Low zinc levels is associated with increased inflammatory activity but not with atherosclerosis, arteriosclerosis or endothelial dysfunction among the very elderly.
Reduced zinc intake has been related to atherogenesis and arteriosclerosis. We verified this assumption in very old individuals, which are particularly prone to both zinc deficiency and structural and functional changes in the arterial wall. Subjects (n = 201, 80-102 years) with uneventful cardiovascular history and who were not in use of anti-inflammatory treatments in the last 30-days were enrolled. Daily intake of zinc, lipid profile, plasma C-reactive protein (CRP), plasma zinc, flow-mediated dilation (FMD), carotid ultrasonography and cardiac computed tomography were obtained. Young's Elastic Modulus, Stiffness Index and Artery Compliance were calculated. There was no significant difference in clinical or laboratorial data between subjects grouped according to plasma zinc tertile, except for CRP (p = 0.01) and blood leukocytes (p = 0.002), of which levels were higher in the upper tertiles. The average daily intake of zinc was not significantly correlated with zinc or CRP plasma levels. The plasma zinc/zinc intake ratio was inversely correlated with plasma CRP levels (- 0.18; p = 0.01). There was no significant difference between the plasma zinc tertiles and FMD, carotid intima-media thickness, coronary calcium score, carotid plaque presence, remodeled noncalcified coronary plaques, or low-attenuation noncalcified coronary plaques. Although plasma zinc level is inversely related to systemic inflammatory activity, its plasma levels of daily intake are not associated to alterations in structure or function of the arterial wall. In the very elderly plasma concentrations or daily intake of zinc is not related to endothelial dysfunction, arteriosclerosis or atherosclerotic burden at coronary or carotid arteries.


Nonmonotonic contactless manipulation of binary droplets via sensing of localized vapor sources on pristine substrates.
Droplet motion on surfaces influences phenomena as diverse as microfluidic liquid handling, printing technology, and energy harvesting. Typically, droplets are set in motion by inducing energy gradients on a substrate or flow on their free surface. Current configurations for controllable droplet manipulation have limited applicability as they rely on carefully tailored wettability gradients and/or bespoke substrates. Here, we demonstrate the nonmonotonic contactless long-range manipulation of binary droplets on pristine substrates due to the sensing of localized water vapor sources. The droplet-source system presents an unexpected off-centered equilibrium position. We capture the underlying mechanism behind this symmetry breaking with a simplified model based on the full two-dimensional functional form of the surface tension gradient induced by the source on the droplet's free surface. This insight on the transport mechanism enables us to demonstrate its versatility for applications by printing, aligning, and reacting materials controllably in space and time on pristine substrates.


CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF alpha.
Human dendritic cells (DC) can now be generated in vitro in large numbers by culturing CD34+ hematopoietic progenitors in presence of GM-CSF+TNF alpha for 12 d. The present study demonstrates that cord blood CD34+ HPC indeed differentiate along two independent DC pathways. At early time points (day 5-7) during the culture, two subsets of DC precursors identified by the exclusive expression of CD1a and CD14 emerge independently. Both precursor subsets mature at day 12-14 into DC with typical morphology and phenotype (CD80, CD83, CD86, CD58, high HLA class II). CD1a+ precursors give rise to cells characterized by the expression of Birbeck granules, the Lag antigen and E-cadherin, three markers specifically expressed on Langerhans cells in the epidermis. In contrast, the CD14+ progenitors mature into CD1a+ DC lacking Birbeck granules, E-cadherin, and Lag antigen but expressing CD2, CD9, CD68, and the coagulation factor XIIIa described in dermal dendritic cells. The two mature DC were equally potent in stimulating allogeneic CD45RA+ naive T cells. Interestingly, the CD14+ precursors, but not the CD1a+ precursors, represent bipotent cells that can be induced to differentiate, in response to M-CSF, into macrophage-like cells, lacking accessory function for T cells. Altogether, these results demonstrate that different pathways of DC development exist: the Langerhans cells and the CD14(+)-derived DC related to dermal DC or circulating blood DC. The physiological relevance of these two pathways of DC development is discussed with regard to their potential in vivo counterparts.


Structural insights into proteoglycan-shaped Hedgehog signaling.
Hedgehog (Hh) morphogens play fundamental roles during embryogenesis and adulthood, in health and disease. Multiple cell surface receptors regulate the Hh signaling pathway. Among these, the glycosaminoglycan (GAG) chains of proteoglycans shape Hh gradients and signal transduction. We have determined crystal structures of Sonic Hh complexes with two GAGs, heparin and chondroitin sulfate. The interaction determinants, confirmed by site-directed mutagenesis and binding studies, reveal a previously not identified Hh site for GAG binding, common to all Hh proteins. The majority of Hh residues forming this GAG-binding site have been previously implicated in developmental diseases. Crystal packing analysis, combined with analytical ultracentrifugation of Sonic Hh-GAG complexes, suggests a potential mechanism for GAG-dependent Hh multimerization. Taken together, these results provide a direct mechanistic explanation of the observed correlation between disease and impaired Hh gradient formation. Moreover, GAG binding partially overlaps with the site of Hh interactions with an array of protein partners including Patched, hedgehog interacting protein, and the interference hedgehog protein family, suggesting a unique mechanism of Hh signaling modulation.


Drowning Prevention in Pediatrics.
Drowning contributes significantly to morbidity and mortality in the pediatric population but it is largely preventable through judicious use of safety measures. To affect outcomes surrounding drowning, pediatricians need to understand the most updated terminology, the basic resuscitation protocols, and the assessment and management of a drowning victim. Most importantly, pediatricians must appreciate the importance of properly counseling patients and families about drowning prevention. Effective preventive measures supported by the literature include constant and reliable adult supervision, swim instruction for most children older than age 4 years, pool isolation fencing, and the proper use of personal floatation devices. [Pediatr Ann. 2018;47(3):e112-e117.].


In the eye of the storm: race and genomics in research and practice.
The difficulties of operationalizing race in research and practice for social, behavioral, and genetic researchers and practitioners are neither new nor related to recent genetic knowledge. For geneticists, the bases for understanding groups are clines, observed traits that gradually change in frequency between geographic regions without distinct identifiable population boundaries and population histories that carry information about the distribution of genetic variants. For psychologists, race may not exist or be a social and cultural construct associated with fluid social inferences. Because definitions of populations and race can be socially and biologically incongruent, the authors suggest that geneticists and social and behavioral scientists and clinicians attend to external validity issues by operationalizing population and racial categories and avoiding race proxies for other biological, social, and cultural constructs in research designs, data analyses, and clinical practice.


Use of Porphysomes to detect primary tumour, lymph node metastases, intra-abdominal metastases and as a tool for image-guided lymphadenectomy: proof of concept in endometrial cancer.
Objective: To investigate Porphysome fluorescence image-guided resection (PYRO-FGR) for detection of uterine tumour, metastatic lymph nodes and abdominal metastases in a model of endometrial cancer. Methods: White New Zealand rabbits were inoculated with VX2 cells via intra-myometrial injection. At 30 days, Porphysomes were administered intravenously. At 24 h the abdomen was imaged and fluorescent tissue identified (PYRO-FGR). After complete resection of fluorescent tissue, fluorescence-negative lymph nodes and peritoneal biopsies were removed. Histopathology including ultra-staging and analysis by a pathologist was used to detect tumour. Fluorescence signal to background ratio (SBR) was calculated and VX2 (+) tissue compared to VX2 (-) tissue. Biodistribution was calculated and Porphysome accumulation in fluorescent VX2 (+) tissue compared to fluorescent VX2 (-) and non-fluorescent VX2 (-) tissue. Results: Of 17 VX2 models, 10 received 4 mg/kg of Porphysomes and 7 received 1 mg/kg. Seventeen tumours (UT), 81 lymph nodes (LN) and 54 abdominal metastases (AM) were fluorescence-positive and resected. Of these, 17 UT, 60 LN and 45 AM were VX2 (+), while 16 LN and 5 AM were VX2 (-). Nine specimens were excluded from analysis. Thirty-one LN and 53 peritoneal biopsies were fluorescence-negative and resected. Of these, all LN and 51/53 biopsies were VX2 (-) with only 2 false-negative biopsies. Sensitivity and specificity of PYRO-FGR for VX2 (+) tissue was 98.4% / 80.0% overall, 100% / 100% for UT, 100% / 66.0 % for LN and 95.7% / 91.4% for AM. Increased SBR and biodistribution was observed in VX2 (+) tissue vs. VX2 (-) tissue. Conclusions: Porphysomes are a highly sensitive imaging agent for intra-operative detection and resection of uterine tumour, metastatic lymph nodes and abdominal metastases.


CA 125 for the monitoring of ovarian carcinoma during primary therapy.
Thirty-one patients with ovarian cancer were monitored with the CA 125 antigenic determinant in the interval between cytoreductive surgery and the completion of subsequent chemotherapy. Distinct CA 125 assay trends have emerged from prospective serial monitoring. Among patients who were clinically and surgically free of disease after the completion of cytoreductive chemotherapy, the CA 125 assay always fell to levels under 35 U/mL within the first three months of cytoreductive chemotherapy, and stayed at low levels. Patients with partial cytoreduction operations had decreases in serum CA 125 levels only if there was a response to further therapy. The rate of fall of the CA 125 levels correlated with clinical outcome. All 13 patients with serum CA 125 above 35 U/mL after three months of treatment invariably had persistent tumors after subsequent chemotherapy, whereas in patients showing reduction of the CA 125 to levels below 35 U/mL, there were no surgically detectable tumors. Measurement of CA 125 during treatment might permit an early change to alternative and optimal forms of therapeutic management. The CA 125 level three months after treatment appears to be a critical predictor of response to therapy.


