title stringlengths 0 901 | abstract stringlengths 3 9.89k | PMID int64 22 25.3M | embedding listlengths 768 768 |
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Synthesis and biological evaluation of 2'-substituted-4'-selenoribofuranosyl pyrimidines as antitumor agents. | The 2'-substituted-4'-selenoribofuranosyl pyrimidines 3a-3j were synthesized from D-ribose and assayed for anticancer activity. The 2'-azido and 2'-fluoro groups with a ribo configuration were introduced by the regioselective opening of the O2,2'-anhydronucleosides with sodium azide and (HF)x-pyridine, respectively. Among the compounds tested, only 2'-fluoro derivative 3j was found to exhibit significant anticancer activity, but was much less potent than the corresponding 2'-arabino analogue 2c. This study will provide medicinal chemists with the insight into the identification of structural requirements for the anticancer activity for the developments of biologically active nucleosides. | 25,239,109 | [
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Variants in angiogenesis-related genes and the risk of clear cell renal cell carcinoma. | Angiogenesis is fundamentally important to the pathogenesis of clear cell renal cell carcinoma (ccRCC). We investigated the association between variations of genes related to angiogenesis and the risk of ccRCC. In a case-control study of 859 ccRCC patients and 1004 cancer-free subjects, we genotyped 24 potentially functional single nucleotide polymorphisms (SNPs) in seven angiogenesis-related genes (HIF1A, EPAS1, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) using the TaqMan or Snapshot method. Unconditional logistic regression, adjusted for potential confounding factors, was used to assess the risk associations. The functionality of selected SNPs was assessed by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) and luciferase reporter gene assays. We found two SNPs (VEGFA rs2010963 and VEGFR3 rs448012) that were significantly associated with increased risk of ccRCC, after adjusting for multiple comparisons [rs2010963 CC/GC cf. GG: false discovery rate (FDR) = 0.048, odds ratio (OR) = 1.36, 95% confidence interval (95% CI) = 1.12-1.66; rs448012 CC/GC cf. GG: FDR = 0.048, OR = 1.38, 95% CI =1.13-1.69]. Real-time quantitative PCR revealed that the variant genotypes of rs2010963, but not rs448012, were associated with increased gene expression in normal tissues of ccRCC patients (CC/GC cf. GG: P = 0.036). The luciferase reporter assay showed that the rs2010963 C allele significantly increased luciferase activity over that of the rs2010963 G allele. Our results indicate that VEGFA rs2010963 and VEGFR3 rs448012 are associated with risk of ccRCC. Furthermore, rs2010963 is a functional SNP that may affect ccRCC susceptibility by modulating endogenous VEGFA expression. | 25,239,121 | [
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An automated telephone nutrition support system for Spanish-speaking patients with diabetes. | In the United States, Spanish-speaking patients with diabetes often receive inadequate dietary counseling. Providing language and culture-concordant dietary counseling on an ongoing basis is critical to diabetes self-care. To determine if automated telephone nutrition support (ATNS) counseling could help patients improve glycemic control by duplicating a successful pilot in Mexico in a Spanish-speaking population in Oakland, California. A prospective randomized open-label trial with blinded endpoint assessment (PROBE) was performed. The participants were seventy-five adult patients with diabetes receiving care at a federally qualified health center in Oakland, California. ATNS, a computerized system that dialed patients on their phones, prompted them in Spanish to enter (via keypad) portions consumed in the prior 24 hours of various cultural-specific dietary items, and then provided dietary feedback based on proportion of high versus low glycemic index foods consumed. The control group received the same ATNS phone calls 14 weeks after enrollment. The primary outcome was hemoglobin A1c % (A1c) 12 weeks following enrollment. Participants had no significant improvement in A1c (-0.3% in the control arm, -0.1% in the intervention arm, P = .41 for any difference) or any secondary parameters. In our study, an ATNS system did not improve diabetes control in a Spanish-speaking population in Oakland. | 25,239,122 | [
