Inhibition of colon carcinoma cell lung colony formation by a soluble form of E-selectin.
During metastasis, tumor cells adhere to vascular endothelia. E-selectin is an adhesive protein expressed by cytokine-activated endothelium that can support adhesion of colon cancer cells through the recognition of specific carbohydrate ligands. Using a series of colon carcinoma cell lines that displayed E-selectin adhesiveness and an increased metastatic capacity in cytokine-treated mice, we examined possible inhibition of cytokine-dependent experimental lung metastasis by a soluble form of E-selectin, the recombinant fusion protein E-selectin-immunoglobulin. We found that E-selectin-immunoglobulin bound to the surfaces of HT-29 colon carcinoma cells and blocked the formation of cytokine-inducible experimental lung metastases; control L-selectin-immunoglobulin also bound to HT-29 cells but had no effect on tumor cell lung colonization. E-selectin-immunoglobulin was found to interfere with E-selectin-dependent adhesion of HT-29 cells to activated vascular endothelium and to block the retention of these cells in the lung, a process that implies tumor cell adhesive interactions with the host vasculature. Our results demonstrate that E-selectin-immunoglobulin inhibits adhesion and formation of lung metastases by colon carcinoma cells and suggest that impairment of tumor cell-endothelium adhesion might represent a therapeutic approach to the metastatic diffusion of tumors.


Pervasive influence of maternal and paternal criminal offending on early childhood development: a population data linkage study.
Parental criminal offending is an established risk factor for offending among offspring, but little evidence is available indicating the impact of offending on early childhood functioning. We used data from a large Australian population cohort to determine associations between exposure to parental offending and a range of developmental outcomes at age 5 years. Multi-generation data in 66 477 children and their parents from the New South Wales Child Development Study were combined using data linkage. Logistic and multinomial regressions tested associations between any and violent offending histories of parents (fathers, mothers, or both parents) obtained from official records, and multiple measures of early childhood developmental functioning (social, emotional-behavioural, cognitive, communication and physical domains) obtained from the teacher-reported 2009 Australian Early Development Census. Parental offending conferred significantly increased risk of vulnerability on all domains, particularly the cognitive domain. Greater risk magnitudes were observed for offending by both parents and by mothers than by fathers, and for violent than for any offending. For all parental offending exposures, vulnerability on multiple domains (where medium to large effects were observed) was more likely than on a single domain (small to medium effects). Relationships remained significant and of comparable magnitude following adjustment for sociodemographic covariates. The effect of parental offending on early childhood developmental outcomes is pervasive, with the strongest effects on functioning apparent when both parents engage in violent offending. Supporting affected families in early childhood might mitigate both early developmental vulnerability and the propensity for later delinquency among these offspring.


Genetic compatibility determines endophyte-grass combinations.
Even highly mutually beneficial microbial-plant interactions, such as mycorrhizal- and rhizobial-plant exchanges, involve selfishness, cheating and power-struggles between the partners, which depending on prevailing selective pressures, lead to a continuum of interactions from antagonistic to mutualistic. Using manipulated grass-endophyte combinations in a five year common garden experiment, we show that grass genotypes and genetic mismatches constrain genetic combinations between the vertically (via host seeds) transmitted endophytes and the out-crossing host, thereby reducing infections in established grass populations. Infections were lost in both grass tillers and seedlings in F(1) and F(2) generations, respectively. Experimental plants were collected as seeds from two different environments, i.e., meadows and nearby riverbanks. Endophyte-related benefits to the host included an increased number of inflorescences, but only in meadow plants and not until the last growing season of the experiment. Our results illustrate the importance of genetic host specificity and trans-generational maternal effects on the genetic structure of a host population, which act as destabilizing forces in endophyte-grass symbioses. We propose that (1) genetic mismatches may act as a buffering mechanism against highly competitive endophyte-grass genotype combinations threatening the biodiversity of grassland communities and (2) these mismatches should be acknowledged, particularly in breeding programmes aimed at harnessing systemic and heritable endophytes to improve the agriculturally valuable characteristics of cultivars.


Gastrin-Releasing Peptide and Glucose Metabolism Following Pancreatitis.
Gastrin-releasing peptide (GRP) is a pluripotent peptide that has been implicated in both gastrointestinal inflammatory states and classical chronic metabolic diseases such as diabetes. Abnormal glucose metabolism (AGM) after pancreatitis, an exemplar inflammatory disease involving the gastrointestinal tract, is associated with persistent low-grade inflammation and altered secretion of pancreatic and gut hormones as well as cytokines. While GRP is involved in secretion of many of them, it is not known whether GRP has a role in AGM. Therefore, we aimed to investigate the association between GRP and AGM following pancreatitis. Fasting blood samples were collected to measure GRP, blood glucose, insulin, amylin, glucagon, pancreatic polypeptide (PP), somatostatin, cholecystokinin, gastric-inhibitory peptide (GIP), gastrin, ghrelin, glicentin, glucagon-like peptide-1 and 2, oxyntomodulin, peptide YY (PYY), secretin, vasoactive intestinal peptide, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP)-1, and interleukin-6. Modified Poisson regression analysis and linear regression analyses were conducted. Four statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. A total of 83 individuals after an episode of pancreatitis were recruited. GRP was significantly associated with AGM, consistently in all four models (P -trend < 0.05), and fasting blood glucose contributed 17% to the variance of GRP. Further, GRP was significantly associated with glucagon (P < 0.003), MCP-1 (P < 0.025), and TNF-α (P < 0.025) - consistently in all four models. GRP was also significantly associated with PP and PYY in three models (P < 0.030 for both), and with GIP and glicentin in one model (P = 0.001 and 0.024, respectively). Associations between GRP and other pancreatic and gut hormones were not significant. GRP is significantly increased in patients with AGM after pancreatitis and is associated with increased levels of pro-inflammatory cytokines, as well as certain pancreatic and gut hormones. Detailed mechanistic studies are now warranted to investigate the exact role of GRP in derangements of glucose homeostasis following pancreatitis.


Detecting Wheat Powdery Mildew and Predicting Grain Yield Using Unmanned Aerial Photography.
High-resolution aerial imaging with an unmanned aerial vehicle (UAV) was used to quantify wheat powdery mildew and estimate grain yield. Aerial digital images were acquired at Feekes growth stage (GS) 10.5.4 from flight altitudes of 200, 300, and 400 m during the 2009-10 and 2010-11 seasons; and 50, 100, 200, and 300 m during the 2011-12, 2012-13, and 2013-14 seasons. The image parameter lgR was consistently correlated positively with wheat powdery mildew severity and negatively with wheat grain yield for all combinations of flight altitude and year. Fitting the data with random coefficient regression models showed that the exact relationship of lgR with disease severity and grain yield varied considerably from year to year and to a lesser extent with flight altitude within the same year. The present results raise an important question about the consistency of using remote imaging information to estimate disease severity and grain yield. Further research is needed to understand the nature of interyear variability in the relationship of remote imaging data with disease or grain yield. Only then can we determine how the remote imaging tool can be used in commercial agriculture.


Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation.
To describe the use of sedatives and neuromuscular blocking agents (NMBs) and their impact in outcome in an international cohort of patients receiving mechanical ventilation. We analyzed the database of a prospective, multicenter cohort of 5,183 adult patients who received mechanical ventilation for > 12 h. We considered that a patient received a given agent when it was administered for at least 3 h in a 24-h period. A total of 3,540 patients (68%; 95% confidence interval [CI], 67 to 69%) received a sedative at any time while receiving mechanical ventilation. The median number of days of use was 3 (interquartile range [IQR], 2 to 6 days). The persistent use of sedative was associated with more days of mechanical ventilation (median, 4 days [IQR, 2 to 8 days], vs 3 days [IQR, 2 to 4 days] in patients who did not receive sedatives [p < 0.001]); more weaning days (median, 2 days [IQR, 1 to 3 days], vs 2 days [IQR, 1 to 5 days] in patients who did not receive sedatives [p < 0.001]); and longer length of stay in the ICU (median, 8 days [IQR, 5 to 15 days], vs 5 days [IQR, 3 to 9 days] in patients who did not receive sedatives [p < 0.001]). Six hundred eighty-six patients (13%; 95% CI, 12 to 14%) received an NMB for at least 1 day. The median number of days of use was 2 (IQR, 1 to 4 days). The administration of an NMB was independently related with age, a normal previous functional status, main reason of mechanical ventilation (patients with ARDS received more NMBs), and with patient management (patients requiring permissive hypercapnia, prone position, high level of positive end-expiratory pressure, and high airways pressure). The use of sedatives is very common, and their use is associated with a longer duration of mechanical ventilation, weaning time, and stay in the ICU. NMBs are used in 13% of the patients and are associated with longer duration of mechanical ventilation, weaning time, stay in the ICU, and higher mortality.


Cardiovascular disease and air pollution in Scotland: no association or insufficient data and study design?
Coronary heart disease and stroke are leading causes of mortality and ill health in Scotland, and clear associations have been found in previous studies between air pollution and cardiovascular disease. This study aimed to use routinely available data to examine whether there is any evidence of an association between short-term exposure to particulate matter (measured as PM₁₀, particles less than 10 micrograms per cubic metre) and hospital admissions due to cardiovascular disease, in the two largest cities in Scotland during the years 2000 to 2006. The study utilised an ecological time series design, and the analysis was based on overdispersed Poisson log-linear models. No consistent associations were found between PM₁₀ concentrations and cardiovascular hospital admissions in either of the cities studied, as all of the estimated relative risks were close to one, and all but one of the associated 95% confidence intervals contained the null risk of one. This study suggests that in small cities, where air quality is relatively good, then either PM₁₀ concentrations have no effect on cardiovascular ill health, or that the routinely available data and the corresponding study design are not sufficient to detect an association.