The molecular mechanism of intestinal levodopa absorption and its possible implications for the treatment of Parkinson's disease.
Levodopa (L-DOPA) is the naturally occurring precursor amino acid for dopamine and the main therapeutic agent for neurologic disorders due to dopamine depletion, such as Parkinson's disease. l-DOPA absorption in small intestine has been suggested to be mediated by the large neutral amino acids transport machinery, but the identity of the involved transporters is unknown. Clinically, coadministration of l-DOPA and dietary amino acids is avoided to decrease competition for transport in intestine and at the blood-brain barrier. l-DOPA is routinely coadministered with levodopa metabolism inhibitors (dopa-decarboxylase and cathechol-O-methyl transferase inhibitors) that share structural similarity with levodopa. In this systematic study involving Xenopus laevis oocytes and Madin-Darby canine kidney epithelia expression systems and ex vivo preparations from wild-type and knockout mice, we identified the neutral and dibasic amino acids exchanger (antiporter) b(0,+)AT-rBAT (SLC7A9-SLC3A1) as the luminal intestinal l-DOPA transporter. The major luminal cotransporter (symporter) B(0)AT1 (SLC6A19) was not involved in levodopa transport. L-Leucine and L-arginine competed with levodopa across the luminal enterocyte membrane as expected for b(0,+)AT-rBAT substrates, whereas dopa-decarboxylase and cathechol-O-methyl transferase inhibitors had no effect. The presence of amino acids in the basolateral compartment mimicking the postprandial phase increased transepithelial levodopa transport by stimulating basolateral efflux via the antiporter LAT2-4F2 (SLC7A8-SLC3A2). Additionally, the aromatic amino acid uniporter TAT1 (SLC16A10) was shown to play a major role in l-DOPA efflux from intestinal enterocytes. These results identify the molecular mechanisms mediating small intestinal levodopa absorption and suggest strategies for optimization of delivery and absorption of this important prodrug.


Sunlight exposure may be a risk factor of hearing impairment: a community-based study in Japanese older men and women.
Oxidative stress is an important factor in the pathology of age-related hearing loss. Recent animal studies have reported that ultraviolet radiation in sunlight is related to systemic induction of oxidative stress. Chronic sun exposure leads to photodamaged skin, which is manifested as facial skin wrinkling and hyperpigmentation. We hypothesized that sunlight exposure, as assessed by the severity of facial skin photodamage, might be associated with hearing impairment through an oxidative stress mechanism. To examine this, we performed a cross-sectional analysis by using the baseline data from a community-based cohort study of older Japanese. A total of 805 residents (342 men and 463 women) aged 65 years or older living in Kurabuchi Town, Gunma prefecture, Japan, were examined between 2005 and 2006. Facial skin condition was quantified by image analysis of standardized facial images. Hearing impairment was defined as a failure to hear a 30-dB signal at 1 kHz and a 40-dB signal at 4 kHz in the better ear in pure-tone audiometric tests. In men, facial wrinkle was positively associated with hearing impairment (for highest vs lowest: multivariate-adjusted odds ratio, 2.16; 95% confidence interval, 1.00-4.66; p for trend = .01). Stratified analysis by age, educational level, smoking status, sunscreen or foundation use, and diabetes showed results similar to those for men as a whole. This association was particularly pronounced in men with the low levels of antioxidants and without occupational noise exposure. We observed no apparent association in women. The results support the hypothesis that chronic sun exposure is a risk factor of hearing impairment.


Integrating barcoded neuroanatomy with spatial transcriptional profiling enables identification of gene correlates of projections.
Functional circuits consist of neurons with diverse axonal projections and gene expression. Understanding the molecular signature of projections requires high-throughput interrogation of both gene expression and projections to multiple targets in the same cells at cellular resolution, which is difficult to achieve using current technology. Here, we introduce BARseq2, a technique that simultaneously maps projections and detects multiplexed gene expression by in situ sequencing. We determined the expression of cadherins and cell-type markers in 29,933 cells and the projections of 3,164 cells in both the mouse motor cortex and auditory cortex. Associating gene expression and projections in 1,349 neurons revealed shared cadherin signatures of homologous projections across the two cortical areas. These cadherins were enriched across multiple branches of the transcriptomic taxonomy. By correlating multigene expression and projections to many targets in single neurons with high throughput, BARseq2 provides a potential path to uncovering the molecular logic underlying neuronal circuits.


Construction and validation of a decision tree for treating metabolic acidosis in calves with neonatal diarrhea.
The aim of the present prospective study was to investigate whether a decision tree based on basic clinical signs could be used to determine the treatment of metabolic acidosis in calves successfully without expensive laboratory equipment. A total of 121 calves with a diagnosis of neonatal diarrhea admitted to a veterinary teaching hospital were included in the study. The dosages of sodium bicarbonate administered followed simple guidelines based on the results of a previous retrospective analysis. Calves that were neither dehydrated nor assumed to be acidemic received an oral electrolyte solution. In cases in which intravenous correction of acidosis and/or dehydration was deemed necessary, the provided amount of sodium bicarbonate ranged from 250 to 750 mmol (depending on alterations in posture) and infusion volumes from 1 to 6.25 liters (depending on the degree of dehydration). Individual body weights of calves were disregarded. During the 24 hour study period the investigator was blinded to all laboratory findings. After being lifted, many calves were able to stand despite base excess levels below -20 mmol/l. Especially in those calves, metabolic acidosis was undercorrected with the provided amount of 500 mmol sodium bicarbonate, which was intended for calves standing insecurely. In 13 calves metabolic acidosis was not treated successfully as defined by an expected treatment failure or a measured base excess value below -5 mmol/l. By contrast, 24 hours after the initiation of therapy, a metabolic alkalosis was present in 55 calves (base excess levels above +5 mmol/l). However, the clinical status was not affected significantly by the metabolic alkalosis. Assuming re-evaluation of the calf after 24 hours, the tested decision tree can be recommended for the use in field practice with minor modifications. Calves that stand insecurely and are not able to correct their position if pushed require higher doses of sodium bicarbonate, if there is clinical evidence of a marked D-lactic acidosis. In those calves, determining the degree of loss of the palpebral reflex was identified as a useful decision criterion to provide an additional amount of 250 mmol sodium bicarbonate. This work demonstrates the clinical relevance of the discovery that D-lactate is responsible for most of the clinical signs expressed in neonatal diarrheic calves suffering from metabolic acidosis.


Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation.
The transcription factor p53 is a tumor suppressor. As such, the P53 gene is frequently altered in human cancers. However, over 80% of the P53 mutations found in human cancers are missense mutations that lead to expression of mutant proteins that not only lack p53 transcriptional activity but exhibit new functions as well. Recent studies show that restoration of p53 expression leads to tumor regression in mice carrying p53 deletions. However, the therapeutic efficacy of restoring p53 expression in tumors containing p53 missense mutations has not been evaluated. Here we demonstrate that restoring wild-type p53 expression halted tumor growth in mice inheriting a p53(R172H) missense mutation that is equivalent to a P53 missense mutation detected in approximately 6% of human cancers. However, it did not lead to tumor regression, as was observed in mice lacking p53. We further showed that the dominant-negative effect of the mutant p53 encoded by p53(R172H) dampened the activity of the restored wild-type p53. We therefore conclude that in a mutant p53 background, p53 restoration has the therapeutic potential to suppress tumor progression. Our findings support using p53 restoration as a strategy to treat human cancers with P53 missense mutations and provide direction for optimizing p53 restoration in cancer therapy.


Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxymethamphetamine): assessment using quantitative autoradiography.
The widely abused "designer" drug MDMA (3,4-methylenedioxymethamphetamine) has been shown to cause marked and long-lasting changes in brain serotonergic systems. The present study uses quantitative in vitro autoradiography of 3H-paroxetine labeled 5-HT uptake sites to assess the time-dependent effects of MDMA on 5-HT neurons in specific neuroanatomic loci. Following treatment with MDMA (20 mg/kg, b.i.d. for 4 days), marked decreases in 5-HT uptake sites were observed in a number of brain regions known to receive projections of 5-HT neurons. These regions included cerebral cortex, caudate nucleus, hippocampus, nucleus accumbens, olfactory tubercle, superior and inferior colliculi, geniculate nuclei, and most thalamic nuclei. In contrast, other areas such as the septal nuclei and some thalamic nuclei which also receive 5-HT projections were not substantially affected by this drug. In most regions, decreases in 5-HT uptake sites occurred within 24 hours of the last dose of MDMA and persisted at the 2 week time point. Some regions such as dorsal striatum exhibited a time-dependent reduction with greater reductions occurring at 2 weeks rather than immediately following the MDMA treatment regimen. The density of 5-HT uptake sites in other regions such as endopiriform nucleus and substantia nigra at the 2 week versus 18 hour time point indicated some degree of region-specific recovery. Regions which demonstrated no significant reduction in 5-HT uptake sites included the dorsal and median raphe nuclei, ventral tegmental area, central grey, interpeduncular nucleus, locus coerulus, pontine reticular formation and cerebellum. Likewise, regions containing 5-HT axons of passage (e.g., indusium griseum and lateral hypothalamus) appeared to be insensitive to the neurotoxic effects of MDMA on 5-HT neurons. Furthermore, the neurotoxic effects of MDMA showed specificity in that the catecholamine neurons labeled by 3H-mazindol were unaffected by the treatment regimen. These data indicate that the preferential degeneration of serotonergic neurons by MDMA is mediated primarily at 5-HT terminal regions, whereas regions containing 5-HT perikarya and axons of passage remain relatively unaffected. In addition, the observed time-dependent reductions and recovery of 5-HT uptake sites which were detected within 2 weeks of the treatment regimen in certain brain regions suggest region-specific differences in recovery of 5-HT systems from MDMA-induced lesion.


