHg). The HR and MAP responses to contraction were significantly lower (P < 0.05) after the administration of Capz (2 +/- 1 bpm; 7 +/- 1 mmHg, respectively), IRTX (3 +/- 2 bpm; 5 +/- 3 mmHg, respectively) and RR (0 +/- 1, bpm; 5 +/- 2 mmHg, respectively). These data suggest that the TRPv1 receptor contributes importantly to activation of the EPR during skeletal muscle contraction in the rat.


Lateral inferotemporal cortex maintains conceptual-semantic representations in verbal working memory.
Verbal working memory, that is, the temporary maintenance of linguistic information in an activated state, is typically assumed to rely on phonological representations. Recent evidence from behavioral, neuropsychological, and electrophysiological studies, however, suggests that conceptual-semantic representations may also be maintained in an activated state. We developed a new semantic working memory task that involves the maintenance of a novel conceptual combination. Functional magnetic resonance imaging data acquired during the maintenance of conceptual combinations, relative to an item recognition task without the possibility of conceptual combination, demonstrate increased activation in the posterior left middle and inferior temporal gyri (known to be involved in conceptual representations) and left inferior frontal gyrus (known to be involved in semantic control processes). We suggest that this temporo-frontal system supports maintenance of conceptual information in working memory, with the frontal regions controlling the sustained activation of heteromodal conceptual representations in the inferior temporal cortex.


Strategies for cutting hospital beds: the impact on patient service.
To develop insights on the impact of size, average length of stay, variability, and organization of clinical services on the relationship between occupancy rates and delays for beds. The primary data source was Beth Israel Deaconess Medical Center in Boston. Secondary data were obtained from the United Hospital Fund of New York reflecting data from about 150 hospitals. Data from Beth Israel Deaconess on discharges and length of stay were analyzed and fit into appropriate queueing models to generate tables and graphs illustrating the relationship between the variables mentioned above and the relationship between occupancy levels and delays. In addition, specific issues of current concern to hospital administrators were analyzed, including the impact of consolidation of clinical services and utilizing hospital beds uniformly across seven days a week rather than five. Using target occupancy levels as the primary determinant of bed capacity is inadequate and may lead to excessive delays for beds. Also, attempts to reduce hospital beds by consolidation of different clinical services into single nursing units may be counterproductive. More sophisticated methodologies are needed to support decisions that involve bed capacity and organization in order to understand the impact on patient service.


Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs.
Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the treatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.


Characterization of the Phenotype Associated with Microduplication Reciprocal to NF1 Microdeletion Syndrome.
17q11.2 microduplication syndrome is a recently described relatively rare condition associated with a nonspecific phenotype. Intellectual disability, developmental delay, and dysmorphisms are the only clinical features common to a majority of cases. Seventeen patients have been reported so far. Here, we present another patient with 17q11.2 duplication and no signs of neurofibromatosis type 1, identified by array-CGH. We compared clinical features and genetic data with those of previously reported patients with 17q11.2 microduplications. We also analyzed the gene content of the duplicated region in order to investigate the possible role of specific genes in the clinical phenotype of our patient.


Cognitive deterioration in adult epilepsy: Does accelerated cognitive ageing exist?
A long-standing concern has been whether epilepsy contributes to cognitive decline or so-called 'epileptic dementia'. Although global cognitive decline is generally reported in the context of chronic refractory epilepsy, it is largely unknown what percentage of patients is at risk for decline. This review is focused on the identification of risk factors and characterization of aberrant cognitive trajectories in epilepsy. Evidence is found that the cognitive trajectory of patients with epilepsy over time differs from processes of cognitive ageing in healthy people, especially in adulthood-onset epilepsy. Cognitive deterioration in these patients seems to develop in a 'second hit model' and occurs when epilepsy hits on a brain that is already vulnerable or vice versa when comorbid problems develop in a person with epilepsy. Processes of ageing may be accelerated due to loss of brain plasticity and cognitive reserve capacity for which we coin the term 'accelerated cognitive ageing'. We believe that the concept of accelerated cognitive ageing can be helpful in providing a framework understanding global cognitive deterioration in epilepsy.


Observation of transient structural-transformation dynamics in a Cu2S nanorod.
The study of first-order structural transformations has been of great interest to scientists in many disciplines. Expectations from phase-transition theory are that the system fluctuates between two equilibrium structures near the transition point and that the region of transition broadens in small crystals. We report the direct observation of structural fluctuations within a single nanocrystal using transmission electron microscopy. We observed trajectories of structural transformations in individual nanocrystals with atomic resolution, which reveal details of the fluctuation dynamics, including nucleation, phase propagation, and pinning of structural domains by defects. Such observations provide crucial insight for the understanding of microscopic pathways of phase transitions.


Docetaxel plus epirubicin as first-line chemotherapy in MBC (KCSG 01-10-05): phase II trial and the predictive values of circulating HER2 extracellular domain and vascular endothelial growth factor.
The anthracyclines and taxanes are considered to be the most active drugs in metastatic breast cancer (MBC). We conducted a multicenter phase II study to evaluate the efficacy and tolerability of the docetaxel plus epirubicin combination chemotherapy as first-line treatment in MBC and performed a prospective assessment of the predictive values of circulating HER2 extracellular domain (ECD) and vascular endothelial growth factor (VEGF). Docetaxel 75 mg/m(2) and epirubicin 75 mg/m(2) were given intravenously every 3 weeks. Prophylactic G-CSF was not used. Pretreatment serum HER2 ECD and VEGF levels were measured by enzyme immunoassay. Forty MBC patients were enrolled, and 39 patients were evaluable for toxicities and 38 for response. Complete response was observed in 3 (7.9%) patients, partial response in 20 (52.6%) (overall response rate 60.5%), stable disease in 11 (28.9%) and disease progression in 4 (10.5%). After a median follow-up of 22.5 months, the median duration of response was 28 weeks, median time to disease progression was 32 weeks, and median survival was 15.8 months. Two-hundred and fifteen cycles of treatment were administered (median, 6 cycles per patient). Grade 3 and 4 neutropenia were observed during 24 (11.2%) and 74 (35%) cycles respectively, and grade 3 or 4 febrile neutropenia in 24 (11.2%) cycles. Elevated circulating HER2 ECD levels were found to be associated with a shorter response duration (p<0.005) and shorter time to progression (p<0.005). However, elevated VEGF levels were not found to be correlated with response rate or survival. We concluded that the docetaxel and epirubicin combination is an effective first-line treatment in MBC patients and that elevated serum HER2 ECD levels, but not circulating VEGF levels, predict a poor outcome.