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Stress is the rule rather than the exception for Metarhizium. | The insect pathogenic plant root symbiont Metarhizium experiences many situations that restrict its growth whether living in host insects or on plant roots. These include a range of physical, chemical and biological effects involving UV and extremes of temperature, pH, nutrient availability, toxic metals and other pollutants, and insect host defenses such as production of reactive oxygen species. Aside virulence, the major impediment to reliable pest control with Metarhizium is its sensitivity to UV and temperature extremes. However, increased levels of stress tolerance can be engineered into Metarhizium quite simply by reprogramming the expression of single downstream endogenous genes. For example, overexpression of RNA-binding proteins resulted in Metarhizium with increased tolerance to cold stress, overexpression of photolyase increased tolerance to UV, and increased expression of heat shock protein 25 improved tolerance to several stress conditions, including heat, and osmotic pressure. Conversely, disruption of these genes greatly reduced persistence, and could provide genetic containment for genetically engineered hypervirulent strains. | 25,239,135 | [
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Satb2-independent acquisition of the cholinergic sudomotor phenotype in rodents. | Expression of Satb2 (Special AT-rich sequence-binding protein-2) elicits expression of the vesicular acetylcholine transporter (VAChT) and choline acetyltransferase (ChAT) in cultured rat sympathetic neurons exposed to soluble differentiation factors. Here, we determined whether or not Satb2 plays a similar role in cholinergic differentiation in vivo, by comparing the postnatal profile of Satb2 expression in the rodent stellate ganglion to that of VAChT and ChAT. Throughout postnatal development, VAChT and ChAT were found to be co-expressed in a numerically stable subpopulation of rat stellate ganglion neurons. Nerve fibers innervating rat forepaw sweat glands on P1 were VAChT immunoreactive, while ChAT was detectable at this target only after P5. The postnatal abundance of VAChT transcripts in the stellate ganglion was at maximum already on P1, whereas ChAT mRNA levels increased from low levels on P1 to reach maximum levels between P5 and P21. Satb2 mRNA was detected in cholinergic neurons in the stellate ganglion beginning with P8, thus coincident with the onset of unequivocal detection of ChAT immunoreactivity in forepaw sweat gland endings. Satb2 knockout mice exhibited no change in the P1 cholinergic VAChT/ChAT co-phenotype in stellate ganglion neurons. Thus, cholinergic phenotype maturation involves first, early target (sweat-gland)-independent expression and trafficking of VAChT, and later, potentially target- and Satb2-dependent elevation of ChAT mRNA and protein transport into sweat gland endings. In rat sudomotor neurons that, unlike mouse sudomotor neurons, co-express calcitonin gene-related peptide (CGRP), Satb2 may also be related to the establishment of species-specific neuropeptide co-phenotypes during postnatal development. | 25,239,161 | [
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Validity, reproducibility, and responsiveness of the oxford hip score in patients undergoing surgery for femoroacetabular impingement. | To examine the validity, reproducibility, and responsiveness of the Oxford Hip Score (OHS) in patients with femoroacetabular impingement (FAI). One hundred twenty-six consecutive patients with FAI and 550 patients undergoing total hip arthroplasty (THA) completed the OHS and the Hip Outcome Score (HOS) at baseline and at 6 and 12 months postoperatively. The patients also rated the global treatment outcome ("How much did the operation help your hip problem?") on a 5-point Likert scale. Sixty-eight FAI and 96 THA patients completed the OHS twice within 2 weeks so that we could assess its reproducibility. The reproducibility of the OHS was good and was similar for THA and FAI patients (standard error of measurement of 5.6% for THA and 6.2% for FAI and intraclass correlation coefficient of 0.97 for both FAI and THA). In the FAI group, the correlations between the OHS and HOS subscale scores were strong (r = 0.67 to 0.85). The internal responsiveness (standardized response mean) of the OHS in FAI patients was high and similar to that of the HOS (from 0.84 to 1.48 for the OHS and from 0.75 to 1.53 for the HOS). External responsiveness was confirmed by the strong correlations between the change scores for the 2 instruments (r = 0.60 to 0.76) and between the change scores of the OHS and the global treatment outcome score (r = 0.52 to 0.60). No floor or ceiling effects were found, and internal consistency was high (Cronbach α = 0.94). Exploratory factor analysis showed a 2-factor structure for the OHS in both the THA and FAI groups. We conclude that the OHS, though originally developed for patients undergoing THA, represents an appropriate outcome instrument for assessing pain and function in FAI patients treated with arthroscopy or mini-open surgery. Level III, diagnostic study of consecutive patients (without consistently applied reference gold standard). | 25,239,174 | [