An atypical case of purple glove syndrome: an avoidable adverse event.
A 73-year-old man presented in status epilepticus. He had a long history of epilepsy for which he was treated with regular phenytoin and phenobarbitone. On admission, his phenytoin level was found to be subtherapeutic and was treated with rectal diazepam and intravenous lorazepam. He was later started on an infusion of phenytoin in preparation to restart his oral medication. The medication was delivered via a peripheral cannula in his forearm. Five days later, he developed redness and swelling of this arm followed by the appearance of a large ulcer. After ruling out infective causes and a compartment syndrome it was felt that the patient had developed a delayed purple glove syndrome secondary to intravenous phenytoin. Following 7 days of regular saline irrigation and dressing changes, the erythema improved and the ulcer showed signs of healing, and eventually resolved.


Sensitization of apoptotically-resistant breast carcinoma cells to TNF and TRAIL by inhibition of p38 mitogen-activated protein kinase signaling.
The mitogen-activated protein kinase (MAPK) cascade is a critical component in the regulation of cell survival and proliferation decisions. In breast carcinoma cells, activation of the p38-MAPK member of this family occurs in response to pro-inflammatory cytokines and cellular stress. The involvement of p38-MAPK in the activation of the transcription factor, NF-kappaB, suggests a potential role and mechanism for regulation of cell survival and drug resistance. Generation of the resistant MCF-7 variant (MCF-7TN-R) was achieved by prolonged exposure of MCF-7N cells to increasing concentrations of TNF. Differences in MAPK activation and function in the MCF-7 cell variants were determined. The role of the p38-MAPK pathway in regulation of resistance was determined using pharmacological (SB 203580) or molecular [Dominant Inhibitory (DI)-p38] inhibition. The effect of p38 inhibition on NF-kappaB transcriptional activation was analyzed. As compared to the sensitive MCF-7N parent cell line, the MCF-7TN-R cell line displayed significant resistance to TNF- and TRAIL-induced cell death. Analysis of the expression and phosphorylation of members of the MAPK family revealed an increased basal activation of p38 in the MCF-7TN-R variant. The p38-mediated phosphorylation and transcriptional activity were suppressed by pharmacologic inhibition with SB 230580. Treatment of MCF-7TN-R cells with SB partially restored sensitivity to TNF-induced cell death. In addition, use of a DI-p38 construct with or without the addition to TNF induced cell death, thus restoring TNF-sensitivity to these cells. The ability of p38 inhibition to restore apoptotic sensitivity was correlated with suppression of the TNF-induced cell survival pathway, NF-kappaB. The increased activation of p38-MAPK in MCF-7TN-R cells demonstrates that this signaling pathway through activation of NF-kappaB is an important route for control of resistance to cell death in breast carcinoma. Molecular and pharmacological inhibition of p38-MAPK signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens and restoration of apoptotic signaling.


Health benefits of physical activity: the evidence.
The primary purpose of this narrative review was to evaluate the current literature and to provide further insight into the role physical inactivity plays in the development of chronic disease and premature death. We confirm that there is irrefutable evidence of the effectiveness of regular physical activity in the primary and secondary prevention of several chronic diseases (e.g., cardiovascular disease, diabetes, cancer, hypertension, obesity, depression and osteoporosis) and premature death. We also reveal that the current Health Canada physical activity guidelines are sufficient to elicit health benefits, especially in previously sedentary people. There appears to be a linear relation between physical activity and health status, such that a further increase in physical activity and fitness will lead to additional improvements in health status.


Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action.
Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors and altering target gene transcription, but estrogens can also have nongenomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the nongenomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, nondegradable poly(amido)amine dendrimer macromolecules that are conjugated to multiple estrogen molecules through chemically robust linkages. Because of their charge and size, these estrogen-dendrimer conjugates (EDCs) remain outside the nucleus. They stimulate ERK, Shc, and Src phosphorylation in MCF-7 breast cancer cells at low concentrations, yet they are very ineffective in stimulating transcription of endogenous estrogen target genes, being approximately 10,000-fold less potent than estradiol in genomic actions. In contrast to estradiol, EDC was not effective in stimulating breast cancer cell proliferation. Because these EDC ligands activate nongenomic activity at concentrations at which they do not alter the transcription of estrogen target genes, they should be useful in studying extranuclear initiated pathways of estrogen action in a variety of target cells.


Firing properties of GABAergic versus non-GABAergic vestibular nucleus neurons conferred by a differential balance of potassium currents.
Neural circuits are composed of diverse cell types, the firing properties of which reflect their intrinsic ionic currents. GABAergic and non-GABAergic neurons in the medial vestibular nuclei, identified in GIN and YFP-16 lines of transgenic mice, respectively, exhibit different firing properties in brain slices. The intrinsic ionic currents of these cell types were investigated in acutely dissociated neurons from 3- to 4-wk-old mice, where differences in spontaneous firing and action potential parameters observed in slice preparations are preserved. Both GIN and YFP-16 neurons express a combination of four major outward currents: Ca(2+)-dependent K(+) currents (I(KCa)), 1 mM TEA-sensitive delayed rectifier K(+) currents (I(1TEA)), 10 mM TEA-sensitive delayed rectifier K(+) currents (I(10TEA)), and A-type K(+) currents (I(A)). The balance of these currents varied across cells, with GIN neurons tending to express proportionately more I(KCa) and I(A), and YFP-16 neurons tending to express proportionately more I(1TEA) and I(10TEA). Correlations in charge densities suggested that several currents were coregulated. Variations in the kinetics and density of I(1TEA) could account for differences in repolarization rates observed both within and between cell types. These data indicate that diversity in the firing properties of GABAergic and non-GABAergic vestibular nucleus neurons arises from graded differences in the balance and kinetics of ionic currents.


Impact of various noises on maximum reach in broadband light source based high-capacity WDM passive optical networks.
We investigated the effects of various noises on the performance of extended-reach WDM-PONs based on broadband light sources (BLSs). The maximum reach in BLS based WDM-PONs was analyzed by taking into account the impact of relative intensity noise of optical source, chromatic dispersion of transmission fiber and in-band crosstalk. We confirmed that the system's performance of BLS based WDM-PONs would be strongly dependent on the equivalent optical bandwidth of optical source. From the results, we found that the maximum reach in BLS based WDM-PONs operating at 1.25 Gb/s could be increased to be approximately 70 km of single-mode fiber as long as the chirp and relative intensity noise (RIN) of optical source would be suppressed properly.


Reptile genomes open the frontier for comparative analysis of amniote development and regeneration.
Developmental genetic studies of vertebrates have focused primarily on zebrafish, frog and mouse models, which have clear application to medicine and well-developed genomic resources. In contrast, reptiles represent the most diverse amniote group, but have only recently begun to gather the attention of genome sequencing efforts. Extant reptilian groups last shared a common ancestor ?280 million years ago and include lepidosaurs, turtles and crocodilians. This phylogenetic diversity is reflected in great morphological and behavioral diversity capturing the attention of biologists interested in mechanisms regulating developmental processes such as somitogenesis and spinal patterning, regeneration, the evolution of "snake-like" morphology, the formation of the unique turtle shell, and the convergent evolution of the four-chambered heart shared by mammals and archosaurs. The complete genome of the first non-avian reptile, the green anole lizard, was published in 2011 and has provided insights into the origin and evolution of amniotes. Since then, the genomes of multiple snakes, turtles, and crocodilians have also been completed. Here we will review the current diversity of available reptile genomes, with an emphasis on their evolutionary relationships, and will highlight how these genomes have and will continue to facilitate research in developmental and regenerative biology.


Antidepressant effects of resveratrol in an animal model of depression.
Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural non-flavonoid polyphenol antioxidant extracted from red grapes in the processing of wine. Initially it was studied for its potential as anticancer drug, and later was found to reduce cardiovascular disease. More recently resveratrol was shown to alleviate depressive-like symptoms induced by stress or other means in mice and rats. The major purpose of this study was to investigate whether resveratrol would manifest an antidepressant effect in Wistar-Kyoto (WKY) rats, a putative and non-induced animal model of depression, and whether this effect might be associated with an increase in hippocampal and frontal cortical brain-derived neurotrophic factor (BDNF), a protein implicated in chronic effects of many antidepressants. Adult male WKY rats were injected with two doses of resveratrol (10 and 40 mg/kg, i.p.) and their behavior in the open field locomotor activity (LMA), forced swim test (FST: a measure of helplessness), and sucrose preference test (SPT: a measure of anhedonia) was evaluated after a single acute injection or following 7 days of daily treatment. Both acute and chronic administration of resveratrol resulted in a dose-dependent decrease in FST. However, only chronic resveratrol resulted in dose-dependent increase in sucrose consumption. LMA was not affected by any treatment. Parallel to the observed behavioral effects the level of hippocampal, but not frontal cortical, BDNF was also dose-dependently elevated after chronic resveratrol administration. These findings indicate an antidepressant-like effect of resveratrol in an animal model of depression possibly via activation of hippocampal BDNF, and suggest therapeutic potential of resveratrol in at least a subpopulation of depressed patients.


Mild and severe muscular dystrophy caused by a single gamma-sarcoglycan mutation.
Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein gamma-sarcoglycan. The previous mutation analysis of gamma-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the gamma-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding gamma-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the gamma-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of alpha-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the gamma-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from gamma-sarcoglycan gene mutations.