Use of Chlorhexidine Preparations in Total Joint Arthroplasty.
Prosthetic joint infection (PJI) is a serious complication after total joint arthroplasty (TJA). Chlorhexidine is a widely used antiseptic because of its rapid and persistent action. It is well tolerated and available in different formulations at various concentrations. Chlorhexidine can be used for pre-operative skin cleansing, surgical site preparation, hand antisepsis of the surgical team and intra-articular irrigation of infected joints. The optimal intra-articular concentration of chlorhexidine gluconate in irrigation solution is 2%, to provide a persistent decrease in biofilm formation, though cytotoxicity might be an issue. Although chlorhexidine is relatively cheap, routine use of chlorhexidine without evidence of clear benefits can lead to unnecessary costs, adverse effects and even emergence of resistance. This review focuses on the current applications of various chlorhexidine formulations in TJA. As the treatment of PJI is challenging and expensive, effective preparations of chlorhexidine could help in the prevention and control of PJI.


Assessing Adherence to Healthy Dietary Habits Through the Urinary Food Metabolome: Results From a European Two-Center Study.
Diet is one of the most important modifiable lifestyle factors in human health and in chronic disease prevention. Thus, accurate dietary assessment is essential for reliably evaluating adherence to healthy habits. The aim of this study was to identify urinary metabolites that could serve as robust biomarkers of diet quality, as assessed through the Alternative Healthy Eating Index (AHEI-2010). We set up two-center samples of 160 healthy volunteers, aged between 25 and 50, living as a couple or family, with repeated urine sampling and dietary assessment at baseline, and 6 and 12 months over a year. Urine samples were subjected to large-scale metabolomics analysis for comprehensive quantitative characterization of the food-related metabolome. Then, lasso regularized regression analysis and limma univariate analysis were applied to identify those metabolites associated with the AHEI-2010, and to investigate the reproducibility of these associations over time. Several polyphenol microbial metabolites were found to be positively associated with the AHEI-2010 score; urinary enterolactone glucuronide showed a reproducible association at the three study time points [false discovery rate (FDR): 0.016, 0.014, 0.016]. Furthermore, other associations were found between the AHEI-2010 and various metabolites related to the intake of coffee, red meat and fish, whereas other polyphenol phase II metabolites were associated with higher AHEI-2010 scores at one of the three time points investigated (FDR < 0.05 or β ≠ 0). We have demonstrated that urinary metabolites, and particularly microbiota-derived metabolites, could serve as reliable indicators of adherence to healthy dietary habits. www.ClinicalTrials.gov, Identifier: NCT03169088.


Transgenic overexpression of bone morphogenetic protein 11 propeptide in skeleton enhances bone formation.
Bone morphogenetic protein 11 (BMP11) is a key regulatory protein in skeletal development. BMP11 propeptide has been shown to antagonize GDF11 activity in vitro. To explore the role of BMP11 propeptide in skeletal formation in vivo, we generated transgenic mice with skeleton-specific overexpression of BMP11 propeptide cDNA. The mice showed a transformation of the seventh cervical vertebra into a thoracic vertebra in our previous report. Presently, further characterizations of the transgenic mice indicated that ossification in calvatia was dramatically enhanced in transgenic fetuses at 16.5 dpc in comparison with their wild-type littermates. At 10 weeks of age, bone mineral content and bone mineral density were significantly (P<0.05) higher in transgenic mice than that in their wild-type littermates based on dual energy X-ray absorptiometry analysis. The relative trabecular bone volume measured by histological analysis was dramatically increased in transgenic mice compared with their wild-type littermates. The enhanced bone formations in the transgenic mice appear to result from increase osteoblast activities as the expressions of four osteoblast markers - α1 type 1 collagen, osteocalcin, alkaline phosphatase and phex were significantly higher in transgenic fetuses than that in their wild-type littermates. These results suggest that over-expression of BMP11 propeptide stimulates bone formation by increasing osteoblast cell functions.


Setting the PACE for frail older adults in the community: An underused opportunity for furthering medical-dental integration.
The integration of dentistry into comprehensive and long-term care has occurred infrequently and with limited success. The authors aim to describe how the Program of All-Inclusive Care for the Elderly (PACE) has the potential for such incorporation for the growing population of nursing home-appropriate older adults preferring to age in place. The authors used a 56-item online survey to explore aspects of oral health care within PACE, including organizational structure, availability and provision of care, preventive protocols, and provider reimbursement. The survey was distributed to all 124 programs nationally. Data analyses included descriptive statistics for each of the variables of interest. Thirty-five programs completed the survey (28%) in 23 states (74%) where PACE is available. Most programs covered comprehensive dental services and predominantly provided care off-site. Most programs reimbursed dentists at Medicaid fee-for-service rates and some at commercial rates. Dentistry was most frequently ranked the second-highest specialty focus behind mental health. PACE is a comprehensive interdisciplinary model of care and an underused opportunity for furthering medical-dental integration. It uses local dental resources in order to accommodate the oral health care needs of the growing population of older adults preferring to age in place. PACE is an opportunity for the dental profession to further medical-dental integration and ensure that newer models of long-term care include comprehensive and coordinated oral health care programs. It is also an opportunity to promote an integrated model of care with policy makers to support integrated oral health care for the nursing home-eligible population.


Targeting FoxO1 with AS1842856 suppresses adipogenesis.
Hyperplasia (i.e., increased adipogenesis) contributes to excess adiposity, the hallmark of obesity that can trigger metabolic complications. As FoxO1 has been implicated in adipogenic regulation, we investigated the kinetics of FoxO1 activation during adipocyte differentiation, and tested the effects of FoxO1 antagonist (AS1842856) on adipogenesis. We found for the first time that the kinetics of FoxO1 activation follows a series of sigmoid curves, and reveals the phases relevant to clonal expansion, cell cycle arrest, and the regulation of PPARγ, adiponectin, and mitochondrial proteins (complexes I and III). In addition, multiple activation-inactivation transitions exist in the stage of terminal differentiation. Importantly, persistent inhibition of FoxO1 with AS1842856 almost completely suppressed adipocyte differentiation, while selective inhibition in specific stages had differential effects on adipogenesis. Our data present a new view of FoxO1 in adipogenic regulation, and suggest AS1842856 can be an anti-obesity agent that warrants further investigation.


Two-wave mixing of phase-modulated beams in GaP under a dc electric field.
Two-wave mixing of phase-modulated light beams in crystals of cubic symmetry is analyzed on the basis of the vectorial theory of light diffraction. We derive an analytical expression for phase-to-intensity transformation in crystals of the 43m point group of symmetry, which differs from the previously obtained solution based on the scalar approach. The most effective transformation is achieved when the amplitude of the space-charge-field grating is equal to the quarter-wave field. It is shown that the space-charge-field grating created in GaP semi-insulating crystal at the wavelength of 632 nm is much smaller than can be predicted from the one-level band-transport model.