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Early postoperative weight loss predicts maximal weight loss after sleeve gastrectomy and Roux-en-Y gastric bypass. | Previous studies show that 'poor responders' to Roux-en-Y gastric bypass (RYGBP) may be identified on the basis of early postoperative weight loss. Early identification of poor responders could allow earlier provision of postoperative behavioural and/or intensive lifestyle interventions and enhance their maximal weight loss. Our aim was to investigate whether early postoperative weight loss predicts the maximal weight loss response after RYGBP and sleeve gastrectomy (SG). We undertook a retrospective cross-sectional study of 1,456 adults who underwent either RYGBP (n = 918) or SG (n = 538) as a primary procedure in one of two European centres. Postoperative weight loss was expressed as weight loss velocity (WLV) and percentage weight loss. Linear regression analyses were performed to determine the association of early postoperative weight loss with maximal %WL, including adjustment for baseline variables. There was marked variability in maximal %WL following both RYGBP (mean 32.9 %, range 4.1-60.9 %) and SG (mean 26.2 %, range 1.1-58.3 %). WLV 3-6 months postoperatively was more strongly associated with maximal %WL (r (2) = 0.32 for RYGBP and r (2) = 0.26 for SG, P < 0.001 for both) than either WLV 0-6 weeks or 6 weeks to 3 months postoperatively (r (2) = 0.14 and 0.10 for RYGBP, respectively; r (2) = 0.18 and 0.21 for SG, respectively; P < 0.001 for all). Multiple linear regression analysis, including baseline variables of age, sex, preoperative BMI, type 2 diabetes, ethnicity, and bariatric centre, revealed that 3-6 month WLV was an independent predictor of maximal %WL in both SG and RYGBP groups (standardised β-coefficients 0.51 and 0.52, respectively; P < 0.001 for both). There is a marked variability in weight loss response following RYGBP and SG. Early postoperative weight loss can be used to identify patients whose predicted weight loss trajectories are suboptimal. Early targeting of poor responders with more intensive postoperative lifestyle and behavioural support could potentially enhance their weight loss response. | 25,239,175 | [
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Effect of γ-irradiation on structure and nutraceutical potential of β-D-glucan from barley (Hordeum vulgare). | This paper reports the characterization and potential antioxidant activity of β-D-glucan isolated from barley treated with γ-rays. The β-D-glucan was irradiated with 0, 2, 4 and 8 kGy by gamma ray. The samples were characterized by Fourier transform-infrared spectroscopy, gel permeation chromatography (GPC) and quantitative estimation by Megazyme β-D-glucan assay kit. The average molecular weight of non-irradiated β-D-glucan was 177 kDa that decreased to 79 kDa at 8 kGy. Antioxidant activity was evaluated by five complementary assays including DPPH, lipid peroxidation, reducing power, metal chelating ability and oxidative DNA damage assays. Further, the antiproliferative potential of irradiated β-D-glucan was tested against three human cancer cell lines including Colo-205, T47D and MCF7 using MTT assay. Irradiated β-D-glucan exhibited dose dependent cancer cell growth inhibition. In conclusion, the present study demonstrates that irradiation leads to the formation of low molecular weight β-D-glucan with enhanced antioxidant and antiproliferative activities. | 25,239,191 | [
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Dietary Astragalus polysaccharide alleviated immunological stress in broilers exposed to lipopolysaccharide. | This study was conducted to investigate whether dietary Astragalus polysaccharide (APS) could alleviate immunological stress response of chickens after challenge with lipopolysaccharide (LPS). A total of 360 one-day-old commercial Arbor Acres broilers were randomly assigned in a 2 × 2 factorial design. The main factors were immunological stress (LPS or saline) and dietary APS (0 or 3g APS/kg feed). At 12, 14, 33 and 35 days of age, chickens were injected intramuscularly with either 500 μg/kg body weight of LPS or sterile saline. The results showed that the decreased daily feed intake and daily weight gain caused by immunological stress were dramatically attenuated by APS supplementation. The LPS challenge led to an increased mRNA abundance of TLR4, NF-κB, IL-1β, IL-6, avian uncoupling protein, α1-acid glycoprotein, hemopexin and y(+)LAT2. However, these negative effects of the LPS administration were ameliorated by APS supplementation. Moreover, dietary APS inhibited the LPS-induced depression of amino acid digestibilities. In conclusion, APS is able to alleviate LPS-induced immunological stress response in chickens. The beneficial effect may be attributed to suppressing the expression of pro-inflammatory cytokines through reducing the TLR4 and NF-κB genes transcription, and therewith improving energy and protein metabolism. | 25,239,195 | [