Contour interactions between pairs of Gabors engaged in binocular rivalry reveal a map of the association field.
A psychophysical study was conducted to investigate contour interactions (the 'association field'). Two Gabor patches were presented to one eye, with random-dot patches in corresponding locations of the other eye so as to produce binocular rivalry. Perceptual alternations of the two rivalry processes were monitored continuously by observers and the two time series were cross-correlated. The Gabors were oriented collinearly, obliquely, or orthogonally, and spatial separation was varied. A parallel condition was also included. Correlation between the rivalry processes strongly depended on separation and relative orientation. Correlations between adjacent collinear Gabors was near-perfect and reduced with spatial separation and as relative orientation departed from collinear. Importantly, variations in cross-correlation did not alter the rivalry processes (average dominance duration, and therefore alternation rate, was constant across conditions). Instead, synchronisation of rivalry oscillations accounts for the correlation variations: rivalry alternations were highly synchronised when contour interactions were strong and were poorly synchronised when contour interactions were weak. The level of synchrony between these two stochastic processes, in depending on separation and relative orientation, effectively reveals a map of the association field. These association fields are not greatly affected by contrast, and can be demonstrated between contours that are presented to separate hemispheres.


Comparison of Fibronectin and Collagen in Supporting the Isolation and Expansion of Endothelial Progenitor Cells from Human Adult Peripheral Blood.
Endothelial colony-forming cells (ECFCs), are circulating endothelial progenitor cells increasingly studied in various diseases because of their potential for clinical translation. Experimental procedures for their ex vivo culture still lack standardization. In particular two different extracellular matrix proteins, either fibronectin or collagen, are commonly used by different Authors for coating plastic plates, both allowing to obtain cells that have all the features of ECFCs. However, possible differences in the impact of each substrate on ECFCs have not been analysed, so far. Therefore, in this study we investigated whether fibronectin and collagen may differentially affect ECFC cultures. ECFCs were isolated and cultured from peripheral blood mononuclear cells of healthy donors. The impact of fibronectin compared with collagen as the only variable of the experimental procedure was analysed separately in the phase of isolation of ECFC colonies and in the following phase of cell expansion. In the isolation phase, although similar frequencies of colonies were obtained on the two substrates, ECFC colonies appeared some days earlier when mononuclear cells were seeded on fibronectin rather than collagen. In the expansion phase, ECFCs cultured on collagen showed a longer lifespan and higher cell yields compared with ECFCs cultured on fibronectin, possibly related to the higher levels of IL-6 and IL-8 measured in their supernatants. ECFCs cultured on both substrates showed similar immunophenotype and ability for in vitro tube formation. Overall, the results of this study indicate that, although both fibronectin and collagen efficiently sustain ECFC cultures, each of them brings some advantages within individual steps of the entire process. We suggest that colony isolation performed on fibronectin followed by cell expansion performed on collagen may represent a novel and the most efficient strategy to obtain ECFCs from adult peripheral blood samples.


Mortality among a Cohort of Persons with an Intellectual Disability in New South Wales, Australia.
The main objective of the study was to compare mortality for people with an intellectual disability (ID) to the general population in New South Wales (NSW), Australia. A second objective was to provide mortality data for people with an intellectual disability from NSW in a standardized format, which allows for international comparisons of the mortality of people with an intellectual disability. The study was a longitudinal cohort study linking retrospective data from the population databases of the NSW Department of Ageing, Disability and Home Care (ADHC) Intellectual Disability Services Dataset (intellectual disability cohort) to the mortality data set of the NSW Registry of Births, Deaths and Marriages (RBDM) for the period 1 June 2005 to 31 December 2011. The two groups of interest for this study were persons with an intellectual disability recorded in the intellectual disability cohort (953 deaths among 42,219 persons over 270,649 person-years of observation) and the rest of the NSW population (312,649 deaths among over 7,218,529 persons [2011 population] and 45,818,946 person-years of observation). In this study, we compared the intellectual disability cohort with the rest of the NSW population using age-adjusted death rates (ADRs), standardized mortality ratios (SMRs) and age standardized death rates (ASDRs) based upon the World Health Organization (WHO) standard population. We found a significantly higher mortality in a cohort of people with an intellectual disability compared to the rest of the NSW population. The intellectual disability cohort compared to the rest of the NSW population had an SMR of 2.48 for all ages and an SMR of 3.15 for those aged 5-69 years. We also found an SMR for females (4.26) with an intellectual disability that was significantly higher than that for males (2.52) with an intellectual disability. The ASDR for the intellectual disability cohort was 4.04 (deaths per 1000) and the ASDR for the rest of the NSW population was 1.58, giving a comparative mortality ratio of 2.55. Our findings indicate excess mortality of people with an intellectual disability when compared to the general population. They also indicate that females with an intellectual disability have a higher relative mortality compared to female same-aged general population peers, and also males with an intellectual disability, a finding replicated in other similar cohort studies. For international comparison using the WHO standard population, our intellectual disability cohort (ages 5-69 years) had a mortality of 4.04 deaths per 1000.


Indoor air pollution.
Although official efforts to control air pollution have traditionally focused on outdoor air, it is now apparent that elevated contaminant concentrations are common inside some private and public buildings. Concerns about potential public health problems due to indoor air pollution are based on evidence that urban residents typically spend more than 90 percent of their time indoors, concentrations of some contaminants are higher indoors than outdoors, and for some pollutants personal exposures are not characterized adequately by outdoor measurements. Among the more important indoor contaminants associated with health or irritation effects are passive tobacco smoke, radon decay products, carbon monoxide, nitrogen dioxide, formaldehyde, asbestos fibers, microorganisms and aeroallergens. Efforts to assess health risks associated with indoor air pollution are limited by insufficient information about the number of people exposed, the pattern and severity of exposures, and the health consequences of exposures. An overall strategy should be developed to investigate indoor exposures, health effects, control options, and public policy alternatives.


Role of dystrophic epidermolysis bullosa in anxiety, depression and self-esteem: A controlled cross-sectional study.
The psychological aspect in patients with dystrophic epidermolysis bullosa (DEB) is poorly documented. We sought to determine the role of DEB in anxiety, depression and self-esteem. We conducted a cross-sectional study, collecting data from 27 DEB patients and 26 healthy individuals. DEB patients and healthy controls completed three different psychometric scales for anxiety and depression and one scale for self-esteem. DEB patients and healthy controls were homogeneous for age and sex (P > 0.05), but not for employment, marital status and economic level (P < 0.05). Median values of all psychometric battery scales were not statistically significant between DEB patients and healthy controls, except for Goldberg scale for anxiety (P = 0.003) and depression (P = 0.037) and slightly significant for Zung Scale for anxiety (P = 0.048) with no difference between DEB patients with dominant versus recessive form in all scales (P > 0.05). Among DEB patients, only employment showed a significant difference in all scales (P < 0.05) but Hamilton for depression, whereas self-esteem seemed to be affected by marriage (P = 0.04) and education (P = 0.016). DEB patients apparently are not more anxious and/or depressed and do not have less self-esteem than healthy individuals.


A neural model of hierarchical reinforcement learning.
We develop a novel, biologically detailed neural model of reinforcement learning (RL) processes in the brain. This model incorporates a broad range of biological features that pose challenges to neural RL, such as temporally extended action sequences, continuous environments involving unknown time delays, and noisy/imprecise computations. Most significantly, we expand the model into the realm of hierarchical reinforcement learning (HRL), which divides the RL process into a hierarchy of actions at different levels of abstraction. Here we implement all the major components of HRL in a neural model that captures a variety of known anatomical and physiological properties of the brain. We demonstrate the performance of the model in a range of different environments, in order to emphasize the aim of understanding the brain's general reinforcement learning ability. These results show that the model compares well to previous modelling work and demonstrates improved performance as a result of its hierarchical ability. We also show that the model's behaviour is consistent with available data on human hierarchical RL, and generate several novel predictions.


Exit, punishment and rewards in commons dilemmas: an experimental study.
Commons dilemmas are interaction situations where a common good is provided or exploited by a group of individuals so that optimal collective outcomes clash with private interests. Although in these situations, social norms and institutions exist that might help individuals to cooperate, little is known about the interaction effects between positive and negative incentives and exit options by individuals. We performed a modified public good game experiment to examine the effect of exit, rewards and punishment, as well as the interplay between exit and rewards and punishment. We found that punishment had a stronger effect than rewards on cooperation if considered by itself, whereas rewards had a stronger effect when combined with voluntary participation. This can be explained in terms of the 'framing effect', i.e., as the combination of exit and rewards might induce people to attach higher expected payoffs to cooperative strategies and expect better behaviour from others.


Germination and root elongation bioassays in six different plant species for testing Ni contamination in soil.
In vitro short-term chronic phytotoxicity germination and root elongation test were applied to test the effects of nickel (Ni) in seed germination and root elongation in six plants species: Cucumis sativus (Cucurbitaceae), Lepidium sativum and Brassica nigra (Brassicaceae), Trifolium alexandrinum and Medicago sativa (Fabaceae), Phacelia tanacetifolia (Boraginaceae). A naturally Ni rich soil was used to compare the results obtained. Unlike root elongation, germination was not affected by Ni in any of the six species tested. EC50 values, calculated on the root elongation, showed that Ni toxicity decreases in the following order: P. tanacetifolia > B. nigra > C. sativus > L. sativum > M. sativa > T. alexandrinum. The test conducted using soil elutriate revealed a significantly lower effect in both seed germination and root elongation when compared to the results obtained using untreated soil. Conversely, the test performed on soil confirmed the high sensitivity of C. sativus, P. tanacetifolia and L. sativum to Ni.