The Laplacian spectrum of neural networks.
The brain is a complex network of neural interactions, both at the microscopic and macroscopic level. Graph theory is well suited to examine the global network architecture of these neural networks. Many popular graph metrics, however, encode average properties of individual network elements. Complementing these "conventional" graph metrics, the eigenvalue spectrum of the normalized Laplacian describes a network's structure directly at a systems level, without referring to individual nodes or connections. In this paper, the Laplacian spectra of the macroscopic anatomical neuronal networks of the macaque and cat, and the microscopic network of the Caenorhabditis elegans were examined. Consistent with conventional graph metrics, analysis of the Laplacian spectra revealed an integrative community structure in neural brain networks. Extending previous findings of overlap of network attributes across species, similarity of the Laplacian spectra across the cat, macaque and C. elegans neural networks suggests a certain level of consistency in the overall architecture of the anatomical neural networks of these species. Our results further suggest a specific network class for neural networks, distinct from conceptual small-world and scale-free models as well as several empirical networks.


Preventing formation of toxic N-terminal huntingtin fragments through antisense oligonucleotide-mediated protein modification.
Huntington's disease (HD) is a progressive autosomal dominant disorder, caused by a CAG repeat expansion in the HTT gene, which results in expansion of a polyglutamine stretch at the N-terminal end of the huntingtin protein. Several studies have implicated the importance of proteolytic cleavage of mutant huntingtin in HD pathogenesis and it is generally accepted that N-terminal huntingtin fragments are more toxic than full-length protein. Important cleavage sites are encoded by exon 12 of HTT. Here we report proof of concept using antisense oligonucleotides to induce skipping of exon 12 in huntingtin pre-mRNA, thereby preventing the formation of a 586 amino acid N-terminal huntingtin fragment implicated in HD toxicity. In vitro studies showed successful exon skipping and appearance of a shorter huntingtin protein. Cleavage assays showed reduced 586 amino acid N-terminal huntingtin fragments in the treated samples. In vivo studies revealed exon skipping after a single injection of antisense oligonucleotides in the mouse striatum. Recent advances to inhibit the formation of mutant huntingtin using oligonucleotides seem promising therapeutic strategies for HD. Nevertheless, huntingtin is an essential protein and total removal has been shown to result in progressive neurodegeneration in vivo. Our proof of concept shows a completely novel approach to reduce mutant huntingtin toxicity not by reducing its expressing levels, but by modifying the huntingtin protein.


Recent insertion of a 52-kb mitochondrial DNA segment in the wheat lineage.
The assembly of a 1.3-Mb size region of the wheat genome has provided the opportunity to study a recent nuclear mitochondrial DNA insertion (NUMT). In the present study, we have studied two bacterial artificial chromosomes (BACs) and characterized a 52-kb NUMT segment from the tetraploid and hexaploid wheat BAC libraries. The conserved orthologous NUMT regions from tetraploid and hexaploid wheat Langdon and Chinese Spring shared identical gene haplotypes even though mutations (insertions, deletions, and substitutions) had occurred. The 52-kb NUMT was present in hexaploid variety Chinese Spring, but absent in variety Hope, by sequence comparison of their corresponding region. Amplifying the NUMT junctions using a set of the wheat materials including diploid, tetraploid, and hexaploid lines showed that none of the diploid wheat carried the region and only some tetraploid and hexaploid wheat were positive for the NUMT. Age estimation of the NUMT displayed the mean ages of Langdon NUMT and Chinese Spring NUMT to be 378,000 and 416,000 years ago, respectively. Reverse transcription PCR and sequencing of the nad7 gene showed 28 C → U RNA editing sites and four partial editing sites, as expected for mitochondrial DNA expression. Specific SNPs discriminated between cDNA from the nucleus and the mitochondria and suggested that the nuclear copy was not expressed. The mitochondrial DNA studied was inserted into the genome quite recently within the wheat lineage and gave rise to the non-coding nuclear nad7 gene. The NUMT segment could be lost and acquired frequently during the wheat evolution.


Immobilisation of a thrombopoietin peptidic mimic by self-assembled monolayers for culture of CD34+ cells.
Compared to soluble cytokines, surface-tethered ligands can deliver biological signalling with precise control of spatial positioning and concentration. A strategy that immobilises ligand molecules on a surface in a uniform orientation using non-cleavable linkages under physiological conditions would enhance the specific and systemic delivery of signalling in the local environment. We used mixed self-assembled monolayers (SAMs) of oxyamine- and oligo(ethylene glycol)-terminated thiols on gold to covalently install aldehyde- or ketone-functionalised ligands via oxime conjugation. Characterisation by electrochemistry and X-ray photoelectron spectroscopy showed quantitative immobilisation of the ligands on SAM surfaces. The thrombopoietin mimetic peptide, RILL, was immobilised on SAMs and the bioactivity of the substrate was demonstrated by culturing factor-dependent cells. We also optimised the immobilisation and wash conditions so that the peptide was not released into the culture medium and the immobilised RILL could be re-used for consecutive cell cultures. The surface also supported the growth of haematopoietic CD34+ cells comparable to the standard thrombopoietin-supplemented culture. Furthermore, the RILL-immobilised SAM surface was as effective in expanding uncommitted CD34+ cells as standard culture. The stimulatory effect of surface-tethered ligands in haematopoietic stem cell expansion supports the use of ligand immobilisation strategies to replicate the haematopoietic stem cell niche.


Pharmacological profile of YM087, a novel potent nonpeptide vasopressin V1A and V2 receptor antagonist, in vitro and in vivo.
The biochemical and pharmacological profile of YM087, 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin- 6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesized nonpeptide vasopressin (AVP) antagonist, was investigated in several in vitro and in vivo studies. YM087 showed high affinity for V1A receptors from rat liver and V2 receptors from rat kidney with Ki values of 0.48 and 3.04 nM, respectively. YM087 also inhibited [3H]oxytocin (OT) binding to rat uterus (OT receptors) plasma membranes with a Ki value of 44.4 nM, and at 100 microM did not affect the binding of [3H]AVP to anterior pituitary (V1B receptors) plasma membranes, which indicated that it had less affinity for these OT and V1B receptors. YM087 had no effect on cytosolic free calcium concentration ([Ca++]i) itself, but suppressed AVP-induced increase in [Ca++]i of cultured vascular smooth muscle cells at the same concentrations as the binding affinities. Furthermore, YM087 potently blocked AVP-induced cAMP production of cultured renal epithelium cells concentration dependently and had no agonistic activities. In in vivo studies, intravenous administration of YM087 inhibited the pressor response to exogenous AVP in pithed rats and produced an aquaretic effect in dehydrated conscious rats in a dose-dependent manner. These results demonstrate that YM087 is a potent and nonpeptide dual AVP V1A and V2 receptors antagonist and can be used in future studies to help clarify the physiological and pathophysiological roles of AVP.