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Advances in Setaria genomics for genetic improvement of cereals and bioenergy grasses. | Recent advances in Setaria genomics appear promising for genetic improvement of cereals and biofuel crops towards providing multiple securities to the steadily increasing global population. The prominent attributes of foxtail millet (Setaria italica, cultivated) and green foxtail (S. viridis, wild) including small genome size, short life-cycle, in-breeding nature, genetic close-relatedness to several cereals, millets and bioenergy grasses, and potential abiotic stress tolerance have accentuated these two Setaria species as novel model system for studying C4 photosynthesis, stress biology and biofuel traits. Considering this, studies have been performed on structural and functional genomics of these plants to develop genetic and genomic resources, and to delineate the physiology and molecular biology of stress tolerance, for the improvement of millets, cereals and bioenergy grasses. The release of foxtail millet genome sequence has provided a new dimension to Setaria genomics, resulting in large-scale development of genetic and genomic tools, construction of informative databases, and genome-wide association and functional genomic studies. In this context, this review discusses the advancements made in Setaria genomics, which have generated a considerable knowledge that could be used for the improvement of millets, cereals and biofuel crops. Further, this review also shows the nutritional potential of foxtail millet in providing health benefits to global population and provides a preliminary information on introgressing the nutritional properties in graminaceous species through molecular breeding and transgene-based approaches. | 25,239,219 | [
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Outcomes of fecal carriage of extended-spectrum β-lactamase after transrectal ultrasound-guided biopsy of the prostate. | To determine the prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (PE) fecal carriage in patients that undergo transrectal ultrasonography-guided biopsy (TRUSbx) and its relationship with post-biopsy infections. A prospective clinical study in 4 different tertiary hospitals between 2008 and 2010 was conducted. Four hundred men with sterile urine who were to undergo a TRUSbx because of the suspicion of prostate cancer were included and followed for 14 days after biopsy. Rectal swab culture specimens were acquired immediately before the procedure. Demographic data, prophylaxis choice, quinolone or any other antibiotic consumption within the past 2 months, history of prostatitis, repeat biopsy, intensive care unit admission, hospitalization, urethral catheterization, diabetes mellitus (DM), and steroid usage were recorded. ESBL carriage was detected in 19% of patients and quinolone use within the last 2 months; other antibiotic use within the last 2 months and DM were found to be significantly associated (P <.05). Symptomatic urinary tract infection (UTI) on the third day after biopsy was seen in 9% of patients and was associated with fluoroquinolone (FQ) consumption before biopsy. Although ESBL-PE carriage was associated with post-biopsy UTI symptoms, it was not found to be associated with post-biopsy symptomatic UTI. Urosepsis was seen in 2 patients (0.5%) after biopsy, and both the patients were ESBL-PE carriers. The presence of ESBL-PE was associated with DM and FQ consumption before biopsy. ESBL-PE carriage was associated with a high rate of post-biopsy UTI symptoms requiring further elucidation; however, it was not associated with microbiologically proven infections. FQ consumption before TRUSbx was also associated with post-biopsy infections. | 25,239,255 | [
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Comparison of geographic methods to assess travel patterns of persons diagnosed with HIV in Philadelphia: how close is close enough? | Travel distance to medical care has been assessed using a variety of geographic methods. Network analyses are less common, but may generate more accurate estimates of travel costs. We compared straight-line distances and driving distance, as well as average drive time and travel time on a public transit network for 1789 persons diagnosed with HIV between 2010 and 2012 to identify differences overall, and by distinct geographic areas of Philadelphia. Paired t-tests were used to assess differences across methods, and analysis of variance was used to assess between-group differences. Driving distances were significantly longer than straight-line distances (p<0.001) and transit times were significantly longer than driving times (p<0.001). Persons living in the northeast section of the city traveled greater distances, and at greater cost of time and effort, than persons in all other areas of the city (p<0.001). Persons living in the northwest section of the city traveled farther and longer than all other areas except the northeast (p<0.0001). Network analyses that include public transit will likely produce a more realistic estimate of the travel costs, and may improve models to predict medical care outcomes. | 25,239,262 | [