Boron stress responsive microRNAs and their targets in barley.
Boron stress is an environmental factor affecting plant development and production. Recently, microRNAs (miRNAs) have been found to be involved in several plant processes such as growth regulation and stress responses. In this study, miRNAs associated with boron stress were identified and characterized in barley. miRNA profiles were also comparatively analyzed between root and leave samples. A total of 31 known and 3 new miRNAs were identified in barley; 25 of them were found to respond to boron treatment. Several miRNAs were expressed in a tissue specific manner; for example, miR156d, miR171a, miR397, and miR444a were only detected in leaves. Additionally, a total of 934 barley transcripts were found to be specifically targeted and degraded by miRNAs. In silico analysis of miRNA target genes demonstrated that many miRNA targets are conserved transcription factors such as Squamosa promoter-binding protein, Auxin response factor (ARF), and the MYB transcription factor family. A majority of these targets were responsible for plant growth and response to environmental changes. We also propose that some of the miRNAs in barley such as miRNA408 might play critical roles against boron exposure. In conclusion, barley may use several pathways and cellular processes targeted by miRNAs to cope with boron stress.


Nonparabolic solar concentrators matching the parabola.
We consider the limit of geometric concentration for a focusing concave mirror, e.g., a parabolic trough or dish, designed to collect all radiation within a finite acceptance angle and direct it to a receiver with a flat or circular cross-section. While a concentrator with a parabolic cross-section indeed achieves this limit, it is not the only geometry capable of doing so. We demonstrate that there are infinitely many solutions. The significance of this finding is that geometries which can be more easily constructed than the parabola can be utilized without loss of concentration, thus presenting new avenues for reducing the cost of solar collectors. In particular, we investigate a low-cost trough mirror profile which can be constructed by inflating a stack of thin polymer membranes and show how it can always be designed to match the geometric concentration of a parabola of similar form.


Household Water Treatment and Cholera Control.
Water, sanitation, and hygiene are one part of a cholera control strategy. Household water treatment (HWT) in particular has been shown to improve the microbiological quality of stored water and reduce the disease burden. We conducted a systematic review of published and gray literature to determine the outcomes and impacts of HWT in preventing cholera specifically. Fourteen manuscripts with 18 evaluations of HWT interventions in cholera were identified. Overall, a moderate quality of evidence suggests that HWT interventions reduce the burden of disease in cholera outbreaks and the risk of disease transmission. Appropriate training for users and community health worker follow-up are necessary for use. Barriers to uptake include taste and odor concerns, and facilitators include prior exposure, ease of use, and links to preexisting development programming. Further research on local barriers and facilitators, HWT filters, scaling up existing development programs, program sustainability, integrating HWT and oral cholera vaccine, and monitoring in low-access emergencies is recommended.


Indigenous knowledge networks in the face of global change.
Indigenous communities rely extensively on plants for food, shelter, and medicine. It is still unknown, however, to what degree their survival is jeopardized by the loss of either plant species or knowledge about their services. To fill this gap, here we introduce indigenous knowledge networks describing the wisdom of indigenous people on plant species and the services they provide. Our results across 57 Neotropical communities show that cultural heritage is as important as plants for preserving indigenous knowledge both locally and regionally. Indeed, knowledge networks collapse as fast when plant species are driven extinct as when cultural diffusion, either within or among communities, is lost. But it is the joint loss of plant species and knowledge that erodes these networks at a much higher rate. Our findings pave the road toward integrative policies that recognize more explicitly the inseparable links between cultural and biological heritage.


Fault-tolerant sub-lithographic design with rollback recovery.
Shrinking feature sizes and energy levels coupled with high clock rates and decreasing node capacitance lead us into a regime where transient errors in logic cannot be ignored. Consequently, several recent studies have focused on feed-forward spatial redundancy techniques to combat these high transient fault rates. To complement these studies, we analyze fine-grained rollback techniques and show that they can offer lower spatial redundancy factors with no significant impact on system performance for fault rates up to one fault per device per ten million cycles of operation (P(f) = 10(-7)) in systems with 10(12) susceptible devices. Further, we concretely demonstrate these claims on nanowire-based programmable logic arrays. Despite expensive rollback buffers and general-purpose, conservative analysis, we show the area overhead factor of our technique is roughly an order of magnitude lower than a gate level feed-forward redundancy scheme.


SU-E-J-09: Performance Optimization of Thick, Segmented Scintillators for Radiotherapy Imaging.
Thick segmented scintillators, incorporating a 2-dimensional matrix of optically-isolated scintillator elements, have shown considerable potential for improving the performance of megavoltage active matrix, flat-panel imagers (MV AMFPIs). While over a factor of 20 improvement in DQE at zero spatial-frequency has been demonstrated for prototypes incorporating CsI(Tl) and BGO scintillators, less-than-optimal element-to-element alignment (misalignment) as well as mis-registration to the underlying AMFPI array pixels can result in spatial resolution loss, reducing DQE improvement at higher spatial frequencies. In this presentation, a method to restore spatial resolution and DQE, based on the use of a high resolution AMFPI array along with special binning techniques, is investigated. The effect of misalignment and mis-registration of segmented scintillators on imaging performance was investigated theoretically and empirically through determination of the modulation transfer function (MTF) and DQE, as well as through realization of reconstructed images of a phantom in a cone-beam CT geometry. The empirical investigation, which was conducted using a 6 MV photon beam, employed a prototype BGO segmented scintillator consisting of 120×60 elements separated by 50 μm-thick septal walls and an element-to-element pitch of 1016 μm. The scintillator was coupled to a higher resolution 127-μm-pitch AMFPI array. Misalignment and mis-registration result in significant degradation of spatial resolution, leading to DQE reduction at non-zero spatial frequencies. While mis-registration for a well-aligned scintillator can be overcome through 8×8 binning of the array pixels to match the scintillator elements, any misalignment will affect such binning and lead to spatial resolution loss. However, the use of 'selective' binning, consisting of the selection of those pixels corresponding to the interior locations of each element, improves resolution while preserving DQE. The use of high-resolution AMFPI arrays combined with selective binning allows prototype AMFPIs incorporating thick, segmented scintillators to achieve imager performance limited only by scintillator performance. Work Supported by NIH grant R01-CA051397.


The financial costs of sadness.
We hypothesized a phenomenon that we term myopic misery. According to our hypothesis, sadness increases impatience and creates a myopic focus on obtaining money immediately instead of later. This focus, in turn, increases intertemporal discount rates and thereby produces substantial financial costs. In three experiments, we randomly assigned participants to sad- and neutral-state conditions, and then offered intertemporal choices. Disgust served as a comparison condition in Experiments 1 and 2. Sadness significantly increased impatience: Relative to median neutral-state participants, median sad-state participants accepted 13% to 34% less money immediately to avoid waiting 3 months for payment. In Experiment 2, impatient thoughts mediated the effects. Experiment 3 revealed that sadness made people more present biased (i.e., wanting something immediately), but not globally more impatient. Disgusted participants were not more impatient than neutral participants, and that lack of difference implies that the same financial effects do not arise from all negative emotions. These results show that myopic misery is a robust and potentially harmful phenomenon.


Experimental evolution of sperm competitiveness in a mammal.
When females mate with multiple partners, sperm from rival males compete to fertilize the ova. Studies of experimental evolution have proven the selective action of sperm competition on male reproductive traits. However, while reproductive traits may evolve in response to sperm competition, this does not necessarily provide evidence that sperm competitive ability responds to selection. Indeed, a study of Drosophila failed to observe divergence in sperm competitive ability of males in lines selected for enhanced sperm offence and defence. Adopting the naturally polygamous house mouse (Mus domesticus) as our vertebrate model, we performed an experimental evolution study and observed genetic divergence in sperm quality; males from the polygamous selection lines produced ejaculates with increased sperm numbers and greater sperm motility compared to males from the monogamous lines. Here, after 12 generations of experimental evolution, we conducted competitive matings between males from lineages evolving under sperm competition and males from lineages subject to relaxed selection. We reduced variation in paternity arising from embryo mortality by genotyping embryos in utero at 14 days gestation. Our microsatellite data revealed a significant paternity bias toward males that evolved under the selective regime of sperm competition. We provide evidence that the sperm competitiveness phenotype can respond to selection, and show that improved sperm quality translates to greater competitive fertilisation success in house mice.


Rs12976445 Polymorphism Is Associated with Post-Ablation Recurrence of Atrial Fibrillation by Modulating the Expression of MicroRNA-125a and Interleukin-6R.
BACKGROUND This study aimed to identify the relationship between miR-125a polymorphism rs12976445 and the post-ablation recurrence of atrial fibrillation (AF), as well as to explore the underlying mechanism of miR-125a in AF recurrence. MATERIAL AND METHODS Microarray analysis was performed to search for miRNAs potentially involved in the regulation of AF recurrence, while real-time PCR (polymerase chain reaction) and Western blot analyses were carried out to study the expression of miR-125a (microRNA-125a), IL-6R (interleukin-6 receptor), and IL-16 (interleukin-16) in different experimental groups, so as to understand the regulatory relationships among miR-125a, IL-6R, and IL-16. Subsequently, a logistic regression analysis was utilized to investigate the survival status of recurrent AF in subjects harboring different genotypes of rs12976445. RESULTS The subjects in the GG and GC/CC groups of miR-125a polymorphism rs12976445 showed no obvious difference regarding all demographic characteristics that were collected in this study. In addition, 19 miRNAs were identified as potentially involved in the regulation of AF recurrence. Among these miRNAs, 6 were upregulated and 13 were downregulated in the group with early recurrence. According to real-time PCR results, the expression of miR-125a was dramatically upregulated in LRAF (late recurrence of atrial fibrillation) as well as in subjects harboring the GG genotype. On the contrary, the level of IL-6R mRNA was dramatically downregulated in LRAF and subjects harboring the GG genotype. Furthermore, IL-6R was confirmed as a candidate target of miR-125a by a luciferase reporter assay. CONCLUSIONS MicroRNA-125a polymorphism rs12976445 plays a role in AF recurrence via the regulation of IL-6R.