Variation in hospital costs and resource utilisation after congenital heart surgery.
Children undergoing cardiac surgery have overall improving survival, though they consume substantial resources. Nationwide inpatient cost estimates and costs at longitudinal follow-up are lacking. Retrospective cohort study of children <19 years of age admitted to Pediatric Health Information System administrative database with an International Classification of Diseases diagnosis code undergoing cardiac surgery. Patients were grouped into neonates (≤30 days of age), infants (31-365 days of age), and children (>1 year) at index procedure. Primary and secondary outcomes included hospital stay and hospital costs at index surgical admission and 1- and 5-year follow-up. Of the 99,670 cohort patients, neonates comprised 27% and had the highest total hospital costs, though daily hospital costs were lower. Mortality declined (5.6% in 2004 versus 2.5% in 2015, p < 0.0001) while inpatient costs rose (5% increase/year, p < 0.0001). Neonates had greater index diagnosis complexity, greater inpatient costs, required the greatest ICU resources, pharmacotherapy, and respiratory therapy. We found no relationship between hospital surgical volume, mortality, and hospital costs. Neonates had higher cumulative hospital costs at 1- and 5-year follow-up compared to infants and children. Inpatient hospital costs rose during the study period, driven primarily by longer stay. Neonates had greater complexity index diagnosis, required greater hospital resources, and have higher hospital costs at 1 and 5 years compared to older children. Surgical volume and in-hospital mortality were not associated with costs. Further analyses comprising merged clinical and administrative data are necessary to identify longer stay and cost drivers after paediatric cardiac surgery.


On stabilization of scattering resonances in recombination reaction that forms ozone.
Calculations of energy transfer in the recombination reaction that forms ozone are carried out within the framework of the mixed quantum/classical theory and using the dimensionally reduced 2D-model of ozone molecule, with bending motion neglected. Recombination rate coefficients are obtained at room temperature for symmetric and asymmetric isotopomers of singly and doubly substituted isotopologues. The processes of resonance formation, spontaneous decay, collisional dissociation, and stabilization by bath gas (Ar) are all characterized and taken into account within the steady-state approximation for kinetics. The focus is on stabilization step, where the mysterious isotopic η-effect was thought to originate from. Our results indicate no difference in cross sections for stabilization of scatteringresonances in symmetric and asymmetric isotopomers. As practical results, the general and simple analytic models for stabilization and dissociation cross sections are presented, which can be applied to resonances in any ozone molecule, symmetric or asymmetric, singly or doubly substituted. Present calculations show some isotope effect that looks similar to the experimentally observed η-effect, and the origin of this phenomenon is in the rates of formation/decay of scatteringresonances, determined by their widths, that are somewhat larger in asymmetric isotopomers than in their symmetric analogues. However, the approximate two-dimensional model used here is insufficient for consistent and reliable description of all features of the isotopic effect in ozone. Calculations using an accurate 3D model are still needed.


Genome interplay in the grain transcriptome of hexaploid bread wheat.
Allohexaploid bread wheat (Triticum aestivum L.) provides approximately 20% of calories consumed by humans. Lack of genome sequence for the three homeologous and highly similar bread wheat genomes (A, B, and D) has impeded expression analysis of the grain transcriptome. We used previously unknown genome information to analyze the cell type-specific expression of homeologous genes in the developing wheat grain and identified distinct co-expression clusters reflecting the spatiotemporal progression during endosperm development. We observed no global but cell type- and stage-dependent genome dominance, organization of the wheat genome into transcriptionally active chromosomal regions, and asymmetric expression in gene families related to baking quality. Our findings give insight into the transcriptional dynamics and genome interplay among individual grain cell types in a polyploid cereal genome.


Pro-apoptotic effect of nonsteroidal anti-inflammatory drugs on synovial fibroblasts.
Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the articular synovial tissues. Although the etiology of RA has not yet been elucidated, physical and biochemical inhibition of synovial hyperplasia, which is the origin of articular destruction, may be an effective treatment for RA. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of RA. The mechanism of action of NSAIDs generally involves the inhibition of cyclooxygenase (COX) at sites of inflammation. Thus, NSAIDs were not generally considered to have a so-called anti-rheumatic effect, including inhibition of progressive joint destruction and induction of remission. However, certain conventional NSAIDs and celecoxib, a selective COX-2 inhibitor, have been reported to inhibit synovial hyperplasia by inducing the apoptosis of human synovial fibroblasts. Therefore, it has been suggested that such NSAIDs may not only have an anti-inflammatory effect but also an anti-rheumatic effect. In this review, we summarize findings about the pro-apoptotic effect, in other words, anti-proliferative effect of NSAIDs on synovial fibroblasts from patients with RA.


Zebra Stripes through the Eyes of Their Predators, Zebras, and Humans.
The century-old idea that stripes make zebras cryptic to large carnivores has never been examined systematically. We evaluated this hypothesis by passing digital images of zebras through species-specific spatial and colour filters to simulate their appearance for the visual systems of zebras' primary predators and zebras themselves. We also measured stripe widths and luminance contrast to estimate the maximum distances from which lions, spotted hyaenas, and zebras can resolve stripes. We found that beyond ca. 50 m (daylight) and 30 m (twilight) zebra stripes are difficult for the estimated visual systems of large carnivores to resolve, but not humans. On moonless nights, stripes are difficult for all species to resolve beyond ca. 9 m. In open treeless habitats where zebras spend most time, zebras are as clearly identified by the lion visual system as are similar-sized ungulates, suggesting that stripes cannot confer crypsis by disrupting the zebra's outline. Stripes confer a minor advantage over solid pelage in masking body shape in woodlands, but the effect is stronger for humans than for predators. Zebras appear to be less able than humans to resolve stripes although they are better than their chief predators. In conclusion, compared to the uniform pelage of other sympatric herbivores it appears highly unlikely that stripes are a form of anti-predator camouflage.


Laser-induced fluorescence spectroscopy of the (0, 0) Schumann-Runge band of O(2).
We report laser-induced fluorescence recording and identification of the R and P branches (J = 1-21) of the (0, 0) Schumann-Runge band of molecular oxygen, excited near 202 nm by a tunable pulsed laser beam (3-MW/cm(2) maximum intensity). The intensity of the excitation spectrum varies linearly with the density of the laser power. In the conditions of the experiment, the detection limit of ground-state O(2) molecules deduced from the R(5) line is ~10(15) cm(-3).