A review of MED-SuMo applications.
Resolved three-dimensional protein structures are a major source of information for understanding protein functional properties. The current explosive growth of publicly available protein structures is producing large volumes of data for computational modelling and drug design methods. Target-based in silico drug design tools aid design and optimize compounds to bind to specific targets. MED-SuMo is a powerful technology for comparing local regions on protein surfaces, allowing similarities to be discovered and explored. This is a target-based tool that can exploit all available macromolecule structures. Its computational efficiency differentiates its approach from widely used methods such as docking and scoring, or map-based methods. As a result, MED-SuMo contributes to a large variety of real-world drug discovery applications. We review specific applications where MED-SuMo performed a significant role. These examples include functional annotation, pocket profiling, structural superposition, and functional binding site classification. We also review cases where MED-SuMo provided an innovative solution to frequent undertakings of the medicinal chemist and molecular modeller during lead discovery and lead optimization. These further cases include drug repurposing and fragment-based drug design.


Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice.
Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and other folk medicines for various purposes as an aphrodisiac, antispasmodic, and expectorant. Previous evidence suggested that Crocus sativus is linked to improving cognitive function in Alzheimer's disease (AD) patients. The aim of this study was to in vitro and in vivo investigate the mechanism(s) by which Crocus sativus exerts its positive effect against AD. The effect of Crocus sativus extract on Aβ load and related toxicity was evaluated. In vitro results showed that Crocus sativus extract increases the tightness of a cell-based blood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo studies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to mice diet) on the BBB tightness and function that was associated with reduced Aβ load and related pathological changes in 5XFAD mice used as an AD model. Reduced Aβ load could be explained, at least in part, by Crocus sativus extract effect to enhance Aβ clearance pathways including BBB clearance, enzymatic degradation and ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in the brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus and known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ load but to a lesser extent when compared to Crocus sativus extract. Collectively, findings from this study support the positive effect of Crocus sativus against AD by reducing Aβ pathological manifestations.


Organizational predictors of staff stress, satisfaction, and intended turnover in a service for people with multiple disabilities.
Questionnaire data were collected from 64 direct-care staff members in a residential facility for people with multiple disabilities. Path analyses identified a number of organizational factors that predicted levels of perceived stress, overall job satisfaction, overall life satisfaction, and perceived likelihood of leaving the organization. Factors found to be common influences on all outcome measures included support from other staff (largely supervisory), job variety, staff perceptions of organizational democracy, goodness-of-fit between the attitudes and aims of staff and those of the organization, staff development, and income. Implications of the findings for service managers were discussed.


Multi foci with diffraction limited resolution.
The generation of multi foci is an established method for high-speed parallel direct laser writing, scanning microscopy and for optical tweezer arrays. However, the quality of multi foci reduces with increasing resolution due to interference effects. Here, we report on a spatial-light-modulator-based method that allows for highly uniform, close to Gaussian spots with diffraction limited resolution using a wavelength of 780 nm. We introduce modifications of a standard algorithm that calculates a field distribution on the entrance pupil of a high numerical aperture objective splitting the focal volume into a multitude of spots. Our modified algorithm compares favourably to a commonly used algorithm in full vectorial calculations as well as in point-spread-function measurements. The lateral and axial resolution limits of spots generated by the new algorithm are found to be close to the diffraction limit.


Biochemical and electrophysiological characterization of two sea anemone type 1 potassium toxins from a geographically distant population of Bunodosoma caissarum.
Sea anemone (Cnidaria, Anthozoa) venom is an important source of bioactive compounds used as tools to study the pharmacology and structure-function of voltage-gated K+ channels (KV). These neurotoxins can be divided into four different types, according to their structure and mode of action. In this work, for the first time, two toxins were purified from the venom of Bunodosoma caissarum population from Saint Peter and Saint Paul Archipelago, Brazil. Sequence alignment and phylogenetic analysis reveals that BcsTx1 and BcsTx2 are the newest members of the sea anemone type 1 potassium channel toxins. Their functional characterization was performed by means of a wide electrophysiological screening on 12 different subtypes of KV channels (KV1.1-KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; hERG and Shaker IR). BcsTx1 shows a high affinity for rKv1.2 over rKv1.6, hKv1.3, Shaker IR and rKv1.1, while Bcstx2 potently blocked rKv1.6 over hKv1.3, rKv1.1, Shaker IR and rKv1.2. Furthermore, we also report for the first time a venom composition and biological activity comparison between two geographically distant populations of sea anemones.


Diagnosis and therapy for airway obstruction in children with Down syndrome.
To document the causes of upper airway obstruction in a population of children with Down syndrome and to highlight the role of associated comorbidities. Review of 23 cases involving children with Down syndrome who were referred for upper airway obstruction over a 2(1/2)-year period to the Pediatric Otolaryngology Service of the University of New Mexico, Albuquerque. Data on the following variables were obtained: reason for referral, demographics, diagnosis, surgical procedures, complications, and comorbidities. The children ranged in age from 1 day to 10.2 years (mean age, 1.8 years; median age, 6 months). Thirteen children were male and 10 were female. None of the children had subglottic stenosis. Laryngomalacia was the primary diagnosis in 10 children (43%), 8 of whom were younger than 1 month. Obstructive sleep apnea was the primary diagnosis in 11 children (48%), 8 of whom were older than 2 years. All children with obstructive sleep apnea and 4 children with laryngomalacia had a secondary ear, nose, and throat disorder. Gastroesophageal reflux was a comorbidity in 14 children (61%). The causes, severity, and presentation of upper airway obstruction in children with Down syndrome are related to the age of the child and to associated comorbidities. The treatment of comorbidities and secondary ear, nose, and throat disorders is an integral component of the surgical management of upper airway obstruction in such cases.


Effect of octreotide on refractory AIDS-associated diarrhea. A prospective, multicenter clinical trial.
To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). A prospective, open-label study. Inpatient metabolic units of four university medical centers. Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (greater than or equal to 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications. After initial baseline studies, patients received octreotide, 50 micrograms every 8 hours for 48 hours. If stool volume was not reduced to less than 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 micrograms. Fifty men and one woman (mean age, 36.3 +/- 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 +/- 0.5 stools per day on day 0 compared with 3.8 +/- 0.3 stools per day on day 21 [P less than 0.001] and 1604 +/- 180 mL/d on day 0 compared with 1084 +/- 162 mL/d on day 14 [P less than 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by greater than or equal to 50% of initial collections or reduction to less than or equal to 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P less than 0.01). Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.


Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Objective testing for DVT is crucial because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. This guideline focuses on the identification of optimal strategies for the diagnosis of DVT in ambulatory adults. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. We suggest that clinical assessment of pretest probability of DVT, rather than performing the same tests in all patients, should guide the diagnostic process for a first lower extremity DVT (Grade 2B). In patients with a low pretest probability of first lower extremity DVT, we recommend initial testing with D-dimer or ultrasound (US) of the proximal veins over no diagnostic testing (Grade 1B), venography (Grade 1B), or whole-leg US (Grade 2B). In patients with moderate pretest probability, we recommend initial testing with a highly sensitive D-dimer, proximal compression US, or whole-leg US rather than no testing (Grade 1B) or venography (Grade 1B). In patients with a high pretest probability, we recommend proximal compression or whole-leg US over no testing (Grade 1B) or venography (Grade 1B). Favored strategies for diagnosis of first DVT combine use of pretest probability assessment, D-dimer, and US. There is lower-quality evidence available to guide diagnosis of recurrent DVT, upper extremity DVT, and DVT during pregnancy.


[Symmetry of the anterior segment morphometric measurements in paired eyes using ultrasound biomicroscopy (UBM)].
To determine the presence of symmetry of anterior segment morphometric measurements between normal adelphic eyes. One hundred and seventy-eight eyes of 89 subjects with normal ophthalmic examination were examined by ultrasound biomicroscopy (UBM). In each eye, the anterior chamber depth (ACD) as well as 11 other measurements that characterize anterior segment morphometry were measured in 4 different quadrants (superior, nasal, inferior and temporal). The presence of symmetry between right and left eye for each of these variables was then compared for each meridian. No significant statistical differences were observed concerning anterior segment morphometry between right and left eyes for most measured parameters. Only two variables, in two different meridians, presented statistical significant differences between right and left eyes. The difference, however, was inferior to 0.025 mm, which is beyond the precision of UBM and therefore was not considered to be clinically significant. Pearson correlation analysis demonstrated the presence of a statistical significant correlation, with a moderate intensity for the majority of the variables except ACD, whose correlation was excellent. This study demonstrated that symmetry of morphometric measurements between right and left eyes is expected to occur, provided these eyes have similar refractive errors and biometric measurements.


Blood pressure and 10-year mortality risk in the Milan Geriatrics 75+ Cohort Study: role of functional and cognitive status.
Optimal blood pressure targets in older adults are controversial. to investigate whether the relation of blood pressure with mortality in older adults varies by age, functional and cognitive status. longitudinal geriatric outpatient cohort. Milan Geriatrics 75+ Cohort Study. One thousand five hundred and eighty-seven outpatients aged 75 years and over. The relations of systolic (SBP) and diastolic blood pressure (DBP) with mortality risk were analysed using Cox proportional hazards models. Blood pressure, Mini-Mental State Examination (MMSE) and Basic Activities of Daily Living (ADL) were assessed at baseline. All analyses were adjusted for socio-demographic factors, co-morbidities and medications. One thousand and forty-six patients died during 10-year follow-up. The relationships of SBP and DBP with mortality risk were U-shaped; SBP of 165 mmHg and DBP of 85 mmHg were associated with the lowest mortality. Patients with SBP < 120 mmHg and patients with SBP 120-139 mmHg had 1.64-fold (95% confidence intervals, CI 1.21-2.23) and 1.32-fold (95% CI 1.10-1.60) higher mortality risk than patients with SBP 160-179 mmHg (P values 0.001 and 0.004, respectively). In patients with SBP below 180 mmHg, higher SBP was associated with lower mortality in patients with impaired ADL and MMSE but not in those with preserved ADL and/or MMSE (P for interaction 0.033). Age did not modify the correlation of SBP with mortality. The correlations of SBP and DBP with mortality were U-shaped. Higher SBP is related to lower mortality in subjects with impaired ADL and MMSE. ADL and MMSE may identify older subjects who benefit from higher blood pressure.