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Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity. | Accurate and timely diagnosis of inherited bone marrow failure and inherited myelodysplastic syndromes is essential to guide clinical management. Distinguishing inherited from acquired bone marrow failure/myelodysplastic syndrome poses a significant clinical challenge. At present, diagnostic genetic testing for inherited bone marrow failure/myelodysplastic syndrome is performed gene-by-gene, guided by clinical and laboratory evaluation. We hypothesized that standard clinically-directed genetic testing misses patients with cryptic or atypical presentations of inherited bone marrow failure/myelodysplastic syndrome. In order to screen simultaneously for mutations of all classes in bone marrow failure/myelodysplastic syndrome genes, we developed and validated a panel of 85 genes for targeted capture and multiplexed massively parallel sequencing. In patients with clinical diagnoses of Fanconi anemia, genomic analysis resolved subtype assignment, including those of patients with inconclusive complementation test results. Eight out of 71 patients with idiopathic bone marrow failure or myelodysplastic syndrome were found to harbor damaging germline mutations in GATA2, RUNX1, DKC1, or LIG4. All 8 of these patients lacked classical clinical stigmata or laboratory findings of these syndromes and only 4 had a family history suggestive of inherited disease. These results reflect the extensive genetic heterogeneity and phenotypic complexity of bone marrow failure/myelodysplastic syndrome phenotypes. This study supports the integration of broad unbiased genetic screening into the diagnostic workup of children and young adults with bone marrow failure and myelodysplastic syndromes. | 25,239,263 | [
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Is physical behavior affected in fatigued persons with multiple sclerosis? | To study physical behavior in detail in fatigued persons with multiple sclerosis (MS). Case-control explorative study. Outpatient rehabilitation department and participants' daily environment. Fatigued persons with MS (n=23) were selected from a randomized controlled trial. Cases were matched by age and sex to healthy, nonfatigued controls (n=23). Eligible persons with MS were severely fatigued (Checklist Individual Strength fatigue domain mean score, 43.2±6.6) and ambulatory (Expanded Disability Status Scale mean score, 2.5±1.5). Not applicable. Measurements were performed using an accelerometer over 7 days. Outcomes included the following: amount of physical activity expressed in counts per day, counts per minute (CPM), and counts per day period (morning, afternoon, evening); duration of activity intensity categories (sedentary, light physical activity, moderate-to-vigorous physical activity [MVPA]); and distribution of MVPA and sedentary periods over the day. Persons with MS had fewer counts per day (mean difference, -156×10(3); 95% confidence interval [CI], -273×10(3) to -39×10(3); P=.010), had fewer CPM (mean difference, -135; 95% CI, -256 to -14; P=.030), and were less physically active in the morning (mean difference, -200; 95% CI, -389 to -11; P=.039) and evening (mean difference, -175; 95% CI, -336 to -14; P=.034) than controls. Persons with MS spent a higher percentage of their time sedentary (mean difference, 5.6; 95% CI, .1-11.1; P=.045) and spent less time at the higher MVPA intensity (mean difference, -2.4; 95% CI, -4.7 to -0.09; P=.042). They had fewer MVPA periods (mean difference, 29; 95% CI, -56.2 to -2.6; P=.032) and a different distribution of sedentary (mean difference, .033; 95% CI, .002 to .064; P=.039) and MVPA periods (mean difference, -.08; 95% CI, -.15 to -.01; P=.023). Detailed analyses of physical behavior showed that ambulatory fatigued persons with MS do differ from healthy controls not only in physical activity level, but also in other physical behavior dimensions (eg, day patterns, intensity, distribution). | 25,239,283 | [
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Frequency and Clinical Correlates of Sleep-Related Problems Among Anxious Youth with Autism Spectrum Disorders. | Sleep-related problems (SRPs) are common and problematic among anxious youth but have not been investigated in anxious youth with autism spectrum disorder (ASD). Participants were 102 youth (ages 7-16 years) with ASD and comorbid anxiety. Youth and their primary caregiver were administered the Pediatric Anxiety Rating Scale. Parents completed the Multidimensional Anxiety Scale for Children-Parent (MASC-P) Report, Social Responsiveness Scale, and the Child Behavior Checklist (CBCL). A measure of SRPs was created from items from the CBCL and MASC-P. Results suggest SRPs were relatively common among youth with ASD and comorbid anxiety. The number of SRPs endorsed directly associated with parent ratings of social deficits, internalizing and externalizing symptoms, and anxiety symptoms, as well as with clinician-rated anxiety symptoms. Parent-rated internalizing symptoms predicted frequency of SRPs over and above social deficits, externalizing symptoms, and parent- and clinician-rated anxiety symptoms. A subset of 40 participants who completed family-based cognitive-behavioral therapy (CBT) experienced reduced SRPs following treatment. Implications, study limitations, and recommendations for future research are discussed. | 25,239,284 | [