Machine-Learning Algorithms Predict Graft Failure After Liver Transplantation.
The ability to predict graft failure or primary nonfunction at liver transplant decision time assists utilization of scarce resource of donor livers, while ensuring that patients who are urgently requiring a liver transplant are prioritized. An index that is derived to predict graft failure using donor and recipient factors, based on local data sets, will be more beneficial in the Australian context. Liver transplant data from the Austin Hospital, Melbourne, Australia, from 2010 to 2013 has been included in the study. The top 15 donor, recipient, and transplant factors influencing the outcome of graft failure within 30 days were selected using a machine learning methodology. An algorithm predicting the outcome of interest was developed using those factors. Donor Risk Index predicts the outcome with an area under the receiver operating characteristic curve (AUC-ROC) value of 0.680 (95% confidence interval [CI], 0.669-0.690). The combination of the factors used in Donor Risk Index with the model for end-stage liver disease score yields an AUC-ROC of 0.764 (95% CI, 0.756-0.771), whereas survival outcomes after liver transplantation score obtains an AUC-ROC of 0.638 (95% CI, 0.632-0.645). The top 15 donor and recipient characteristics within random forests results in an AUC-ROC of 0.818 (95% CI, 0.812-0.824). Using donor, transplant, and recipient characteristics known at the decision time of a transplant, high accuracy in matching donors and recipients can be achieved, potentially providing assistance with clinical decision making.


Monocyte and macrophage dysfunction as a cause of HIV-1 induced dysfunction of innate immunity.
HIV-1 can establish both long lived and productive infection of macrophages (Mϕ) but circulating monocytes are less permissive to infection. Multiple studies have identified extensive changes to monocyte and Mϕ phenotype, differentiation or function. These include alterations in Toll-like receptor signaling and resultant changes to cytokine responses, specific defects in phagocytosis and microbial killing and modulation of apoptotic responses, all of which may perturb the important role of these cells in innate immunity. Interpretation of contradictory data however, is complicated by the use of different experimental models and many of the reported effects may be an indirect consequence of HIV 1 infection that result from exposure to viral products or from disruption of cellular and cytokine networks in the immune system, rather than the direct consequence of productive HIV 1 infection. Future research should focus on refining experimental models and on elucidating the physiological mechanisms of monocyte/ Mϕ dysfunction during HIV 1 infection.


Anaesthesia for shock wave therapy in musculoskeletal disorders: a preliminary report.
The potential for using external applied energy to rectify or ameliorate musculoskeletal disorders has been explored for decades. A shock wave is a pressure disturbance: tissue effect is cavitation, producing microtrauma or microfracture and haematoma formation, inducing, as to date is thought, increase in vascularization, increased soft callus and faster enchondral ossification. Anaesthesiological interest in this field is focused in non-union or delayed osseous union, joint stiffness or osteochondrosis and femoral head necrosis in adults. Actually, because of the pain associated with high energy extracorporeal shock wave therapy on bones, anaesthesia is necessary, but, since almost all patients have no complaint after treatment, there is no need of postoperative analgesia. Therefore, short duration anaesthetic techniques and agents should be preferred. Loco-regional anaesthesia or general anaesthesia are both suitable to the purpose. Fifty patients have been treated nowadays in our Institution with shock wave therapy needing anaesthesia. 18 patients (36%) received general anaesthesia. Since patient's stay in hospital was expected to be short, short duration agents have been used, avoiding those causing unpleasent side effects, first emesis. We used Propofol or Remifentanil by continuous infusion, titrated to maintain stable haemodynamics and an appropriate level of anaesthesia. The short duration of action of Propofol depends on its rapid elimination, whereas Remifentanil undergoes rapid biotransformation to minimally active metabolites. 32 patients (64%) received regional anaesthesia. We avoided long acting agents or high concentration drugs. Spinal blocks have been performed with 0.5% hyperbaric bupivacaine; brachial plexus blocks, sciatic-femoral blocks and an epidural block have been performed with 0.5-1% xylocaine or 1% mepivacaine. Shock Wave Therapy has been done during a 3-day hospital stay. With suitable anaesthesiological treatment and preparation, almost all patients could be treated as outpatients or with an overnight hospital stay.


Bypass surgery for complex middle cerebral artery aneurysms: impact of the exact location in the MCA tree.
The object of this study was to describe the authors' institutional experience in the treatment of complex middle cerebral artery (MCA) aneurysms necessitating bypass and vessel sacrifice. Cases in which patients with MCA aneurysms were treated with a combination of bypass and parent artery sacrifice were reviewed retrospectively. The authors identified 24 patients (mean age 46 years) who were treated with bypass and parent artery sacrifice. The aneurysms were located in the M1 segment in 7 patients, MCA bifurcation in 8, and more distally in 9. The mean aneurysm diameter was 30 mm (range 7-60 mm, median 26 mm). There were 8 saccular and 16 fusiform aneurysms. Twenty-one extracranial-intracranial and 4 intracranial-intracranial bypasses were performed. Partial or total trapping (only) of the parent artery was performed in 17 cases, trapping with resection of aneurysm in 3, and aneurysm clipping with sacrifice of an M2 branch in 4. The mean follow-up period was 27 months. The aneurysm obliteration rate was 100%. No recanalization of the aneurysms was detected during follow-up. There was 1 perioperative death (4% mortality rate) and 6 cerebrovascular accidents, causing permanent morbidity in 5 patients. The median modified Rankin Scale score of patients with an M1 aneurysm increased from 0 preoperatively to 2 at latest follow-up, while the score was unchanged in other patients. Most of the permanent deficits were associated with M1 aneurysms. Twenty-one patients (88%) had good outcome as defined by a Glasgow Outcome Scale score of 4 or 5. Bypass in combination with parent vessel occlusion is a useful technique with acceptable frequencies of morbidity and mortality for complex MCA aneurysms when conventional surgical or endovascular techniques are not feasible. The location of the aneurysm should be considered when planning the type of bypass and the site of vessel occlusion. Flow alteration by partial trapping may be preferable to total trapping for the M1 aneurysms.


Alcohol use and selected health conditions of 1991 Gulf War veterans: survey results, 2003-2005.
A sizable literature has analyzed the frequency of alcohol consumption and patterns of drinking among veterans. However, few studies have examined patterns of alcohol use in veterans of the first Gulf War or factors associated with problem drinking in this population. We examined the frequency and patterns of alcohol use in male and female veterans who served in the 1991 Gulf War or during the same era and the relationships between alcohol use and selected health conditions. We analyzed data from a follow-up survey of health information among population-based samples of 15,000 Gulf War and 15,000 Gulf Era veterans. Data had been collected from 9,970 respondents during 2003 through 2005 via a structured questionnaire or telephone survey. Posttraumatic stress disorder (PTSD), major depressive disorder (MDD), unexplained multisymptom illness (MSI), and chronic fatigue syndrome (CFS)-like illness were more frequent among veterans with problem drinking than those without problem drinking. Approximately 28% of Gulf War veterans with problem drinking had PTSD compared with 13% of Gulf War veterans without problem drinking. In multivariate analysis, problem drinking was positively associated with PTSD, MDD, unexplained MSI, and CFS-like illness after adjustment for age, sex, race/ethnicity, branch of service, rank, and Gulf status. Veterans who were problem drinkers were 2.7 times as likely to have PTSD as veterans who were not problem drinkers. These findings indicate that access to evidence-based treatment programs and systems of care should be provided for veterans who abuse alcohol and who have PTSD and other war-related health conditions and illnesses.