Long-term death and recurrence in patients with acute venous thromboembolism: the MASTER registry.
The long-term clinical outcome of VTE has been essentially assessed in cohorts of selected patients. The aim of this multicenter registry was to prospectively assess the long-term clinical outcome in a cohort of unselected patients with objectively confirmed acute VTE. Death and VTE recurrence at 24 months were the main study outcomes. Univariate and multivariate survival analyses were performed according to the Kaplan-Meyer and Cox proportional hazard model, respectively. 2119 patients with acute VTE were included in the registry: 1541 (72.7%) with deep vein thrombosis, 206 (9.7%) with pulmonary embolism and 372 (17.6%) with both. Information about death was available in 2021 patients (95.4%) and about recurrence in 1988 patients (93.8%). 167 patients (4.55% patient-year) died during follow-up. After adjusting for age, cancer (Hazard ratio [HR]: 7.2; 95%CI 4.8-10.8), long-term heparin treatment (HR: 2.5; 95%CI 1.8-3.5), in-hospital management of VTE (HR: 2.0; 95%CI 1.3-3.0), and ileo-caval thrombosis (HR: 1.7; 95%CI 1.2-2.4) were found to be independent predictors of death. 124 (3.63% patient-year) patients had a VTE recurrence during follow-up. In-hospital management of VTE (HR: 1.8; 95%CI 1.2-2.9), male gender (HR: 1.7; 95%CI 1.2-2.4) were independent risk factors for recurrent VTE. Cancer (HR: 1.6; 95%CI 1.0-2.8) showed a trend for increased risk of VTE recurrence (p=0.056). The reported rate of major bleeding was 2.5%. In a large cohort of unselected VTE patients, cancer, ileo-caval thrombosis, long-term heparin treatment and in-hospital management were associated with increased mortality during long-term follow-up. In-hospital management, male gender were associated with an increased risk of VTE recurrence.


Changes in impaired self-awareness after acquired brain injury in patients following intensive neuropsychological rehabilitation.
The objective of this study was to investigate changes in self-awareness impairments in outpatients with acquired brain injury (ABI) and the effects these changes have on rehabilitation. Participants were 78 patients with ABI (8.3 years post-injury) who followed an intensive outpatient neuropsychological rehabilitation programme. This longitudinal study comprised pre (T1) and post (T2) measurements and a one-year follow-up (T3). Thirty-eight patients completed the study. The main outcome domains were self-awareness, depressive symptoms, psychological and physical dysfunction, and health-related quality of life (HRQoL). Patients were divided into three awareness groups: underestimation, accurate estimation, and overestimation of competencies. Most patients who underestimated their competencies at the start of treatment accurately estimated their competencies directly after treatment (9 out of 11 patients). These patients also exhibited the largest treatment effects regarding depressive symptoms, psychological and physical dysfunction, and HRQoL. Most patients with impaired self-awareness (i.e., overestimation of competencies) at the start of treatment continued to overestimate their competencies after treatment (10 out of 14 patients). These patients exhibited a significant decrease in depressive symptoms but no other treatment effects. The results indicate that changes in outcome are related to changes in awareness, which underline the importance of taking into account different awareness groups with respect to treatment effects.


Neural-cardiac coupling in threat-evoked anxiety.
Anxiety is a debilitating symptom of many psychiatric disorders including generalized anxiety disorder, mood disorders, schizophrenia, and autism. Anxiety involves changes in both central and peripheral biology, yet extant functional imaging studies have focused exclusively on the brain. Here we show, using functional brain and cardiac imaging in sequential brain and cardiac magnetic resonance imaging (MRI) sessions in response to cues that predict either threat (a possible shock) or safety (no possibility of shock), that MR signal change in the amygdala and the prefrontal and insula cortices predicts cardiac contractility to the threat of shock. Participants with greater MR signal change in these regions show increased cardiac contractility to the threat versus safety condition, a measure of the sympathetic nervous system contribution to the myocardium. These findings demonstrate robust neural-cardiac coupling during induced anxiety and indicate that individuals with greater activation in brain regions identified with aversive emotion show larger magnitude cardiac contractility increases to threat.


Reconfigurable microfluidics: real-time shaping of virtual channels through hydrodynamic forces.
To break the current paradigm in microfluidics that directly links device design to functionality, we introduce microfluidic "virtual channels" that can be dynamically shaped in real-time. A virtual channel refers to a flow path within a microfluidic flow cell, guiding an injected reagent along a user-defined trajectory solely by hydrodynamic forces. Virtual channels dynamically reproduce key microfluidic functionality: directed transport of minute volumes of liquid, splitting, merging and mixing of flows. Virtual channels can be formed directly on standard biological substrates, which we demonstrate by sequential immunodetection at arrays of individual reaction sites on a glass slide and by alternating between local and global processing of surface-adherent cell-block sections. This approach is simple, versatile and generic enough to form the basis of a new class of microfluidic techniques.


Binding of natural and synthetic polyphenols to human dihydrofolate reductase.
Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) are potent inhibitors of DHFR with dissociation constants (K(D))of 0.9 and 1.8 microM, respectively, while polyphenols lacking the ester bound gallate moiety [e.g., (-)-epigallocatechin (EGC) and (-)-epicatechin (EC)] did not bind to this enzyme. To avoid stability and bioavailability problems associated with tea catechins we synthesized a methylated derivative of ECG (3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin; TMECG), which effectively binds to DHFR (K(D) = 2.1 microM). In alkaline solution, TMECG generates a stable quinone methide product that strongly binds to the enzyme with a K(D) of 8.2 nM. Quercetin glucuronides also bind to DHFR but its effective binding was highly dependent of the sugar residue, with quercetin-3-xyloside being the stronger inhibitor of the enzyme with a K(D) of 0.6 microM. The finding that natural polyphenols are good inhibitors of human DHFR could explain the epidemiological data on their prophylactic effects for certain forms of cancer and open a possibility for the use of natural and synthetic polyphenols in cancer chemotherapy.


An Efficient Catalytic DNA that Cleaves L-RNA.
Many DNAzymes have been isolated from synthetic DNA pools to cleave natural RNA (D-RNA) substrates and some have been utilized for the design of aptazyme biosensors for bioanalytical applications. Even though these biosensors perform well in simple sample matrices, they do not function effectively in complex biological samples due to ubiquitous RNases that can efficiently cleave D-RNA substrates. To overcome this issue, we set out to develop DNAzymes that cleave L-RNA, the enantiomer of D-RNA, which is known to be completely resistant to RNases. Through in vitro selection we isolated three L-RNA-cleaving DNAzymes from a random-sequence DNA pool. The most active DNAzyme exhibits a catalytic rate constant ~3 min-1 and has a structure that contains a kissing loop, a structural motif that has never been observed with D-RNA-cleaving DNAzymes. Furthermore we have used this DNAzyme and a well-known ATP-binding DNA aptamer to construct an aptazyme sensor and demonstrated that this biosensor can achieve ATP detection in biological samples that contain RNases. The current work lays the foundation for exploring RNA-cleaving DNAzymes for engineering biosensors that are compatible with complex biological samples.


Vicarious posttraumatic growth among interpreters.
An emerging evidence base indicates that posttraumatic growth might be experienced vicariously by those working alongside trauma survivors. In this study we explored the vicarious experiences of eight interpreters working in a therapeutic setting with asylum seekers and refugees. We adopted a qualitative approach, using semistructured interviews and interpretative phenomenological analysis. Four interrelated themes emerged from the findings: feeling what your client feels, beyond belief, finding your own way to deal with it, and a different person. Although all participants experienced distress, they also perceived themselves to have grown in some way. The implications for a theory of vicarious posttraumatic growth are discussed, along with clinical applications.


An MLH1 mutation links BACH1/FANCJ to colon cancer, signaling, and insight toward directed therapy.
Defects in MLH1, as with other mismatch repair (MMR) proteins, are the primary cause of hereditary nonpolyposis colon cancer (HNPCC). Mutations in MMR genes often disrupt mismatch repair and MMR signaling functions. However, some HNPCC-associated mutations have unknown pathogenicity. Here, we uncover an MLH1 clinical mutation with a leucine (L)-to-histidine (H) amino acid change at position 607 that ablates MLH1 binding to FANCJ. Given that a DNA helicase is not essential for mammalian MMR in vitro, we considered that loss of MLH1 binding to FANCJ could alter MMR signaling. Consistent with this hypothesis, FANCJ-deficient cells exhibit delayed MMR signaling and apoptotic responses that generate resistance to agents that induce O(6)-methylguanine lesions. Our data indicate that the delay in MMR signaling provides time for the methylguanine methyltransferase (MGMT) enzyme to reverse DNA methylation. In essence, FANCJ deficiency alters the competition between two pathways: MGMT-prosurvival versus MMR-prodeath. This outcome could explain the HNPCC familial cancers that present as microsatellite stable and with intact MMR, such as MLH(L607H). Importantly, the link between FANCJ and HNPCC provides insight toward directed therapies because loss of the FANCJ/MLH1 interaction also uniquely sensitizes cells to DNA cross-linking agents.