New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease.
Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial cells and resident fibroblasts), and monocyte-derived macrophages. Indeed, the production of pro-inflammatory cytokines and oxidative stress by monocyte-derived macrophages is responsible for the osteogenic transformation and mineralization of vascular/valvular cells. However, monocytes/macrophages show the ability to modify their phenotype, and consequently their functions, when facing environmental modifications. This plasticity complicates efforts to understand the pathogenesis of CVC-particularly in a CKD setting, where both uraemic toxins and CKD treatment may affect monocyte/macrophage functions and thereby influence CVC. Here, we review (i) the mechanisms by which each monocyte/macrophage subset either promotes or prevents CVC, and (ii) how both uraemic toxins and CKD therapies might affect these monocyte/macrophage functions.


Outcomes of disabling cervical spine disorders in compensation injuries. A prospective comparison to tertiary rehabilitation response for chronic lumbar spinal disorders.
A prospective, longitudinal cohort study assessing quantitative socioeconomic outcomes of tertiary rehabilitation for chronically disabled patients with cervical spinal disorders compared with those with more common chronic lumbar spinal disorders. To assess 1-year socioeconomic outcomes of a worst-case cohort of consecutive patients with chronic cervical spinal disorders compared with those of patients with lumbar spinal disorders and to assess differences in an array of variables between those patients who reported any period of work during the posttreatment year and those who did not. Few investigators have evaluated outcomes in patients with cervical spinal disorders. None have specifically studied distinctions in socioeconomic outcomes in patients with chronic cervical spinal disorders and in patients with other spinal disorders. Reports of pain are noted to persist in a high percentage of patients with whiplash receiving compensation even 10 years after injury, but the status of work, use of health care resources, financial disputes, or recurrent injury are unknown. A cohort of consecutive chronically disabled patients with spinal disorders (N = 1198) was assessed for prospectively collected demographic, self-report, and physical performance data. A subset of patients (n = 421) with work-related cervical spinal disorders was compared with a group with various lumbar spinal disorders (n = 777). A structured clinical interview was administered 1 year after patients entered an interdisciplinary functional restoration program. High rates of return to work and continuation of work were recorded in the cervical and lumbar spinal disorder groups, with low rates of recurrent injury, new surgery in the injured area, and use of health care resources. There were no statistically significant differences between the groups. Multivariate analyses showed several variables that differentiated between those patients who had any reported period of work during the post-treatment year versus those who did not in the cervical and the lumbar spinal disorder groups. This first large cohort study of outcomes in chronically disabled patients with work-related cervical spinal disorder produced results similar to those found in tertiary functional restoration rehabilitation in chronic lumbar spinal disorders. In spite of poor outcomes reported in the literature for similar cervical and lumbar spinal disorders in patients receiving workers' compensation for disability, successful outcomes can be anticipated after effective rehabilitation, regardless of response to prerehabilitation treatment.


Nanoscale Surface Characterization of Human Erythrocytes by Atomic Force Microscopy: A Critical Review.
Erythrocytes (red blood cells, RBCs), the most common type of blood cells in humans are well known for their ability in transporting oxygen to the whole body through hemoglobin. Alterations in their membrane skeletal proteins modify shape and mechanical properties resulting in several diseases. Atomic force microscopy (AFM), a new emerging technique allows non-invasive imaging of cell, its membrane and characterization of surface roughness at micrometer/nanometer resolution with minimal sample preparation. AFM imaging provides direct measurement of single cell morphology, its alteration and quantitative data on surface properties. Hence, AFM studies of human RBCs have picked up pace in the last decade. The aim of this paper is to review the various applications of AFM for characterization of human RBCs topology. AFM has been used for studying surface characteristics like nanostructure of membranes, cytoskeleton, microstructure, fluidity, vascular endothelium, etc., of human RBCs. Various modes of AFM imaging has been used to measure surface properties like stiffness, roughness, and elasticity. Topological alterations of erythrocytes in response to different pathological conditions have also been investigated by AFM. Thus, AFM-based studies and application of image processing techniques can effectively provide detailed insights about the morphology and membrane properties of human erythrocytes at nanoscale.


Palmitoylation, pathogens and their host.
S-Palmitoylation, the only reversible post-translational lipid modification, confers unique biochemical and functional properties to proteins. Although it has long been known that viral proteins are palmitoylated, recent studies reveal that this modification plays a critical role for pathogens of all kinds and at multiple steps of their life cycle. The present review examines the involvement of S-palmitoylation in infection by viruses, bacteria and parasites and illustrates how pathogens have evolved to manipulate the host palmitoylation machinery.


6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party.
Recently, the suggestion to use 6-thioguanine (6-TG) as an alternative thiopurine in patients with inflammatory bowel disease (IBD) has been discarded due to reports about possible (hepato) toxicity. During meetings arranged in Vienna and Prague in 2004, European experts applying 6-TG further on in IBD patients presented data on safety and efficacy of 6-TG. After thorough evaluation of its risk-benefit ratio, the group consented that 6-TG may still be considered as a rescue drug in stringently defined indications in IBD, albeit restricted to a clinical research setting. As a potential indication for administering 6-TG, we delineated the requirement for maintenance therapy as well as intolerance and/or resistance to aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate and infliximab. Furthermore, indications are preferred in which surgery is thought to be inappropriate. The standard 6-TG dosage should not exceed 25 mg daily. Routine laboratory controls are mandatory in short intervals. Liver biopsies should be performed after 6-12 months, three years and then three-yearly accompanied by gastroduodenoscopy, to monitor for potential hepatotoxicity, including nodular regenerative hyperplasia (NRH) and veno-occlusive disease (VOD). Treatment with 6-TG must be discontinued in case of overt or histologically proven hepatotoxicity.


Trends in BMI, diet and lifestyle between 1976 and 2005 in North Sydney.
Although the prevalence of overweight and obesity in Australia has increased during the past 30 years, little is known about the dietary and behavioural antecedents of body mass index (BMI). We examined changes in mean BMI, diet, and other lifestyle behaviours between 1976 and 2005 and described the cross-sectional associations between these factors and BMI. A series of biennial biomedical surveys by Sydney Adventist Hospital from 1976 to 2005 allowed examination of BMI trends, while the selection of three surveys enabled detailed examination of likely dietary and lifestyle associations. Subjects included in this study were: 384 men and 338 women in 1976; 160 men and 146 women in 1978; 166 men and 141 women in 1980; 164 men and 142 women in 1982; 177 men and 13 women in 1984; 239 men and 227 women in 1986; 210 men and 225 women in 1988; 165 men and 148 women in 1990; 138 men and 167 women in 1992 and 270 men and 62 women in 2005. Height and weight were measured by hospital staff. Mean BMI increased in the early 1990s. Salt, coffee, cola, alcohol and meat consumption, dieting to lose weight and eating between meals were positively associated with BMI while physical activity, food variety, large breakfasts and consumption of spreads were negatively associated. Food consumption and daily activities have important associations with BMI, though their specific associations differ by sex. "Affluent" lifestyle patterns appear to contribute to higher BMI, while a more "prudent" lifestyle seems to protect from such increases.


Pelvic Inflammatory Disease and the Risk of Ovarian Cancer and Borderline Ovarian Tumors: A Pooled Analysis of 13 Case-Control Studies.
Inflammation has been implicated in ovarian carcinogenesis. However, studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent. We investigated the association between PID and the risk of epithelial ovarian cancer according to tumor behavior and histotype. We pooled data from 13 case-control studies, conducted between 1989 and 2009, from the Ovarian Cancer Association Consortium (OCAC), including 9,162 women with ovarian cancers, 2,354 women with borderline tumors, and 14,736 control participants. Study-specific odds ratios were estimated and subsequently combined into a pooled odds ratio using a random-effects model. A history of PID was associated with an increased risk of borderline tumors (pooled odds ratio (pOR) = 1.32, 95% confidence interval (CI): 1.10, 1.58). Women with at least 2 episodes of PID had a 2-fold increased risk of borderline tumors (pOR = 2.14, 95% CI: 1.08, 4.24). No association was observed between PID and ovarian cancer risk overall (pOR = 0.99, 95% CI: 0.83, 1.19); however, a statistically nonsignificantly increased risk of low-grade serous tumors (pOR = 1.48, 95% CI: 0.92, 2.38) was noted. In conclusion, PID was associated with an increased risk of borderline ovarian tumors, particularly among women who had had multiple episodes of PID. Although our results indicated a histotype-specific association with PID, the association of PID with ovarian cancer risk is still somewhat uncertain and requires further investigation.


Characterization and molecular epidemiology of rotavirus strains recovered in Northern Pretoria, South Africa during 2003-2006.
Rotavirus infection is the most common cause of severe dehydrating gastroenteritis in infants and young children and remains a significant clinical problem worldwide. The severity and the burden of rotavirus disease could be reduced through the implementation of an effective vaccine. The aim of this study was to characterize rotavirus strains circulating in the local community as part of an ongoing hospital burden of disease study when a G1P[8] rotavirus vaccine candidate was being evaluated in the same community. From 2003 through 2006, 729 rotavirus-positive stool specimens were collected from children <5 years of age who were treated for diarrhea at Dr George Mukhari Hospital, Ga-Rankuwa, South Africa. Molecular characterization of the strains was performed by polyacrylamide gel electrophoresis and genotyping of the VP4 and VP7 alleles using well-established seminested multiplex reverse-transcription polymerase chain reaction methods. In 2003, 62% of strains exhibited the short rotavirus electropherotype, and the most common rotavirus strain was G2P[4]. In subsequent years, predominant rotavirus strains included G1P[8] and G1P[6] in 2004, G3P[8] and G3P[6] in 2005, and G1P[8] in 2006. For the 4 years of the study, rotavirus strains with P[6] genotype were detected in 25% of all rotavirus-positive specimens. In addition, unusual G12P[6] and G8 strains were detected at a low frequency. These results reflect the diversity of rotavirus strains circulating in South African communities.