Hematogenous dissemination of glioblastoma multiforme.
Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor in adults. The dogma that GBM spread is restricted to the brain was challenged by reports on extracranial metastases after organ transplantation from GBM donors. We identified circulating tumor cells (CTCs) in peripheral blood (PB) from 29 of 141 (20.6%) GBM patients by immunostaining of enriched mononuclear cells with antibodies directed against glial fibrillary acidic protein (GFAP). Tumor cell spread was not significantly enhanced by surgical intervention. The tumor nature of GFAP-positive cells was supported by the absence of those cells in healthy volunteers and the presence of tumor-specific aberrations such as EGFR gene amplification and gains and losses in genomic regions of chromosomes 7 and 10. Release of CTCs was associated with EGFR gene amplification, suggesting a growth potential of these cells. We demonstrate that hematogenous GBM spread is an intrinsic feature of GBM biology.


Early Protective Role of Inflammation in Cardiac Remodeling and Heart Failure: Focus on TNFα and Resident Macrophages.
Cardiac hypertrophy, initiated by a variety of physiological or pathological stimuli (hemodynamic or hormonal stimulation or infarction), is a critical early adaptive compensatory response of the heart. The structural basis of the progression from compensated hypertrophy to pathological hypertrophy and heart failure is still largely unknown. In most cases, early activation of an inflammatory program reflects a reparative or protective response to other primary injurious processes. Later on, regardless of the underlying etiology, heart failure is always associated with both local and systemic activation of inflammatory signaling cascades. Cardiac macrophages are nodal regulators of inflammation. Resident macrophages mostly attenuate cardiac injury by secreting cytoprotective factors (cytokines, chemokines, and growth factors), scavenging damaged cells or mitochondrial debris, and regulating cardiac conduction, angiogenesis, lymphangiogenesis, and fibrosis. In contrast, excessive recruitment of monocyte-derived inflammatory macrophages largely contributes to the transition to heart failure. The current review examines the ambivalent role of inflammation (mainly TNFα-related) and cardiac macrophages (Mφ) in pathophysiologies from non-infarction origin, focusing on the protective signaling processes. Our objective is to illustrate how harnessing this knowledge could pave the way for innovative therapeutics in patients with heart failure.


Trauma Immediately Preceding REM-Behavior Disorder: A Valuable Prognostic Marker?
Background: The definition of rapid eye movement (REM) sleep behavior disorder (RBD) has varied over the years. Rapid eye movement sleep behavior disorder can be considered isolated or idiopathic or can occur in the context of other disorders, including trauma-associated sleep disorder (TSD) and overlap parasomnia. However, whether trauma in RBD carries any prognostic specificity is currently unknown. Study Objectives: To test the hypothesis that RBD secondary to trauma is less likely to result in the development of neurodegeneration compared to idiopathic RBD (iRBD) without trauma in the general population. Methods: A retrospective cohort study of 122 consecutive RBD patients (103 males) at two tertiary sleep clinics in Europe between 2005 and 2020 was studied. Patients were diagnosed as having iRBD by video polysomnography (vPSG) and had a semi-structured interview at presentation, including specifically eliciting any history of trauma. Patients with secondary RBD to recognized causes were excluded from the study. Patients with iRBD were categorized into three groups according to reported trauma history: (1) No history of trauma, (2) traumatic experience at least 12 months prior to RBD symptom onset, and (3) traumatic experience within 12 months of RBD symptom onset. Idiopathic RBD duration was defined as the interval between estimated onset of RBD symptoms and last hospital visit or death. Follow-up duration was defined as the interval between iRBD diagnosis and last hospital visit or death. Results: In a follow-up period of up to 18 years, no patient who experienced trauma within 12 months preceding their iRBD diagnosis received a diagnosis of a neurodegenerative disorder (n = 35), whereas 38% of patients without trauma within the 12 months of symptom onset developed a neurodegenerative illness. These patients were also significantly more likely to have a family history of α-synucleinopathy or tauopathy. Conclusions: The development of RBD within 12 months of experiencing a traumatic life event, indistinguishable clinically from iRBD, did not lead to phenoconversion to a neurodegenerative disorder even after 18 years (mean follow up 6 years). We suggest that a sub-type of RBD be established and classified as secondary RBD due to trauma. Additionally, we advocate that a thorough psychological and trauma history be undertaken in all patients presenting with dream enactment behaviors (DEB).


The Potential of High-Dimensional Propensity Scores in Health Services Research: An Exemplary Study on the Quality of Care for Elective Percutaneous Coronary Interventions.
Evaluating the potential of the high-dimensional propensity score (HDPS) to control for residual confounding in studies analyzing quality of care based on administrative health insurance data. Secondary data from 2004 to 2009 from three German statutory health insurance providers. We conducted a retrospective cohort study in patients with elective percutaneous coronary interventions (PCIs) and compared the mortality risk between the in- and outpatient setting using Cox regression. Adjustment for predefined confounders was performed using conventional propensity score (PS) techniques. Further, an HDPS was calculated based on predefined and empirically selected confounders from the database. Conventional PS methods showed a decreased mortality risk for outpatient compared to inpatient PCIs, while trimming of patients with nonoverlap in the HDPS distribution and weighting resulted in a comparable risk. Most comorbidities were less prevalent in the HDPS-trimmed population compared to the original one. The HDPS methodology may reduce residual confounding by rendering the studied cohort more comparable through restriction. However, results cannot be generalized for the entire study population. To provide unbiased results, full assessment of all unmeasured confounders from proxy information in the database would be necessary.


Do cigarette prices motivate smokers to quit? New evidence from the ITC survey.
To examine the importance of cigarette prices in influencing smoking cessation and the motivation to quit. We use longitudinal data from three waves of the International Tobacco Control Policy Evaluation Survey (ITC). The study contrasts smoking cessation and motivation to quit among US and Canadian smokers and evaluates how this relationship is modified by cigarette prices, nicotine dependence and health knowledge. Different price measures are used to understand how the ability to purchase cheaper cigarettes may reduce the influence of prices. Our first model examines whether cigarette prices affect motivation to quit smoking using Generalized Estimating Equations to predict cessation stage and a least squares model to predict the change in cessation stage. The second model evaluates quitting behavior over time. The probability of quitting is estimated with Generalized Estimating Equations and a transition model to account for the 'left-truncation' of the data. US and Canada. 4352 smokers at Wave 1, 2000 smokers completing all three waves. Motivation to quit, cigarette prices, nicotine dependence and health knowledge. Smokers living in areas with higher cigarette prices are significantly more motivated to quit. There is limited evidence to suggest that price increases over time may also increase quit motivation. Higher cigarette prices increase the likelihood of actual quitting, with the caveat that results are statistically significant in one out of two models. Access to cheaper cigarette sources does not impede cessation although smokers would respond more aggressively (in terms of cessation) to price increases if cheaper cigarette sources were not available. This research provides a unique opportunity to study smoking cessation among adult smokers and their response to cigarette prices in a market where they are able to avoid tax increases by purchasing cigarettes from cheaper sources. Higher cigarette prices appear to be associated with greater motivation to stop smoking, an effect which does not appear to be mitigated by cheaper cigarette sources. The paper supports the use of higher prices as a means of encouraging smoking cessation and motivation to quit.