Rapid transepithelial transport of prions following inhalation.
Prion infection and pathogenesis are dependent on the agent crossing an epithelial barrier to gain access to the recipient nervous system. Several routes of infection have been identified, but the mechanism(s) and timing of in vivo prion transport across an epithelium have not been determined. The hamster model of nasal cavity infection was used to determine the temporal and spatial parameters of prion-infected brain homogenate uptake following inhalation and to test the hypothesis that prions cross the nasal mucosa via M cells. A small drop of infected or uninfected brain homogenate was placed below each nostril, where it was immediately inhaled into the nasal cavity. Regularly spaced tissue sections through the entire extent of the nasal cavity were processed immunohistochemically to identify brain homogenate and the disease-associated isoform of the prion protein (PrP(d)). Infected or uninfected brain homogenate was identified adhering to M cells, passing between cells of the nasal mucosa, and within lymphatic vessels of the nasal cavity at all time points examined. PrP(d) was identified within a limited number of M cells 15 to 180 min following inoculation, but not in the adjacent nasal mucosa-associated lymphoid tissue (NALT). While these results support M cell transport of prions, larger amounts of infected brain homogenate were transported paracellularly across the respiratory, olfactory, and follicle-associated epithelia of the nasal cavity. These results indicate that prions can immediately cross the nasal mucosa via multiple routes and quickly enter lymphatics, where they can spread systemically via lymph draining the nasal cavity.


Integrated microfluidic biophotonic chip for laser induced fluorescence detection.
Integrated Lab-on-a-Chip or Micro-Total Analysis Systems offer several advantages for the detection of active chemical and biological species. In this work, an integrated microfluidic biophotonic chip is proposed for carrying out laser induced fluorescence detection. A Spectrometer-on-Chip device, specifically designed for multiple fluorescence detections at different emission wavelengths is integrated with the opto-microfluidic chip fabricated on Silicon-Polymer hybrid platform. The input fiber from the laser source, and output fiber coupled with a Spectrometer-on-Chip were integrated with the microfluidic channel so as to make a robust setup. Fluorescence detection was carried out using Alexafluor 647 tagged antibody particles. The experimental results show that the proposed biophotonic microfluidic device is highly suitable for high throughput detection of chemical and biological specimens.


Project nGage: Network Supported HIV Care Engagement for Younger Black Men Who Have Sex with Men and Transgender Persons.
Young Black men who have sex with men and transgender persons (YBMSMT) aged 13-29 carry the nation's highest burden of new HIV infections. Studies indicate that YBMSMT have poor retention in care, which is associated with reduced medication adherence and increased virologic failure. Project nGage is a randomized controlled (RCT) trial evaluating the feasibility and preliminary efficacy of a brief, dyadic intervention designed to promote adherence to HIV primary care in safety-net clinics. Network visualization is used to identify and engage a support confidant (SC) from participants' social networks. A social work interventionist then meets with the SC and SC-participant dyad to activate and maintain HIV-specific social support. Project nGage is operating in two phases. In Phase I, the Team refined study protocols based on pilot testing. In Phase II, 94 HIV infected YBMSMT ages 16-29 will be recruited, enrolled and randomly assigned to receive Project nGage or treatment as usual (TAU). The primary outcome is appointment attendance; the secondary outcomes are medication adherence and viral load. Implementation challenges include coordinating sites, managing dyadic intervention logistics, and recruiting non-adherent patients or those who have fallen out of care. The team continues to address implementation issues as the study progresses. Project nGage is addressing a gap in HIV care-related research by focusing on supportive relationships as a mechanism through which to promote retention in care. Pending study results, a larger RCT would compare the relative effectiveness of the Project nGage intervention versus TAU over 18 to 24 months.


Longitudinal patterns and predictors of multiple health risk behaviors among adolescents: The TRAILS study.
Most studies on multiple health risk behaviors among adolescents have cross-sectionally studied a limited number of health behaviors or determinants. To examine the prevalence, longitudinal patterns and predictors of individual and multiple health risk behaviors among adolescents. Eight health risk behaviors (no regular consumption of fruit, vegetables or breakfast, overweight or obesity, physical inactivity, smoking, alcohol use and cannabis use) were assessed in a prospective population study (second and third wave). Participants were assessed in three waves between ages 10 and 17 (2001-2008; n=2230). Multiple linear regression was used to assess the influence of gender, self-control, parental health risk behaviors, parental monitoring and socioeconomic factors on the number of health risk behaviors adjusted for preceding multiple health risk behaviors (analysis: 2013-2014). Rates of >5 health risk behaviors were high: 3.6% at age 13.5 and 10.2% at age 16. Smoking at age 13.5 was frequently associated with health risk behaviors at age 16. No regular consumption of fruit, vegetables and breakfast, overweight or obesity, physical inactivity and smoking predicted the co-occurrence of health risk behaviors at follow-up. Significant predictors of the development of multiple health risk behaviors were adolescents' levels of self-control, socioeconomic status and maternal smoking. Multiple health risk behaviors are common among adolescents. Individual and social factors predict changes in multiple health risk behaviors, showing that prevention targeting multiple risk behaviors is needed. Special attention should be paid to adolescents with low self-control and families with low socioeconomic status or a mother who smokes.


A Structured Cleaving Mesh for Bioheat Transfer Application.
Goal: The thermoregulation mechanism is a complex system that executes vital processes in the human body. Various models have been proposed to simulate the thermoregulatory response of an adult human to environmental stimuli. However, these models generally rely on stylized phantoms that lack the anatomical details of voxel phantoms used in radiation dosimetry and shielding research. The goal of this work is to introduce voxel phantoms to thermoregulation research by modeling the physical energy exchange between tissue and its surroundings, discuss a specific challenge associated with voxel phantoms, propose a method to address this challenge, and demonstrate its application. Method: One of the major challenges in using voxel phantoms is the stair-step effect on the surface of the voxelized domain. This effect causes over-estimation of surface area, accurate knowledge of which is critical for modeling heat exchanging systems. A methodology to generate a voxel domain from medical imaging data and reduce error in the surface area caused by the stair-step effect is presented. The methodology, based on a structured mesh and finite-volume method, is demonstrated with tumors generated from magnetic resonance imaging (MRI) scans of mice. Results: The methodology discussed in the paper shows a decrease in surface area over-estimation from 50% to 15% for a sphere and 47% to 17% for tumor models generated directly from MRI scans. Conclusion: This work provides a direct method to generate a smoother domain from medical imaging data and reducing surface area error in a voxelized domain. The technique presented is independent of domain material, including tissue type, and can be extended to any homogeneous or inhomogeneous domain. The increase in surface area accuracy obtained by smoothing the voxel domain results in more accurate temperature estimates in heat transfer simulation.


A single residue, Lys108, of the delta-opioid receptor prevents the mu-opioid-selective ligand [D-Ala2,N-MePhe4,Gly-ol5]enkephalin from binding to the delta-opioid receptor.
Previously, we found that replacement of the region around the first extracellular loop of the delta-opioid receptor (OPR) with the corresponding region of the mu-OPR gives the high affinity for [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO), a mu-opioid-selective ligand, to the resultant chimeric receptor, DMDD, suggesting that the difference in the amino acid sequence within this region between the mu- and delta-OPRs is critical for the discrimination between these receptors by DAMGO. In the current study, we carried out systematic replacements of seven non-conserved residues in this region of the delta-OPR with the corresponding amino acid found in the mu-OPR. Among the seven mutant receptors, only one mutant receptor, delta K108N, showed high affinity (Ki = 18.68 +/- 5.27 nM) for DAMGO, which was comparable to that of the DMDD receptor (Ki = 23.77 +/- 4.27 nM) and 75-fold higher than that of the wild-type delta-OPR (Ki = 1405 +/- 161 nM). Lys108 in the delta-OPR was systematically replaced with 19 kinds of amino acids other than lysine. Among the resultant mutant receptors, 14 mutants bound DAMGO with Ki values comparable to those of the DMDD receptor, ranging from 4.20 to 43.38 nM. These findings suggest that Lys108 of the delta-OPR prevents DAMGO from binding to the delta-OPR rather than that the asparagine residue at the corresponding position in the mu-OPR is necessary for DAMGO binding. In addition, the replacement of Lys108 of the delta-OPR with asparagine dramatically increased the affinity for other peptidic mu receptor-selective ligands, such as dermorphin and D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2.


Socio-Economic Inequalities in Lung Cancer Outcomes: An Overview of Systematic Reviews.
In the past decade, evidence has accumulated about socio-economic inequalities in very diverse lung cancer outcomes. To better understand the global effects of socio-economic factors in lung cancer, we conducted an overview of systematic reviews. Four databases were searched for systematic reviews reporting on the relationship between measures of socio-economic status (SES) (individual or area-based) and diverse lung cancer outcomes, including epidemiological indicators and diagnosis- and treatment-related variables. AMSTAR-2 was used to assess the quality of the selected systematic reviews. Eight systematic reviews based on 220 original studies and 8 different indicators were identified. Compared to people with a high SES, people with a lower SES appear to be more likely to develop and die from lung cancer. People with lower SES also have lower cancer survival, most likely due to the lower likelihood of receiving both traditional and next-generation treatments, higher rates of comorbidities, and the higher likelihood of being admitted as emergency. People with a lower SES are generally not diagnosed at later stages, but this may change after broader implementation of lung cancer screening, as early evidence suggests that there may be socio-economic inequalities in its use.


Amygdala sensitivity to race is not present in childhood but emerges over adolescence.
Neuroimaging research in adults has consistently found that differential perception of race is associated with increased amygdala activity. We hypothesized that such neural biases unlikely reflect innate processes but instead emerge over development. In the current study, we used fMRI to examine the neurodevelopmental trajectory of the amygdala in response to race across childhood and adolescence ranging from 4 to 16 years. Thirty-two youths viewed African American and European American faces during a functional brain scan. Results suggest that differential amygdala response to African American faces does not emerge until adolescence, reflecting the increasing salience of race across development. In addition, greater peer diversity was associated with attenuated amygdala response to African American faces, suggesting that intergroup racial contact may reduce the salience of race.