Human platelet lysate permits scale-up of dental pulp stromal cells for clinical applications.
BACKGROUND AIMS. Dental pulp stromal cells (DPSC) are considered to be a promising source of stem cells in the field of regenerative therapy. However, the usage of DPSC in transplantation requires large-scale expansion to cater for the need for clinical quantity without compromising current good manufacturing practice (cGMP). Existing protocols for cell culturing make use of fetal bovine serum (FBS) as a nutritional supplement. Unfortunately, FBS is an undesirable additive to cells because it carries the risk of transmitting viral and prion diseases. Therefore, the present study was undertaken to examine the efficacy of human platelet lysate (HPL) as a substitute for FBS in a large-scale set-up. METHODS. We expanded the DPSC in Dulbecco's modified Eagle's medium-knock-out (DMEM-KO) with either 10% FBS or 10% HPL, and studied the characteristics of DPSC at pre- (T25 culture flask) and post- (5-STACK chamber) large-scale expansion in terms of their identity, quality, functionality, molecular signatures and cytogenetic stability. RESULTS. In both pre- and post-large-scale expansion, DPSC expanded in HPL showed extensive proliferation of cells (c. 2-fold) compared with FBS; the purity, immune phenotype, colony-forming unit potential and differentiation were comparable. Furthermore, to understand the gene expression profiling, the transcriptomes and cytogenetics of DPSC expanded under HPL and FBS were compared, revealing similar expression profiles. CONCLUSIONS. We present a highly economized expansion of DPSC in HPL, yielding double the amount of cells while retaining their basic characteristics during a shorter time period under cGMP conditions, making it suitable for therapeutic applications.


Parsing radiographs by integrating landmark set detection and multi-object active appearance models.
This work addresses the challenging problem of parsing 2D radiographs into salient anatomical regions such as the left and right lungs and the heart. We propose the integration of an automatic detection of a constellation of landmarks via rejection cascade classifiers and a learned geometric constellation subset detector model with a multi-object active appearance model (MO-AAM) initialized by the detected landmark constellation subset. Our main contribution is twofold. First, we propose a recovery method for false positive and negative landmarks which allows to handle extreme ranges of anatomical and pathological variability. Specifically we (1) recover false negative (missing) landmarks through the consensus of inferences from subsets of the detected landmarks, and (2) choose one from multiple false positives for the same landmark by learning Gaussian distributions for the relative location of each landmark. Second, we train a MO-AAM using the true landmarks for the detectors and during test, initialize the model using the detected landmarks. Our model fitting allows simultaneous localization of multiple regions by encoding the shape and appearance information of multiple objects in a single model. The integration of landmark detection method and MO-AAM reduces mean distance error of the detected landmarks from 20.0mm to 12.6mm. We assess our method using a database of scout CT scans from 80 subjects with widely varying pathology.


Real-world outcomes of concomitant antidepressant and statin use in primary care patients with depression: a population-based cohort study.
Antidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression. We conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18-100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions. Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs). Compared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR2months 0.88, 99% CI 0.85 to 0.91; aOR6months 0.81, 99% CI 0.79 to 0.84; aOR12months 0.78, 99% CI 0.75 to 0.81) and tolerability (aOR2months 0.92, 99% CI 0.87 to 0.98; aOR6months 0.94, 99% CI 0.89 to 0.99, though not long term aOR12 months 1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR2-12 months 1.00 and 1.02 for response and remission, range aOR2-12 months - 0.01 and - 0.02 for change in depression score). On real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences.


B cell lymphoma 10 is essential for FcepsilonR-mediated degranulation and IL-6 production in mast cells.
The adaptor protein B cell lymphoma 10 (Bcl10) plays an essential role in the functions of the AgRs in T and B cells. In this study, we report that Bcl10 also plays an important role in mast cells. Bcl10 is expressed in mast cells. Although Bcl10-deficient mast cells undergo normal development, we demonstrate that Bcl10 is essential for specific functions of FcepsilonR. Although Bcl10-deficient mast cells have normal de novo synthesis and release of the lipid mediator arachidonic acid, the mutant cells possess impaired FcepsilonR-mediated degranulation, indicated by decreased serotonin release, and impaired cytokine production, measured by release of IL-6. In addition, Bcl10-deficient mice display impaired IgE-mediated passive cutaneous anaphylaxis. Moreover, although Bcl10-deficient mast cells have normal FcepsilonR-mediated Ca(2+) flux, activation of PI3K, and activation of the three types of MAPKs (ERKs, JNK, and p38), the mutant cells have markedly diminished FcepsilonR-mediated activation of NF-kappaB and decreased activation of AP-1. Thus, Bcl10 is essential for FcepsilonR-induced activation of AP-1, NF-kappaB, degranulation, and cytokine production in mast cells.


Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear.
Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory disease characterized by extensive joint tissue inflammation. Implantable bioelectronic devices targeting the inflammatory reflex reduce TNF production and inflammation in preclinical models of inflammatory disease, and in patients with RA and Crohn's disease. Here, we assessed the effect of applying a vibrotactile device to the cymba concha of the external ear on inflammatory responses in healthy subjects, as well as its effect on disease activity in RA patients. Six healthy subjects received vibrotactile treatment at the cymba concha, and TNF production was analyzed at different time points post-stimulation. In a separate study, nineteen healthy subjects were enrolled in a randomized cross-over study, and effects of vibrotactile treatment at either the cymba concha or gastrocnemius on cytokine levels were assessed. In addition, the clinical efficacy of vibrotactile treatment on disease activity in RA was assessed in nine patients with RA in a prospective interventional study. Vibrotactile treatment at the cymba concha reduced TNF levels, and the suppressive effect persisted up to 24 h. In the cross-over study with 19 healthy subjects, vibrotactile treatment at the cymba concha but not at the gastrocnemius significantly reduced TNF, IL-1β, and IL-6 levels compared to pre-treatment baseline (TNF p < 0.05, IL-6 p < 0.01, IL-1β p < 0.001). In healthy subjects, vibrotactile treatment at the cymba concha inhibited TNF by 80%, IL-6 by 73%, and IL-1β by 50% as compared to pre-treatment baseline levels. In RA patients, a significant decrease in DAS28-CRP scores was observed two days post-vibrotactile stimulation at the cymba concha (DAS28-CRP score pre-treatment = 4.19 ± 0.33 vs post-treatment = 3.12 ± 0.25, p < 0.05). Disease activity remained significantly reduced 7 days following vibrotactile treatment (DAS28-CRP score 7 days post-treatment = 2.79 ± 0.21, p < 0.01). In addition, a persistent improvement in visual analogue scale scores, a patient derived measure of global health assessment, was observed in RA patients following vibrotactile treatment. Application of a vibrotactile device to the cymba concha inhibits peripheral blood production of TNF, IL-1β, and IL-6 in healthy subjects, and attenuates systemic inflammatory responses in RA patients. ClinicalTrials.gov Identifier: NCT01569789 and NCT00859859. The AMC trial conducted in The Netherlands does not have a ClinicalTrials.gov Identifier.


Patterning of the mesoderm in Xenopus: dose-dependent and synergistic effects of Brachyury and Pintallavis.
Widespread expression of the DNA-binding protein Brachyury in Xenopus animal caps causes ectopic mesoderm formation. In this paper, we first show that two types of mesoderm are induced by different concentrations of Brachyury. Animal pole explants from embryos injected with low doses of Xbra RNA differentiate into vesicles containing mesothelial smooth muscle and mesenchyme. At higher concentrations somitic muscle is formed. The transition from smooth muscle formation to that of somitic muscle occurs over a two-fold increase in Brachyury concentration. Brachyury is required for differentiation of notochord in mouse and fish embryos, but even the highest concentrations of Brachyury do not induce this tissue in Xenopus animal caps. Co-expression of Brachyury with the secreted glycoprotein noggin does cause notochord formation, but it is difficult to understand the molecular basis of this phenomenon without knowing more about the noggin signal transduction pathway. To overcome this difficulty, we have now tested mesoderm-specific transcription factors for the ability to synergize with Brachyury. We find that co-expression of Pintallavis, but not goosecoid, with Brachyury causes formation of dorsal mesoderm, including notochord. Furthermore, the effect of Pintallavis, like that of Brachyury, is dose-dependent: a two-fold increase in Pintallavis RNA causes a transition from ventral mesoderm formation to that of muscle, and a further two-fold increase induces notochord and neural tissue. These results suggest that Pintallavis cooperates with Brachyury to pattern the mesoderm in Xenopus.


Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1.
Human cytomegalovirus (HCMV) is a member of the betaherpesvirus family that, unlike other herpesviruses, triggers a strong innate immune response in infected cells that includes transcription of the beta interferon gene via activation of interferon regulatory factor 3 (IRF3). IRF3 activation requires signaling from pattern recognition receptors that is initiated by their interaction with specific pathogen-associated molecules. However, while IRF3-activating pathways are increasingly well characterized, the cellular molecules involved in HCMV-mediated IRF3-dependent beta interferon transcription are virtually unknown. We undertook a systematic examination of new and established IRF3-terminal pathway components to identify those that are essential to HCMV-triggered IRF3 activation. We show here that IRF3 activation induced by HCMV infection involves the newly identified protein STING but, in contrast to infections with other herpesviruses, occurs independently of the adaptor molecule IPS-1. We also show that the protein DDX3 contributes to HCMV-triggered expression of beta interferon. Moreover, we identify Z-DNA binding protein 1 (ZBP1) as being essential for IRF3 activation and interferon beta expression triggered by HCMV, as well as being sufficient to enhance HCMV-stimulated beta interferon transcription and secretion. ZBP1 transcription was also found to be induced following exposure to HCMV in a JAK/STAT-dependent manner, thus perhaps also contributing to a positive feedback signal. Finally, we show that constitutive overexpression of ZBP1 inhibits HCMV replication. ZBP1 was recently identified as a cytosolic pattern recognition receptor of double-stranded DNA, and thus, we propose a model for HCMV-mediated IRF3 activation that involves HCMV-associated DNA as the principal innate immune-activating pathogen-associated molecular pattern.