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An algorithm to decompose ground reaction forces and moments from a single force platform in walking gait. | In walking experimental conditions, subjects are sometimes unable to perform two steps on two different forceplates. This leads the authors to develop methods for discerning right and left ground reaction data while they are summed during the double support in walking. The aim of this study is to propose an adaptive transition function that considers the walking speed and ground reaction forces (GRF). A transition function is used to estimate left and right side GRF signals in double support. It includes a shape coefficient adjusted using single support GRF parameters. This shape coefficient is optimized by a non-linear least-square curve-fitting procedure to match the estimated signals with real GRF. A multiple regression is then performed to identify GRF parameters of major importance selected to compute the right and left GRF of the double support. Relative RMSE (RMSER), maximum GRF differences normalized to body mass and differences of center of pressure (CoP) are computed between real and decomposed signals. During double support, RMSER are 6%, 18%, 3.8%, 4.3%, 3%, and 12.3% for anterior force, lateral force, vertical force, frontal moment, sagittal moment and transverse moment, respectively. Maximum GRF differences normalized to body mass are lower than 1N/kg and mean CoP difference is 0.0135 m, when comparing real to decomposed signals during double support. This work shows the accuracy of an adaptive transition function to decompose GRF and moment of right and left sides. This method is especially useful to accurately discern right and left GRF data in single force platform configurations. | 25,239,287 | [
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Airway wall eosinophilia is not a feature of equine heaves. | The objective of this study was to determine whether eosinophils infiltrate the airway wall of horses with heaves. Eosinophils were evaluated using paraffin embedded lung tissues from six heaves-affected horses in crisis and six aged-matched controls. Slides were stained using Luna's method and eosinophils enumerated using histomorphometric techniques. Total eosinophil counts (expressed per mm(2) of basement membrane) were significantly higher in the airways of controls horses than in horses with heaves. Intraluminal, intraepithelial, and airway smooth muscle eosinophils counts were also increased in control horses. The results suggest that eosinophils do not contribute to the persistent airway obstruction in heaves. | 25,239,297 | [
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The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. | Deficiency of the phospholipid flippase ATPase, aminophospholipid transporter, class I, type 8B, member 1 (ATP8B1) causes progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1). Apart from cholestasis, many patients also suffer from diarrhea of yet unknown etiology. Here we have studied the hypothesis that intestinal ATP8B1 deficiency results in bile salt malabsorption as a possible cause of PFIC1/BRIC1 diarrhea. Bile salt transport was studied in ATP8B1-depleted intestinal Caco-2 cells. Apical membrane localization was studied by a biotinylation approach. Fecal bile salt and electrolyte contents were analyzed in stool samples of PFIC1 patients, of whom some had undergone biliary diversion or liver transplantation. Bile salt uptake by the apical sodium-dependent bile salt transporter solute carrier family 10 (sodium/bile acid cotransporter), member 2 (SLC10A2) was strongly impaired in ATP8B1-depleted Caco-2 cells. The reduced SLC10A2 activity coincided with strongly reduced apical membrane localization, which was caused by impaired apical membrane insertion of SLC10A2. Moreover, we show that endogenous ATP8B1 exists in a functional heterodimer with transmembrane protein 30A (CDC50A) in Caco-2 cells. Analyses of stool samples of post-transplant PFIC1 patients demonstrated that bile salt content was not changed, whereas sodium and chloride concentrations were elevated and potassium levels were decreased. The ATP8B1-CDC50A heterodimer is essential for the apical localization of SLC10A2 in Caco-2 cells. Diarrhea in PFIC1/BRIC1 patients has a secretory origin to which SLC10A2 deficiency may contribute. This results in elevated luminal bile salt concentrations and consequent enhanced electrolyte secretion and/or reduced electrolyte resorption. | 25,239,307 | [