DeepIso: A Deep Learning Model for Peptide Feature Detection from LC-MS map.
Liquid chromatography with tandem mass spectrometry (LC-MS/MS) based quantitative proteomics provides the relative different protein abundance in healthy and disease-afflicted patients, which offers the information for molecular interactions, signaling pathways, and biomarker identification to serve the drug discovery and clinical research. Typical analysis workflow begins with the peptide feature detection and intensity calculation from LC-MS map. We are the first to propose a deep learning based model, DeepIso, that combines recent advances in Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN) to detect peptide features of different charge states, as well as, estimate their intensity. Existing tools are designed with limited engineered features and domain-specific parameters, which are hardly updated despite a huge amount of new coming proteomic data. On the other hand, DeepIso consisting of two separate deep learning based modules, learns multiple levels of representation of high dimensional data itself through many layers of neurons, and adaptable to newly acquired data. The peptide feature list reported by our model matches with 97.43% of high quality MS/MS identifications in a benchmark dataset, which is higher than the matching produced by several widely used tools. Our results demonstrate that novel deep learning tools are desirable to advance the state-of-the-art in protein identification and quantification.


The metal-binding features of the recombinant mussel Mytilus edulis MT-10-IV metallothionein.
In contrast with the paradigmatic mammalian metallothioneins (MTs), mollusc MT systems consist at least of a high-cadmium induced form, possibly involved in detoxification, and another isoform either constitutive or regulated by essential metals and probably associated with housekeeping metabolism. With the aim of providing a deeper characterization of the coordination features of a molluscan MT peptide of the latter kind, we have analyzed here the metal-binding abilities of the recombinant MeMT-10-IV isoform of Mytilus edulis (MeMT). Also, comparison with other MTs of this type has been undertaken. A synthetic complementary DNA was constructed, cloned and expressed into two Escherichia coli systems. Upon zinc coordination, MeMT folds in vivo into highly chiral and stable Zn(7) complexes, with an exceptional reluctance to fully substitute cadmium(II) and/or copper(I) for zinc(II). In vivo cadmium binding leads to homometallic Cd(7) complexes that structurally differ from any of the in vitro prepared Cd(7) complexes. Homometallic Cu-MeMT can only be obtained in vitro from Zn(7)-MeMT after a great molar excess of copper(I) has been added. In vivo, two different heterometallic Zn,Cu-MeMT complexes are recovered, which nicely correspond to two distinct stages of the in vitro zinc/copper replacement. These MeMT metal-binding features are consistent with a physiological role related to basal/housekeeping metal, mainly zinc, metabolism, and confirm the correspondence between the MeMT gene response pattern and the functional properties of the encoded protein.


Lineage analysis of the late otocyst stage mouse inner ear by transuterine microinjection of a retroviral vector encoding alkaline phosphatase and an oligonucleotide library.
The mammalian inner ear subserves the special senses of hearing and balance. The auditory and vestibular sensory epithelia consist of mechanically sensitive hair cells and associated supporting cells. Hearing loss and balance dysfunction are most frequently caused by compromise of hair cells and/or their innervating neurons. The development of gene- and cell-based therapeutics will benefit from a thorough understanding of the molecular basis of patterning and cell fate specification in the mammalian inner ear. This includes analyses of cell lineages and cell dispersals across anatomical boundaries (such as sensory versus nonsensory territories). The goal of this study was to conduct retroviral lineage analysis of the embryonic day 11.5(E11.5) mouse otic vesicle. A replication-defective retrovirus encoding human placental alkaline phosphatase (PLAP) and a variable 24-bp oligonucleotide tag was microinjected into the E11.5 mouse otocyst. PLAP-positive cells were microdissected from cryostat sections of the postnatal inner ear and subjected to nested PCR. PLAP-positive cells sharing the same sequence tag were assumed to have arisen from a common progenitor and are clonally related. Thirty five multicellular clones consisting of an average of 3.4 cells per clone were identified in the auditory and vestibular sensory epithelia, ganglia, spiral limbus, and stria vascularis. Vestibular hair cells in the posterior crista were related to one another, their supporting cells, and nonsensory epithelial cells lining the ampulla. In the organ of Corti, outer hair cells were related to a supporting cell type and were tightly clustered. By contrast, spiral ganglion neurons, interdental cells, and Claudius' cells were related to cells of the same type and could be dispersed over hundreds of microns. These data contribute new information about the developmental potential of mammalian otic precursors in vivo.


Junctional Tourniquet Use During Combat Operations in Afghanistan: The Prehospital Trauma Registry Experience.
Hemorrhage is the leading cause of potentially preventable death on the battlefield. Although the resurgence of limb tourniquets revolutionized hemorrhage control in combat casualties in the recent conflicts, the mortality rate for patients with junctional hemorrhage is still high. Junctional tourniquets (JTQs) offer a mechanism to address the high mortality rate. The success of these devices in the combat setting is unclear given a dearth of existing data. From the Prehospital Trauma Registry (PHTR) and the Department of Defense Trauma Registry, we extracted cases of JTQ use in Afghanistan. We identified 13 uses of a JTQ. We excluded one case in which an improvised pelvic binder was used. Of the remaining 12 cases of JTQ use, seven had documented success of hemorrhage control, three failed to control hemorrhage, and two were missing documentation regarding success or failure. We report 12 cases of prehospital use of JTQ in Afghanistan. The findings from this case series suggest these devices may have some utility in achieving hemorrhage control strictly at junctional sites (e.g., inguinal creases). However, they also highlight device limitations. This analysis demonstrates the need for continued improvements in technologies for junctional hemorrhage control, prehospital documentation, data fidelity and collection, as well as training and sustainment of the training for utilization of prehospital hemorrhage control techniques.


ZTE imaging with enhanced flip angle using modulated excitation.
Zero echo time (ZTE) imaging is a fast, robust, and silent three-dimensional technique for direct MRI of tissues with rapid transverse relaxation. It is conventionally performed with hard, block-shaped excitation pulses short enough to excite spins uniformly over a large bandwidth. With this approach, the achievable flip angle (FA) is limited by the available B1 amplitude. The purpose of this work is to accomplish ZTE imaging with larger FAs by combined amplitude and frequency modulation of the excitation pulse while keeping the pulse duration short enough to limit acquisition dead time. Quantitative performance criteria for FA yield and uniformity of radio frequency (RF) pulses were developed and used to optimize hyperbolic secant pulse shapes. The RF pulses were implemented on a 4.7 T animal MRI system, included in algebraic image reconstruction, and tested in experiments on phantoms and tissue samples. The optimized modulated pulses provide considerably improved performance with respect to uniformity and mean FA as compared with block-shaped counterparts of the same maximum length. Using these pulses, ZTE images of excellent uniformity were obtained with enhanced FA and thus expanded contrast versatility. The performance of ZTE imaging can be significantly improved by employing optimized short amplitude- and frequency-modulated RF pulses.


Cross-national changes in time-use: some sociological (hi)stories re-examined.
The paper addresses some macro-sociological questions about changes in broad categories of time-use. The focus is on large-scale cross-national time trends from developed countries in paid and unpaid work, and leisure. Reference is made to some well-known sociological and historical accounts of such change, and to the fact that time-use diary data has only relatively recently become available for analysing trends over time. The data used are drawn from a comparative cross-time data archive held by the Institute for Social and Economic Research at Essex University, comprising successive time-use diary surveys from a range of industrialized countries collected from the 1960s to the 1990s. The time use evidence suggests relative stability in the balance between work and leisure time over the period covered by the analyses. Some alternative explanations are advanced for why there seems to be a gap between this evidence and, on the one hand, the burgeoning literature in both academic and popular media addressing the 'time famine' and, on the other, people's professed experience of what is happening to their time.


Mitogenomes Uncover Extinct Penguin Taxa and Reveal Island Formation as a Key Driver of Speciation.
The emergence of islands has been linked to spectacular radiations of diverse organisms. Although penguins spend much of their lives at sea, they rely on land for nesting, and a high proportion of extant species are endemic to geologically young islands. Islands may thus have been crucial to the evolutionary diversification of penguins. We test this hypothesis using a fossil-calibrated phylogeny of mitochondrial genomes (mitogenomes) from all extant and recently extinct penguin taxa. Our temporal analysis demonstrates that numerous recent island-endemic penguin taxa diverged following the formation of their islands during the Plio-Pleistocene, including the Galápagos (Galápagos Islands), northern rockhopper (Gough Island), erect-crested (Antipodes Islands), Snares crested (Snares) and royal (Macquarie Island) penguins. Our analysis also reveals two new recently extinct island-endemic penguin taxa from New Zealand's Chatham Islands: Eudyptes warhami sp. nov. and a dwarf subspecies of the yellow-eyed penguin, Megadyptes antipodes richdalei ssp. nov. Eudyptes warhami diverged from the Antipodes Islands erect-crested penguin between 1.1 and 2.5 Ma, shortly after the emergence of the Chatham Islands (∼3 Ma). This new finding of recently evolved taxa on this young archipelago provides further evidence that the radiation of penguins over the last 5 Ma has been linked to island emergence. Mitogenomic analyses of all penguin species, and the discovery of two new extinct penguin taxa, highlight the importance of island formation in the diversification of penguins, as well as the extent to which anthropogenic extinctions have affected island-endemic taxa across the Southern Hemisphere's isolated archipelagos.


Dietary effects of melatonin on growth performance by modulation of protein bioavailability and behavior in early weaned rats and pigs.
Melatonin, which is produced from tryptophan, exerts various biological functions, including the regulation of circadian rhythm, sedative agents, and antioxidant ability. Therefore, we conducted two experiments with early-weaned rats and pigs to investigate the antioxidant and sedative effects of melatonin. In the rat experiment, a total of 42 rats (21 days old) were used, and the antioxidant capacity was determined. Next, we used 120 early-weaned piglets (21 days old) to conduct a 5-week experiment to evaluate the reductive effect of melatonin on energy-wasting movement, including roaming and fight states. Dietary melatonin supplementation significantly improved growth in both rats and pigs compared to the control groups. Additionally, rats fed a melatonin-supplemented diet showed advanced antioxidant capacity with a decrease in hepatic malondialdehyde concentration compared to rats fed a basal diet. Moreover, dietary melatonin ingestion increased resting and feeding behaviors and reduced roaming and fight behaviors during Days 8-21 compared to the control diet group. Collectively, early weaned animals given dietary melatonin supplementation showed improved growth through upregulation of hepatic antioxidant capacity and minimization of energy-wasting behavior, including roaming and fight states, after pigs' social hierarchy establishment.