Homing behavior, orientation, and home range of salamanders tagged with tantalum-182.
Using radioactive tags, we recorded movements of salamanders (Plethodon jordani) in their home areas and during homing. Males occupied home areas about three times larger than those of females and made occasional excursions into outlying regions. Homing after 22-to 60-meter displacements was direct and rapid, once initiated. Course headings at 1 meter from release were random; those at 2 meters and more were home-oriented. Males initiated homing movements sooner than females, although both sexes traveled at similar rates. Increased incidence of climbing on vegetation after displacement suggests olfactory mechanisms of orientation. These observations give direct evidence of homing orientation in caudate amphibians.


The RANKL-OPG system in clinical periodontology.
The receptor activator of NF-κB ligand-osteoprotegerin (RANKL-OPG) bi-molecular system is the "bottle-neck" regulator of osteoclastogenesis and bone resorption, both in physiological and pathological conditions. This review aims to elaborate the current knowledge on RANKL and OPG in periodontal disease, and to evaluate their diagnostic and prognostic potential as biomarkers of the disease. To pursue this aim, electronic and manual searches were performed for identifying clinical and in vivo studies on RANKL and OPG in gingival tissue, gingival crevicular fluid, saliva and blood. Smoking and diabetes mellitus were also considered for their potential effects. Papers fulfilling the inclusion criteria demonstrate that RANKL is up-regulated, whereas OPG is down-regulated in periodontitis, compared to periodontal health, resulting in an increased RANKL/OPG ratio. This ratio is further up-regulated in smokers and diabetics, and is not affected by conventional periodontal treatment. The increased RANKL/OPG ratio may serve as a biomarker that denotes the occurrence of periodontitis, but may not necessarily predict on-going disease activity. Its steadily elevated levels post treatment may indicate that the molecular mechanisms of bone resorption are still active, holding an imminent risk for relapse of the disease. Additional adjunct treatment modalities that would "switch-off" the RANKL/OPG ratio may therefore be required.


Pharmacological isolation of postsynaptic currents mediated by NR2A- and NR2B-containing NMDA receptors in the anterior cingulate cortex.
NMDA receptors (NMDARs) are involved in excitatory synaptic transmission and plasticity associated with a variety of brain functions, from memory formation to chronic pain. Subunit-selective antagonists for NMDARs provide powerful tools to dissect NMDAR functions in neuronal activities. Recently developed antagonist for NR2A-containing receptors, NVP-AAM007, triggered debates on its selectivity and involvement of the NMDAR subunits in bi-directional synaptic plasticity. Here, we re-examined the pharmacological properties of NMDARs in the anterior cingulate cortex (ACC) using NVP-AAM007 as well as ifenprodil, a selective antagonist for NR2B-containing NMDARs. By alternating sequence of drug application and examining different concentrations of NVP-AAM007, we found that the presence of NVP-AAM007 did not significantly affect the effect of ifenprodil on NMDAR-mediated EPSCs. These results suggest that NVP-AAM007 shows great preference for NR2A subunit and could be used as a selective antagonist for NR2A-containing NMDARs in the ACC.


Inpatient care of the adult with an exacerbation of cystic fibrosis.
Patients with cystic fibrosis (CF) are living longer, albeit with chronic and progressive lung disease. Pulmonary exacerbations in CF are characterized by an increase in respiratory symptoms and a decrease in pulmonary function and gas exchange. Exacerbations that do not respond to outpatient management require hospitalization. Complications of CF can be devastating and life-threatening. Care of these patients is challenging not only because of the scope and severity of their medical problems, but also because of the need to coordinate services and to maintain continuity during transitions between hospital and home.


Sales of Nicotine-Containing Electronic Cigarette Products: United States, 2015.
To assess the proportion of electronic cigarette (e-cigarette) products sold in the United States that contain nicotine according to retail scanner data. We obtained unit sales data from January 11, 2015, to December 12, 2015, from The Nielsen Company for convenience stores; supermarkets; mass merchandisers; drug, club, and dollar stores; and Department of Defense commissaries. The data did not include purchases from tobacco specialty shops, "vape shops," or online sources. Nicotine content was assessed by product type (disposables, rechargeables, and refills), region, and flavor status based on nicotine strength listed in the Universal Product Codes. For the 36.7% of entries lacking nicotine content information, we conducted Internet searches by brand, product, and flavor. In 2015, 99.0% of e-cigarette products sold contained nicotine, including 99.0% of disposables, 99.7% of rechargeables, and 98.8% of refills. Overall, 98.7% of flavored e-cigarette products and 99.4% of nonflavored e-cigarette products contained nicotine. In 2015, almost all e-cigarette products sold in US convenience stores and other assessed channels contained nicotine. Public Health Implications. Findings reinforce the importance of warning labels for nicotine-containing products, ingredient reporting, and restrictions on sales to minors.


Vagal and recurrent laryngeal neuropathy following stereotactic ablative radiation therapy in the chest.
To identify clinical and dosimetric factors associated with vagus nerve (VN) and recurrent laryngeal nerve (RecLN) injury following stereotactic ablative radiation therapy (SABR) in the chest. We examined the clinical courses and SABR plans of 67 patients treated for T1 or T2 non-small cell lung cancer of the upper right or left lung, including 2 who developed vocal cord paresis (VCP) following treatment. After developing a contouring atlas for the VN and RecLN in the thorax, dose to those structures was retrospectively determined for each patient, and we identified 12 patients whose treatment imparted significant dose to either nerve and who were assessable for more than 12 months follow-up. Biologically effective doses using linear-quadratic (LQ) and linear quadratic-linear (LQ-L) modeling were correlated with VN and RecLN toxicity. Of 12 patients, 2 developed VCP. The first underwent repeat SABR and received a cumulative single fraction equivalent dose (alpha/beta = 3; SFED3) of 37.4 or 64.5 Gy to the VN and 13.7 or 15.3 Gy to the RecLN (by LQ or LQ-L modeling, respectively). This was the highest VN dose and fifth highest RecLN dose in the cohort. The second had rheumatoid arthritis and connective tissue disease and received a SFED3 of 16 Gy to the VN and 19.5 Gy to the RecLN (by both LQ and LQ-L modeling). This was in the upper tertile of VN and RecLN doses for the cohort. Following SABR for non-small cell lung cancer, VCP was associated with high cumulative dose to the VN in 1 patient and a moderately high dose to the VN and RecLN in another patient with rheumatoid arthritis and connective tissue disease. Particularly in the setting of reirradiation or connective tissue disease, potential toxicity to the VN or RecLN should be considered.


Development and Validation of a State-Based Measure of Emotion Dysregulation.
Existing measures of emotion dysregulation typically assess dispositional tendencies and are therefore not well suited for study designs that require repeated assessments over brief intervals. The aim of this study was to develop and validate a state-based multidimensional measure of emotion dysregulation. Psychometric properties of the State Difficulties in Emotion Regulation Scale (S-DERS) were examined in a large representative community sample of young adult women drawn from four sites ( N = 484). Exploratory factor analysis suggested a four-factor solution, with results supporting the internal consistency, construct validity, and predictive validity of the total scale and the four subscales: Nonacceptance (i.e., nonacceptance of current emotions), Modulate (i.e., difficulties modulating emotional and behavioral responses in the moment), Awareness (i.e., limited awareness of current emotions), and Clarity (i.e., limited clarity about current emotions). S-DERS scores were significantly associated with trait-based measures of emotion dysregulation, affect intensity/reactivity, experiential avoidance, and mindfulness, as well as measures of substance use problems. Moreover, significant associations were found between the S-DERS and state-based laboratory measures of emotional reactivity, even when controlling for the corresponding original DERS scales. Results provide preliminary support for the reliability and validity of the S-DERS as a state-based measure of emotion regulation difficulties.


Activity-Guided Fractionation of Red Fruit Extracts for the Identification of Compounds Influencing Glucose Metabolism.
An activity-guided search for compounds influencing glucose metabolism in extracts from aronia (Aronia melanocarpa, A.), pomegranate (Punica granatum L., P.), and red grape (Vitis vinifera, RG) was carried out. The three extracts were fractionated by means of membrane chromatography to separate the anthocyanins from other noncolored phenolic compounds (copigments). In addition, precipitation with hexane was performed to isolate the polymers (PF). The anthocyanin and copigment fractions (AF, CF) of aronia, pomegranate, and red grape were furthermore fractionated with high-performance countercurrent chromatography (HPCCC) and the subfractions were characterized by HPLC-PDA-MS/MS analyses. Each of the (sub-)fractions was examined by in vitro-tests, i.e., the inhibition of the activity of α-amylase and α-glucosidase. On the basis of this screening, several potent inhibitors of the two enzymes could be identified, which included flavonols (e.g., quercetin), ellagitannins (e.g., pedunculagin), and anthocyanins (e.g., delphinidin-3-glucoside and petunidin-3-glucoside). In the α-glucosidase assay all of the examined fractions and subfractions of the fruit extracts were more active than the positive control acarbose.