The in vivo effect of endothelins on retinal circulation in nondiabetic and diabetic rats.
The endothelins are potent vasoactive peptides. This study was performed to characterize the in vivo effects of the endothelin peptides on the retinal circulation in nondiabetic and diabetic rats. The video fluorescein angiography methodology was used to quantitate retinal hemodynamic responses to endothelin-1 (ET-1) and endothelin-3 (ET-3) in rats. A total of 99 rats were used for these experiments. Video fluorescein angiography recordings were performed before and at different times after intravitreal injection of different concentrations of ET-1 and ET-3 in nondiabetic and diabetic rats. Vascular diameters and retinal circulation times were determined using computer-assisted image analysis of the recorded angiograms. The maximal response to ET-1 was observed at 15 minutes after intravitreal injection and was maintained for as long as 30 minutes after injection. Subsequent data measured at 15 minutes after intravitreal injection showed significant prolongation of retinal circulation times and retinal artery constriction. For example, at a concentration of 10(-7) M, the retinal circulation time increased by 270% +/- 121% of the baseline value. In contrast, 10(-7) M ET-3 injection showed a 52% +/- 29.5% increase in circulation time compared to baseline. In diabetic animals, 10(-7) M ET-1 injection showed a blunted response (only 26% +/- 8% of baseline) compared to the same ET-1 injected concentration in nondiabetic rats. The rat retinal circulation shows a pronounced retinal response to ET-1 intravitreal injection. The response to ET-3 is significantly less than it is to ET-1, and in diabetic animals there was also a significant blunting of the retinal response to ET-1. The blunted response to ET-3 is consistent with the lower affinity of retinal vessel ET-1 receptors to ET-3. The blunted ET-1 response in diabetic rats is consistent with previously reported results, demonstrating resistance to ET-1 action in retinal pericytes exposed to high glucose.


Impact of periodontal disease on quality of life.
To determine the impact of periodontal disease on quality of life using the Oral Health Impact Profile (OHIP) 14, simplified version. A cross-sectional study was conducted involving a convenience sample of 401 patients of both sexes aged 19 to 71 years. After diagnoses of periodontal condition, the patients voluntarily completed a form to collect the OHIP-14, as well as socioeconomic and demographic data. Chronic periodontitis was the most prevalent, affecting 227 patients (56.7%). With regard to the impact of periodontal disease on quality of life, functional limitation was the predominant item, affecting 91.5% of the sample. The patients with aggressive periodontitis achieved the highest impact scores. The highest scores on the OHIP-14 index were those of patients with a diagnosis of chronic or aggressive periodontitis. OHIP-14 scores were associated with sex, age, and income (P < .001). Functional limitation was the most affected dimension, and impact was significantly associated with age, income, and a diagnosis of periodontal disease.


The association between lichen sclerosus and antigens of the HLA system.
Although frequently linked clinically with autoimmune disease, no immunogenetic basis for lichen sclerosus has ever been established. In this study, we examined in detail the HLA antigens of 84 patients with histologically proven disease, compared with 357 controls. Patients with lichen sclerosus did not have the expected HLA A1, B8, DR3, DQ2 autoimmune profile. Instead, DQ7 was present in 39 of 78 (50%) of patients compared with 89 (25%) controls (P < 0.001). In addition, 61 of 78 patients (78%) had either DQ7, DQ8 or DQ9 antigens, or a combination of these, compared with 142 (40%) controls (P < 0.01). Raised levels of DQ7 correspond to a glutamic acid residue at position 45 of the DQB1 locus. Proline amino acids at position 55 of this DQB1 locus could explain the raised levels of DQ7, 8 and 9, and exert a secondary effect. There is preliminary evidence that the immunogenetic profile of patients with this disease may affect disease expression with regard to site and extent of involvement.


Improving emergency medical services for children with special health care needs: does training make a difference?
This study evaluated the impact of a paramedic training program on emergency medical services (EMS) responses for children with special health care needs. EMS responses for children with a congenital or acquired condition or a chronic physical or mental illness, were reviewed. Responses, related to the child's special health care need, involving paramedics who had completed our training program were compared with responses with paramedics not participating in the training. There was significantly more advanced life support treatment for responses with paramedics completing the training program compared with other responses. However, there was no significant difference in transport to a hospital or in-hospital admission between these 2 groups. This finding suggests that existing EMS protocols may play a more important role in emergency treatment and transport of children with special health care needs than specialized training of already certified paramedics.


Performance of different clinical trial designs to evaluate treatments during an epidemic.
In the 2013-2016 west Africa outbreak of Ebola Virus Disease (EVD), most of the planned clinical trials failed to reach a conclusion within the time frame of the epidemic. The performance of clinical trial designs for the evaluation of one or more experimental treatments in the specific context of an ongoing epidemic with changing case fatality rates (CFR) and unpredictable case numbers is unclear. We conduct a comprehensive evaluation of commonly used two- and multi-arm clinical trial designs based on real data, which was recorded during the 2013-16 EVD epidemic in west Africa. The primary endpoint is death within 14 days of hospitalization. The impact of the recruitment start times relative to the time course of the epidemic on the operating characteristics of the clinical trials is analysed. Designs with frequent interim analyses with the possibility of early stopping are shown to outperform designs with only a single analysis not only in terms of average time to conclusion and average sample size, but also in terms of the probability of reaching any conclusion at all. Historic control designs almost always result in substantially inflated false positive rates, when the case fatality rate changes over time. Response-adaptive randomization may be a compromise between the goal of scientific validity and the ethical goal of minimizing the number of patients allocated to ineffective treatments.


The trimerization domain of NEMO is composed of the interacting C-terminal CC2 and LZ coiled-coil subdomains.
NEMO (NF-kappaB essential modulator) plays a key role in the canonical NF-kappaB pathway as the scaffold/regulatory component of the IkappaB kinase (IKK) complex. The self-association of NEMO involves the C-terminal halves of the polypeptide chains containing two putative coiled-coil motifs (a CC2 and a LZ leucine zipper), a proline-rich region, and a ZF zinc finger motif. Using purified truncation mutants, we showed that the minimal oligomerization domain of NEMO is the CC2-LZ segment and that both CC2 and LZ subdomains are necessary to restore the LPS-dependent activation of the NF-kappaB pathway in a NEMO-deficient cell line. We confirmed the association of the oligomerization domain in a trimer and investigated the specific role of CC2 and LZ subdomains in the building of the oligomer. Whereas a recombinant CC2-LZ polypeptide self-associated into a trimer with an association constant close to that of the wild-type protein, the isolated CC2 and LZ peptides, respectively, formed trimers and dimers with weaker association constants. Upon mixing, isolated CC2 and LZ peptides associated to form a stable hetero-hexamer as shown by gel filtration and fluorescence anisotropy experiments. We propose a structural model for the organization of the oligomerization domain of activated NEMO in which three C-terminal domains associate into a pseudo-hexamer forming a six-helix bundle. This model is discussed in relation to the mechanism of activation of the IKK complex by upstream activators.