Somatic dysfunction and its association with chronic low back pain, back-specific functioning, and general health: results from the OSTEOPATHIC Trial.
Somatic dysfunction is diagnosed by the presence of any of 4 TART criteria: tissue texture abnormality, asymmetry, restriction of motion, or tenderness. To measure the prevalence of somatic dysfunction in patients with chronic low back pain (LBP) and to study the associations of somatic dysfunction with LBP severity, back-specific functioning, and general health. Cross-sectional study nested within a randomized controlled trial. University-based study in Dallas-Fort Worth, Texas. A total of 455 adult research patients with non-specific chronic LBP. Somatic dysfunction in the lumbar, sacrum/pelvis, and pelvis/innominate regions, including key lesions representing severe somatic dysfunction. A 10-cm visual analog scale (VAS), the Roland-Morris Disability Questionnaire (RMDQ), and the Medical Outcomes Study Short Form-36 Health Survey (SF-36) were used to measure LBP severity, back-specific functioning, and general health, respectively. Severe somatic dysfunction was most prevalent in the lumbar (225 [49%]), sacrum/pelvis (129 [28%]), and pelvis/innominate (48 [11%]) regions. Only 30 patients (7%) had no somatic dysfunction in the lumbar, sacrum/pelvis, or pelvis/innominate regions. There were 4 statistically significant pairwise correlations for severe somatic dysfunction: thoracic (T) 10-12 with ribs; T10-12 with lumbar; lumbar with sacrum/pelvis; and sacrum/pelvis with pelvis/innominate. Having a key lesion in the lumbar region (ρ=0.80) or sacrum/pelvis region (ρ=0.71) was strongly correlated with the overall number of key lesions. There were no consistent demographic or clinical predictors of somatic dysfunction. The presence (vs absence) of severe somatic dysfunction in the lumbar region was associated with greater LBP severity (median VAS score, 4.7 vs 3.8, respectively; P=.003) and greater back-specific disability (median RMDQ score, 6 vs 4, respectively; P=.01). The presence (vs absence) of severe somatic dysfunction in the sacrum/pelvis region was associated with greater back-specific disability (median RMDQ score, 6 vs 5, respectively; P=.02) and poorer general health (median SF-36 score, 62 vs 72, respectively; P=.002). An increasing number of key lesions was associated with back-specific disability (P=.009) and poorer general health (P=.02). The present study demonstrates that somatic dysfunction, particularly in the lumbar and sacrum/pelvis regions, is common in patients with chronic LBP. Forthcoming extensions of the OSTEOPATHIC Trial will assess the efficacy of OMT according to baseline levels of somatic dysfunction.


Methotrexate-Associated Lymphoproliferative Disorder Developed Ectopically in the Maxillary Gingiva and Bilateral Lungs.
A 58-year-old Japanese woman complained of a painful right maxillary premolar gingiva and ulcer. The patient had RA and had been treated with several immunosuppressive drugs such as methotrexate. Head and neck CT indicated no obvious bone destruction with maxillary. However, chest CT indicated the presence of nodular mass of the bilateral lungs. FDG-PET/CT indicated the presence of increased uptake in both lesions. On immunohistochemistry, atypical large-sized lymphocytes were positive for CD20 and EBER-ISH and negative for CD3, CD5, and CD10; the Ki-67 labeling index was high, the histopathological diagnosis was EBV-positive DLBCL, and the clinical diagnosis was MTX-LPD. The patient's treatment with MTX was then discontinued; we removed the alveolar bone which necrosed after 5 weeks. The lesion and the nodular mass at the bilateral lungs had completely disappeared after 7 weeks.


Explaining clinical behaviors using multiple theoretical models.
In the field of implementation research, there is an increased interest in use of theory when designing implementation research studies involving behavior change. In 2003, we initiated a series of five studies to establish a scientific rationale for interventions to translate research findings into clinical practice by exploring the performance of a number of different, commonly used, overlapping behavioral theories and models. We reflect on the strengths and weaknesses of the methods, the performance of the theories, and consider where these methods sit alongside the range of methods for studying healthcare professional behavior change. These were five studies of the theory-based cognitions and clinical behaviors (taking dental radiographs, performing dental restorations, placing fissure sealants, managing upper respiratory tract infections without prescribing antibiotics, managing low back pain without ordering lumbar spine x-rays) of random samples of primary care dentists and physicians. Measures were derived for the explanatory theoretical constructs in the Theory of Planned Behavior (TPB), Social Cognitive Theory (SCT), and Illness Representations specified by the Common Sense Self Regulation Model (CSSRM). We constructed self-report measures of two constructs from Learning Theory (LT), a measure of Implementation Intentions (II), and the Precaution Adoption Process. We collected data on theory-based cognitions (explanatory measures) and two interim outcome measures (stated behavioral intention and simulated behavior) by postal questionnaire survey during the 12-month period to which objective measures of behavior (collected from routine administrative sources) were related. Planned analyses explored the predictive value of theories in explaining variance in intention, behavioral simulation and behavior. Response rates across the five surveys ranged from 21% to 48%; we achieved the target sample size for three of the five surveys. For the predictor variables, the mean construct scores were above the mid-point on the scale with median values across the five behaviors generally being above four out of seven and the range being from 1.53 to 6.01. Across all of the theories, the highest proportion of the variance explained was always for intention and the lowest was for behavior. The Knowledge-Attitudes-Behavior Model performed poorly across all behaviors and dependent variables; CSSRM also performed poorly. For TPB, SCT, II, and LT across the five behaviors, we predicted median R2 of 25% to 42.6% for intention, 6.2% to 16% for behavioral simulation, and 2.4% to 6.3% for behavior. We operationalized multiple theories measuring across five behaviors. Continuing challenges that emerge from our work are: better specification of behaviors, better operationalization of theories; how best to appropriately extend the range of theories; further assessment of the value of theories in different settings and groups; exploring the implications of these methods for the management of chronic diseases; and moving to experimental designs to allow an understanding of behavior change.


Developing a Framework for a Program Theory-Based Approach to Evaluating Policy Processes and Outcomes: Health in All Policies in South Australia.
The importance of evaluating policy processes to achieve health equity is well recognised but such evaluation encounters methodological, theoretical and political challenges. This paper describes how a program theorybased evaluation framework can be developed and tested, using the example of an evaluation of the South Australian Health in All Policies (HiAP) initiative. A framework of the theorised components and relationships of the HiAP initiative was produced to guide evaluation. The framework was the product of a collaborative, iterative process underpinned by a policy-research partnership and drew on social and political science theory and relevant policy literature. The process engaged key stakeholders to capture both HiAP specific and broader bureaucratic knowledge and was informed by a number of social and political science theories. The framework provides a basis for exploring the interactions between framework components and how they shape policy-making and public policy. It also enables an assessment of HiAP's success in integrating health and equity considerations in policies, thereby laying a foundation for predicting the impacts of resulting policies. The use of a program theory-based evaluation framework developed through a consultative process and informed by social and political science theory has accommodated the complexity of public policy-making. The framework allows for examination of HiAP processes and impacts, and for the tracking of contribution towards distal outcomes through the explicit articulation of the underpinning program theory.


Meeting Report: Global Alliance for Research on Avian Diseases 2018, International Conference, January 17 to 19, 2018, Hanoi, Vietnam.
Poultry production is one of the fastest growing sectors of the livestock industry, growing at a rate of around 5% per year (2015-16) to meet the global demands and food security, as shown by European Union Open Data Portal. One of the major challenges for the sustainable growth of this sector comes from the plethora of diseases, including viral diseases, which have devastating effects on productivity. With a significant growth in poultry production in Asia, South America, and Africa, most of the disease challenges are in these regions. Because of the global nature of these diseases, it is of vital importance to work collaboratively to generate effective mitigation opportunities via innovative strategies. In the spirit of this international collaboration, the second International Conference of the Global Alliance for Research on Avian Diseases (GARAD) was held from January 17 to January 19, 2018, in Hanoi, Vietnam. The conference, attended by over 150 delegates from academia, poultry breeding/farming, and the pharmaceutic industry, discussed the major challenges and research advances related to the control of poultry diseases. The topics reviewed included the continuous threat from avian influenza and its antigenic shifts/drifts, the risks of disease transmission within and from live bird markets, the challenges from antigenic diversity of other avian viruses, innovative approaches for poultry vaccine development, and the potential opportunities to introduce genetic resistance to infectious agents through novel gene editing techniques. In separate interactive sessions, delegates actively debated the challenges, priorities, and opportunities for academia in driving avian disease research, the importance of developing improved disease measures by industry, and the contribution by the farming sector in the low- and middle-income countries.