The student with a writing block--the ethics of psychotherapy.
The potential role of the psychotherapist as ethical interventionist is considered with reference to a patient who presented with a writing block. The case for the therapist to act paternalistically is followed by the counterargument which revolves around the respect for autonomy. A bridge between these two opposing positions is then offered which depends on viewing informed consent as a dynamic process. As part of this procedure it is made clear that while autonomy is the desired end-state of psychotherapy, it is not the be all and end all of treatment. Therapy is necessarily value-laden since it aims for the enhancement of the patient's state of autonomy; it is value-free inasmuch as the therapist desists from guiding the patient in how she should live her life.


Characteristics of joint involvement and relationships with systemic inflammation in systemic sclerosis: results from the EULAR Scleroderma Trial and Research Group (EUSTAR) database.
To determine the prevalence of and independent factors associated with joint involvement in a large population of patients with systemic sclerosis (SSc). This study was cross-sectional, based on data collected on patients included in the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) registry. We queried this database to extract data regarding global evaluation of patients with SSc and the presence of any clinical articular involvement: synovitis (tender and swollen joints), tendon friction rubs (rubbing sensation detected as the tendon was moved), and joint contracture (stiffness of the joints that decreased their range of motion). Overall joint involvement was defined by the occurrence of synovitis and/or joint contracture and/or tendon friction rubs. We recruited 7286 patients with SSc; their mean age was 56 +/- 14 years, disease duration 10 +/- 9 years, and 4210 (58%) had a limited cutaneous disease subset. Frequencies of synovitis, tendon friction rubs, and joint contractures were 16%, 11%, and 31%, respectively. Synovitis, tendon friction rubs, and joint contracture were more prevalent in patients with the diffuse cutaneous subset and were associated together and with severe vascular, muscular, renal, and interstitial lung involvement. Moreover, synovitis had the highest strength of association with elevated acute-phase reactants taken as the dependent variable. Our results highlight the striking level of articular involvement in SSc, as evaluated by systematic examination in a large cohort of patients with SSc. Our data also show that synovitis, joint contracture, and tendon friction rubs are associated with a more severe disease and with systemic inflammation.


Stakeholder Voices: Interpreting Caregiving Research and Designing Next Steps.
Stakeholder engagement can enhance interpretation of research findings and promote meaningful dissemination into policy and practice. Several organizations dedicated to understanding the needs of diverse older adults and family caregivers and advancing practice and policy to improve their health came together in a series of discussions. More than 120 participants, including family/friend caregivers and their advocates and leaders and researchers from public and private organizations, generated an action agenda for those engaged with family caregivers in service delivery, research, and policy across three virtual sessions. Although there are common experiences and demands for caregivers, the meanings of these experiences are shaped by a cultural context, and the intersectionality of caregiver experiences by age, race/ethnicity, gender identity, sexual orientation, immigrant status, and other factors bring into focus the diversity of life and caregiving experience. This heterogeneity of experience crystalizes the importance of assuring the caregiver is at the center, and that design for programs, research, and policy recognize the importance of understanding caregivers and their unique needs before pre-supposing solutions. [Journal of Gerontological Nursing, 47(9), 5-12.].


Poly(ethylene glycol) brush-b-poly(N-vinylpyrrolidone)-based double hydrophilic block copolymer particles crosslinked via crystalline α-cyclodextrin domains.
Self-assembly of block copolymers is a significant area of polymer science. The self-assembly of completely water-soluble block copolymers is of particular interest, albeit a challenging task. In the present work the self-assembly of a linear-brush architecture block copolymer, namely poly(N-vinylpyrrolidone)-b-poly(oligoethylene glycol methacrylate) (PVP-b-POEGMA), in water is studied. Moreover, the assembled structures are crosslinked via α-CD host/guest complexation in a supramolecular way. The crosslinking shifts the equilibrium toward aggregate formation without switching off the dynamic equilibrium of double hydrophilic block copolymer (DHBC). As a consequence, the self-assembly efficiency is improved without extinguishing the unique DHBC self-assembly behavior. In addition, decrosslinking could be induced without a change in concentration by adding a competing complexation agent for α-CD. The self-assembly behavior was followed by DLS measurement, while the presence of the particles could be observed via cryo-TEM before and after crosslinking.


Exploring the relationship between autism spectrum disorder and epilepsy using latent class cluster analysis.
Epilepsy co-occurs frequently in autism spectrum disorders (ASD). Understanding this co-occurrence requires a better understanding of the ASD-epilepsy phenotype (or phenotypes). To address this, we conducted latent class cluster analysis (LCCA) on an ASD dataset (N = 577) which included 64 individuals with epilepsy. We identified a 5-cluster solution with one cluster showing a high rate of epilepsy (29%), earlier age at first recognition, and high rates of repetitive object use and unusual sensory interests. We also conducted LCCA on an ASD-epilepsy subset from the overall dataset (N = 64) which yielded three clusters, the largest of which had impairments in language and motor development; the remaining clusters, while not as developmentally impaired were characterized by different levels of repetitive and sensory behaviors.


Hot-spots-guided receptor-based pharmacophores (HS-Pharm): a knowledge-based approach to identify ligand-anchoring atoms in protein cavities and prioritize structure-based pharmacophores.
The design of biologically active compounds from ligand-free protein structures using a structure-based approach is still a major challenge. In this paper, we present a fast knowledge-based approach (HS-Pharm) that allows the prioritization of cavity atoms that should be targeted for ligand binding, by training machine learning algorithms with atom-based fingerprints of known ligand-binding pockets. The knowledge of hot spots for ligand binding is here used for focusing structure-based pharmacophore models. Three targets of pharmacological interest (neuraminidase, beta2 adrenergic receptor, and cyclooxygenase-2) were used to test the evaluated methodology, and the derived structure-based pharmacophores were used in retrospective virtual screening studies. The current study shows that structure-based pharmacophore screening is a powerful technique for the fast identification of potential hits in a chemical library, and that it is a valid alternative to virtual screening by molecular docking.


High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).
Hydroxymethylglutaryl coenzyme A reductase inhibitors ('statins') reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke. We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7-13% toxicity. We enrolled 33 patients (16 men/17 women, age range 23-82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.


Accuracy of bioelectrical impedance analysis and skinfold thickness in the assessment of body composition in people with chronic spinal cord injury.
Cross-sectional study. This study: (1) investigated the accuracy of bioelectrical impedance analysis (BIA) and skinfold thickness relative to dual-energy X-ray absorptiometry (DXA) in the assessment of body composition in people with spinal cord injury (SCI), and whether sex and lesion characteristics affect the accuracy, (2) developed new prediction equations to estimate fat free mass (FFM) and percentage fat mass (FM%) in a general SCI population using BIA and skinfolds outcomes. University, the Netherlands. Fifty participants with SCI (19 females; median time since injury: 15 years) were tested by DXA, single-frequency BIA (SF-BIA), segmental multi-frequency BIA (segmental MF-BIA), and anthropometry (height, body mass, calf circumference, and skinfold thickness) during a visit. Personal and lesion characteristics were registered. Compared to DXA, SF-BIA showed the smallest mean difference in estimating FM%, but with large limits of agreement (mean difference = -2.2%; limits of agreement: -12.8 to 8.3%). BIA and skinfold thickness tended to show a better estimation of FM% in females, participants with tetraplegia, or with motor incomplete injury. New equations for predicting FFM and FM% were developed with good explained variances (FFM: R2 = 0.94; FM%: R2 = 0.66). None of the measurement techniques accurately estimated FM% because of the wide individual variation and, therefore, should be used with caution. The accuracy of the techniques differed in different subgroups. The newly developed equations for predicting FFM and FM% should be cross-validated in future studies.


The Processing of Attended and Predicted Sounds in Time.
Neural responses to an attended event are typically enhanced relative to those from an unattended one (attention enhancement). Conversely, neural responses to a predicted event are typically reduced relative to those from an unpredicted one (prediction suppression). What remains to be established is what happens with attended and predicted events. To examine the interaction between attention and prediction, we combined two robust paradigms developed for studying attention and prediction effects on ERPs into an orthogonal design. Participants were presented with sounds in attended or unattended intervals with onsets that were either predicted by a moving visual cue or unpredicted (no cue was provided). We demonstrated an N1 enhancement effect for attended sounds and an N1 suppression effect for predicted sounds; furthermore, an interaction between these effects was found that emerged early in the N1 (50-95 msec), indicating that attention enhancement only occurred when the sound was unpredicted. This pattern of results can be explained by the precision of the predictive cue that reduces the need for attention selection in the attended and predicted condition.


Motivational factors for initiating, implementing, and maintaining physical activity behavior following a rehabilitation program for patients with type 2 diabetes: a longitudinal, qualitative, interview study.
To explore motivational factors for initiating, implementing, and maintaining physical activity following a rehabilitation program for patients with type 2 diabetes mellitus. Semi-structured, individual, qualitative interviews with five informants from the InterWalk trial were conducted at three separate occasions; at initiation of the rehabilitation program, at completion of the 12-week program, and 52 weeks after enrolment. Interviews were audio-recorded, transcribed, and analyzed according to Systematic Text Condensation. The framework of Self-Determination Theory was applied to guide analysis after identification of preliminary themes. Commitment and obligation were emphasized as being motivational in initiating physical activity. Toward the termination of the program, this was challenged by an expressed need for autonomy. Successful behavioral change was characterized by transfer of commitment to a new structure in everyday life, which also honored the request for autonomy. Feeling capable of participating in physical activity was facilitated through knowledge, practical experience, and progress and considered motivational, whereas lack of progress extinguished motivation. Finally, enjoyment of the activity was determining for long-term maintenance of physical activity behavior. Satisfaction of innate psychological needs leads to more autonomous regulation of behavior and, through this study, we investigated determining factors for extrinsically motivated behavior and factors of importance to the internalization process.