Head Direction Cell Activity Is Absent in Mice without the Horizontal Semicircular Canals.
Head direction (HD) cells fire when an animal faces a particular direction in its environment, and they are thought to represent the neural correlate of the animal's perceived spatial orientation. Previous studies have shown that vestibular information is critical for generating the HD signal but have not delineated whether information from all three semicircular canals or just the horizontal canals, which are primarily sensitive to angular head rotation in the horizontal (yaw) plane, are critical for the signal. Here, we monitored cell activity in the anterodorsal thalamus (ADN), an area known to contain HD cells, in epstatic circler (Ecl) mice, which have a bilateral malformation of the horizontal (lateral) semicircular canals. Ecl mice and their littermates that did not express the mutation (controls) were implanted with recording electrodes in the ADN. Results confirm the important role the horizontal canals play in forming the HD signal. Although normal HD cell activity (Raleigh's r > 0.4) was recorded in control mice, no such activity was found in Ecl mice, although some cells had activity that was mildly modulated by HD (0.4 > r > 0.2). Importantly, we also observed activity in Ecl mice that was best characterized as bursty--a pattern of activity similar to an HD signal but without any preferred firing direction. These results suggest that the neural structure for the HD network remains intact in Ecl mice, but the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable HD signal. Significance statement: Cells in the anterior dorsal thalamic nucleus normally fire in relation to the animal's directional heading with respect to the environment--so-called head direction cells. To understand how these head direction cells generate their activity, we recorded single-unit activity from the anterior dorsal thalamus in transgenic mice that lack functional horizontal semicircular canals. We show that the neural network for the head direction signal remains intact in these mice, but that the absence of normal horizontal canals results in an inability to control the network properly and brings about an unstable head direction signal.


Olivine-garnet transformation in a meteorite.
Garnet has been identified for the first time as a meteorite mineral in the Coorara chondrite from Western Australia. It replaces olivine grains in a 1-millimeter veinlet traversing the body of the meteorite. The associated olivine has abnormally low birefringence, which suggests a highly shocked condition. Microprobe analyses do not distinguish the garnet from the associated olivine, which has the composition (Mg(.75)Fe(.25))(2) SiO(4); the garnet may have the composition Mg(3)Fe(2)Si(3)O(12) but be unresolvable from the accompanying olivine, or alternatively is nonstoichiometric. Transformation of olivine to garnet under high pressure could have significant implications for the phase composition of the Earth's mantle.


Assessment of long-term work attendance within human service organisations.
Terms and theories of work attendance vary according to their use and focus. This paper analyzes long-term work attendance in relation to social, psychosocial, and health-related factors. Register-based and questionnaire-based data covering 3,804 human service organisation workers over a three-year period were analyzed at individual and work-unit level. The results showed positive relationships between work attendance and male gender, high income, work commitment, job satisfaction, and having positive feelings towards work. High work attendance combined with work commitment, stress, or pain did not show any negative long-term effects upon short-term or long-term sick leave. Instead, work attendance seemed to be more associated with stable patterns of behaviour. Register-based measures of work attendance (at most 4-7 days of sick leave per worker per year) may be a useful tool in managing psychosocial work environment and related behaviour, but their inability to encompass information regarding individual health and disease must be borne in mind.


2'-fluoro-2'-deoxycytidine inhibits Borna disease virus replication and spread.
Borna disease virus (BDV) causes neurological diseases in a variety of warm-blooded animal species, possibly including humans. To date, there is no effective treatment against BDV infection. Recently, we reported on the antiviral activity of 1-beta-D-arabinofuranosylcytosine (Ara-C). However, Ara-C's cytotoxic side effects are a major obstacle for its therapeutic use. Herein, we demonstrate that the nucleoside analog 2'-fluoro-2'-deoxycytidine (2'-FdC) exhibits potent antiviral activity against BDV. Importantly, 2'-FdC-associated cytotoxicity is negligible, indicating 2'-FdC as an excellent candidate for the development of antiviral therapy against BDV.


Patients' perspectives of living with a percutaneous endoscopic gastrostomy (PEG).
Since enteral nutrition therapy is the preferred nutritional support for dysphagic patients with a range of diagnoses, PEG has become part of traditional care. However, enteral nutrition with PEG transfers treatment responsibility and activity to the patients and their carers, so the advantages should be discussed. The aim of this study was therefore to investigate patients' experience of living with a percutaneous endoscopic gastrostomy (PEG) in order to increase the understanding of patients' need for support. In a prospective study at Karolinska University Hospital in Sweden, data were collected consecutively at the time of PEG and two months later using a study-specific questionnaire about each patient's experience of living with a PEG. Fishers exact test was used to test for statistically significant difference at five per cent level. There were 104 responders (response rate of 70%). Women felt more limited in daily activity compared to men (p = 0.004). Older patients experienced a more limited ability to influence the number of feeding times compared to younger (p = 0.026). Highly educated patients found feeding more time-consuming (p = 0.004). Patients with a cancer diagnosis reported that the PEG feeding interfered with their oral feeding more than patients with a neurological disease (p = 0.009). Patients mostly contacted the PEG outpatient clinic with problems regarding their PEG, and were mainly assisted by their spouse rather than district nurses. PEG feeding is time-consuming and interferes with daily life. Although 73% was satisfied, patients' experiences of living with a PEG may be dependent on age, sex, education and diagnosis. Spouses are the main carers for PEG patients at home, and patients prefer to go to the PEG outpatient clinic for help if problems occur.


Plate tectonics and hotspots: the third dimension.
High-resolution seismic tomographic models of the upper mantle provide powerful new constraints on theories of plate tectonics and hotspots. Midocean ridges have extremely low seismic velocities to a depth of 100 kilometers. These low velocities imply partial melting. At greater depths, low-velocity and high-velocity anomalies record, respectively, previous positions of migrating ridges and trenches. Extensional, rifting, and hotspot regions have deep (> 200 kilometers) low-velocity anomalies. The upper mantle is characterized by vast domains of high temperature rather than small regions surrounding hotspots; the asthenosphere is not homogeneous or isothermal. Extensive magmatism requires a combination of hot upper mantle and suitable lithospheric conditions. High-velocity regions of the upper 200 kilometers of the mantle correlate with Archean cratons.