Breastfeeding and maternal and infant iodine nutrition.
The aim of this review is to explore information available regarding iodine secretion in milk, both mothers and infants iodine nutrition during breastfeeding and to make recommendations for appropriate iodine supplementation during lactation. MEDLINE was queried for studies between 1960 and 2007 that included lactation and breastfeeding with iodine and iodine deficiency. Studies were selected if they studied (i) Secretion of iodine in breast milk; (ii) breastfeeding and iodine nutrition; (iii) factors affecting maternal iodine metabolism and (iv) recommendations for iodine supplementation during breastfeeding. Thirty-six articles met the selection criteria. The iodine content of breast milk varies with dietary iodine intake, being lowest in areas of iodine deficiency with high prevalence of goitre. Milk iodine levels are correspondingly higher when programs of iodine prophylaxis such as salt iodization or administration of iodized oil have been introduced. The small iodine pool of the neonatal thyroid turns over very rapidly and is highly sensitive to variations in dietary iodine intake. Expression of the sodium iodide symporter is up-regulated in the lactating mammary gland which results in preferential uptake of iodide. In areas of iodine sufficiency breast milk iodine concentration should be in the range of 100-150 microg/dl. Studies from France, Germany, Belgium, Sweden, Spain, Italy, Denmark, Thailand and Zaire have shown breast milk concentrations of < 100 microg/l. Adequate levels of iodine in breast milk have been reported from Iran, China, USA and some parts of Europe. Adequate concentration of iodine in breast milk is essential to provide for optimal neonatal thyroid hormone stores and to prevent impaired neurological development in breast-fed neonates. In many countries of the world, low iodine content of the breast milk indicates less than optimum maternal and infant iodine nutrition. The current WHO/ICCIDD/UNICEF recommendation for daily iodine intake (250 microg for lactating mothers) has been selected to ensure that iodine deficiency dose not occur in the postpartum period and that the iodine content of the milk is sufficient for the infant's iodine requirement.


Three-dimensional immersive virtual reality for studying cellular compartments in 3D models from EM preparations of neural tissues.
Advances in the application of electron microscopy (EM) to serial imaging are opening doors to new ways of analyzing cellular structure. New and improved algorithms and workflows for manual and semiautomated segmentation allow us to observe the spatial arrangement of the smallest cellular features with unprecedented detail in full three-dimensions. From larger samples, higher complexity models can be generated; however, they pose new challenges to data management and analysis. Here we review some currently available solutions and present our approach in detail. We use the fully immersive virtual reality (VR) environment CAVE (cave automatic virtual environment), a room in which we are able to project a cellular reconstruction and visualize in 3D, to step into a world created with Blender, a free, fully customizable 3D modeling software with NeuroMorph plug-ins for visualization and analysis of EM preparations of brain tissue. Our workflow allows for full and fast reconstructions of volumes of brain neuropil using ilastik, a software tool for semiautomated segmentation of EM stacks. With this visualization environment, we can walk into the model containing neuronal and astrocytic processes to study the spatial distribution of glycogen granules, a major energy source that is selectively stored in astrocytes. The use of CAVE was key to the observation of a nonrandom distribution of glycogen, and led us to develop tools to quantitatively analyze glycogen clustering and proximity to other subcellular features.


The postconcussion syndrome in sports and recreation: clinical features and demography in 138 athletes.
There are still many unanswered questions about postconcussion syndrome (PCS) in sports and recreation. The predictors of PCS are unknown, although a history of previous concussion has been suspected. To explore the clinical features and demography of PCS in athletes. A retrospective cohort study was performed by chart review of clinical and demographic data of 285 consecutive concussed patients, 138 of whom had sports-related PCS based on ≥ 3 postconcussion symptoms lasting ≥ 1 month. The 138 athletes with PCS averaged 22.8 years of age, and 70 (50.7%) were ≤ 18 years of age. They averaged 3.4 concussions (range, 1 to > 12). Only 19.6% had no previous concussion. There was a history of previous psychiatric condition, attention-deficit disorder or attention-deficit/hyperactive disorder, learning disability, or previous migraine headaches in 21.0%. Ice hockey caused the highest number of the most recent concussions at 72 cases (52.2%). Soccer, snow skiing, equestrian sports, and basketball were less frequent causes. The average number of persistent symptoms was 7.6, and the median duration of PCS was 6 months at the first examination. More than 80% of PCS cases had at least 1 other previous concussion. Half of the athletes with PCS were ≤ 18 years of age. PCS was associated with 7.6 symptoms per athlete. The duration of PCS and the number of symptoms were not related to the number of previous concussions, loss of consciousness, or return to play. Further research on treatment and prevention of PCS is required.


Integrative analysis of Dupuytren's disease identifies novel risk locus and reveals a shared genetic etiology with BMI.
Dupuytren's disease is a common inherited tissue-specific fibrotic disorder, characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand. Although genome-wide association study (GWAS) have identified 24 genomic regions associated with Dupuytrens risk, the biological mechanisms driving signal at these regions remain elusive. We identify potential biological mechanisms for Dupuytren's disease by integrating the most recent, largest GWAS (3,871 cases and 4,686 controls) with eQTLs (47 tissue panels from five consortia, total n = 3,975) to perform a transcriptome-wide association study. We identify 43 tissue-specific gene associations with Dupuytren's risk, including one in a novel risk region. We also estimate the genome-wide genetic correlation between Dupuytren's disease and 45 complex traits and find significant genetic correlations between Dupuytren's disease and body mass index (BMI), type II diabetes, triglycerides, and high-density lipoprotein (HDL), suggesting a shared genetic etiology between these traits. We further examine local genetic correlation to identify 8 and 3 novel regions significantly correlated with BMI and HDL respectively. Our results are consistent with previous epidemiological findings showing that lower BMI increases risk for Dupuytren's disease. These 12 novel risk regions provide new insight into the biological mechanisms of Dupuytren's disease and serve as a starting point for functional validation.


The functional false discovery rate with applications to genomics.
The false discovery rate (FDR) measures the proportion of false discoveries among a set of hypothesis tests called significant. This quantity is typically estimated based on p-values or test statistics. In some scenarios, there is additional information available that may be used to more accurately estimate the FDR. We develop a new framework for formulating and estimating FDRs and q-values when an additional piece of information, which we call an "informative variable", is available. For a given test, the informative variable provides information about the prior probability a null hypothesis is true or the power of that particular test. The FDR is then treated as a function of this informative variable. We consider two applications in genomics. Our first application is a genetics of gene expression (eQTL) experiment in yeast where every genetic marker and gene expression trait pair are tested for associations. The informative variable in this case is the distance between each genetic marker and gene. Our second application is to detect differentially expressed genes in an RNA-seq study carried out in mice. The informative variable in this study is the per-gene read depth. The framework we develop is quite general, and it should be useful in a broad range of scientific applications.


Adherence to medication in stroke survivors: a qualitative comparison of low and high adherers.
The aim of this study was to investigate factors that may explain variance in adherence to medication in stroke patients. Design. A qualitative comparison of high and low adherers to medication. Thirteen participants, selected from a sample of 180 stroke survivors because they self-reported the lowest adherence to medication regimes, were matched with 13 reporting maximal adherence. All took part in semi-structured qualitative interviews. Thematic analysis revealed that those with poor adherence to medication reported both intentional and non-intentional non-adherence. Two main themes emerged: the importance of stability of a medication routine and beliefs about medication and treatment. High adherers reported remembering to take their medication and seeking support from both family and health professionals. They also had a realistic understanding of the consequences of non-adherence, and believed their medicine did them more good than harm. Low adherers reported forgetting their medication, sometimes intentionally not taking their medication and receiving poor support from medical staff. They disliked taking their medication, had limited knowledge about the medication rationale or intentions, and often disputed its benefits. Our findings suggest that appropriate medication and illness beliefs coupled with a stable medication routine are helpful in achieving optimal medication adherence in stroke patients. Interventions designed to target both intentional and non-intentional adherence may help maximize medication adherence in stroke patients.


Clearance of Pseudomonas aeruginosa from the murine gastrointestinal tract is effectively mediated by O-antigen-specific circulating antibodies.
The colonization of mucosal surfaces by Pseudomonas aeruginosa can lead to local or disseminated disease. Secretory immunoglobulin A (IgA) has been assumed to be responsible for preventing mucosal colonization by interfering with the binding of bacterial ligands to epithelial surface receptors. However, the efficacy of this mechanism of immunity derives little actual support from in vivo experiments. In an investigation of the role of local and systemic immunization strategies in reducing colonization of the gastrointestinal tract of mice by P. aeruginosa, the bacterial antigens that were potential targets for immune effectors promoting mucosal clearance were identified. Levels of gastrointestinal colonization were reduced when immunity to homologous O antigens, but not that to pili or flagella, was elicited. Oral vaccination with attenuated Salmonella typhimurium expressing P. aeruginosa serogroup O11 antigen elicited mucosal and serum IgA antibodies and serum IgG antibodies specific for the recombinant antigen. Oral challenge of immunized mice with P. aeruginosa serogroup O11 demonstrated protection against gastrointestinal colonization. Intraperitoneal immunization with a serogroup O11 high-molecular-weight O-polysaccharide antigen elicited only serum IgG and IgM antibodies yet was as effective as oral vaccination in protecting mice against gastrointestinal colonization. This finding was confirmed by the demonstration that intraperitoneal immunization with purified lipopolysaccharide was also protective against mucosal surface colonization. These results call into question the need for local immune effectors, particularly secretory IgA, directed at bacterial ligands for epithelial surface components, in protecting a mucosal surface from bacterial challenge.


Computed tomography and magnetic resonance imaging of tuberculous meningitis.
Tuberculous meningitis usually results from hematogenous seeding of the central nervous system from a primary pulmonary source of infection. Initially, the meningitic process can mimic a flu-like syndrome, followed rapidly by the development of profound neurologic deficits. Computed tomography scanning or magnetic resonance imaging of the head often demonstrates a characteristic pattern of basal cistern involvement with Mycobacterium tuberculosis. The incidence of tuberculous meningitis in the more developed countries has increased during the past 5 years because of the growing number of cases in patients with acquired immunodeficiency syndrome, the spread among the homeless, and the expanding immigrant population. The significant morbidity and mortality rates associated with tuberculous meningitis--generally considered to be a disease of the past--emphasize the need for greater clinical awareness, early diagnosis, and prompt treatment.