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Is intraoperative parathyroid hormone monitoring necessary with ipsilateral parathyroid gland visualization during anticipated unilateral exploration for primary hyperparathyroidism: a two-institution analysis of more than 2,000 patients. | Intraoperative parathyroid hormone (ioPTH) monitoring during focused parathyroidectomy for primary hyperparathyroidism (PHPT) is used commonly, but some argue that ioPTH adds little if a normal ipsilateral parathyroid gland (IPG) is visualized. This hypothesis was tested for validity. The prospective databases of consecutive patients with PHPT undergoing initial parathyroidectomy with ioPTH at two academic institutions were queried. Patients with ectopic adenoma, familial PHPT, previous parathyroidectomy, planned bilateral exploration, or <6 months follow-up were excluded. Persistence was defined as hypercalcemia at <6 months. From 1998 to 2013, 2,162 patients met inclusion criteria, and the rate of persistent disease was 1.5%. Most (n = 1,353; 63.5%) underwent single-gland resection with ioPTH and no IPG visualization, with 1% persistence. Among patients with a single adenoma resected and a normal IPG visualized, 15.2% had contralateral disease. Resection based on IPG appearance alone would have resulted in 13% persistent disease. In PHPT, the cure rate for initial unilateral exploration guided by ioPTH is 98.5% versus a predicted rate of 87% when decision making is based on IPG appearance alone. Routine visualization of IPG is not necessary during exploration for suspected single adenoma guided by ioPTH. ioPTH remains useful in optimizing outcomes. | 25,239,313 | [
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Novel microRNA correlations in the severely injured. | Severe injury initiates an inflammatory response that can perpetuate immunological dysfunction, uncontrolled inflammation, and subsequent multisystem organ failure. MicroRNAs (miRNAs) have recently been identified as regulators of this inflammatory response. Our study sought to identify the differential expression of unique miRNAs and their correlations with genes of the Toll-like receptor (TLR) pathways, and clinical parameters in the severely injured. Fourteen trauma patients requiring transfusion were prospectively enrolled in this institutional review board-approved study. Inclusion criteria consisted of adult patients deemed clinically to be in hemorrhagic shock necessitating transfusion in the acute phase of their injury care. Peripheral blood samples were obtained after admission to the surgical intensive care unit. Expression of circulating mature miRNA from each patient, as well as from 10 healthy, age-matched controls, was determined and compared using the HiSeq 2500 sequencing system and the R software system. Gene expression of TLR signaling pathways for each patient was examined using custom gene expression polymerase chain reaction arrays. Statistical analyses were performed using general linear models and empirical Bayes methods to determine differential expression and Spearman's nonparametric correlation analysis. Subjects were 21-77 years old (mean, 42), 80% male, Injury Severity Score 11-43 (mean, 26), with 11 blunt and 3 penetrating injuries. Three were intubated and 5 received blood products before arrival. Base deficit upon hospital admission was 3 to 20 (mean, 9). All patients required blood transfusion secondary to blood loss sustained during injury. Survival to discharge was 93%. Controls were 27-64 years old (mean, 40) and 60% male. Sequencing analysis revealed 69 differentially expressed miRNAs (P < .05) in the severely injured. Within the differentially expressed miRNAs, there were 12 direct and 6 indirect correlations with multiple genes involved in the TLR3 and TLR4 signaling pathways. The relationships between these same miRNAs and clinical parameters were also analyzed. We discovered 4 direct correlations with base deficit and HCO3, and 7 indirect correlations involving total fresh frozen plasma transfused, base deficit, HCO3, and PaCO2 levels. Differential expression and correlations between miRNAs, genes of the TLR pathways, and clinical parameters are unique findings in the severely injured and may lead to a greater understanding of the regulation of sterile inflammation after severe injury. | 25,239,329 | [
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Outpatient follow-up versus 30-day readmission among general and vascular surgery patients: a case for redesigning transitional care. | The association between early outpatient follow-up and 30-day readmission has not been evaluated in any surgical population. Our study characterizes the relationship between outpatient follow-up and early readmissions among surgical patients. We queried the medical record at a large, tertiary care institution (July 2008-December 2012) to determine rates of 30-day outpatient follow-up and readmission for general or vascular operative procedures. The majority of discharges for general (84% of 7,552) and vascular (75% of 2,362) surgery had a follow-up visit before readmission or within 30 days of discharge. General surgery patients who were not readmitted had high rates of follow-up (88%) and received follow-up at approximately 2 weeks postdischarge (median, 11 days after discharge). In contrast, readmitted general surgery patients received first follow-up at 1 week (median, 8 days); 49% had follow-up. Vascular surgery patients showed a similar trend. More than one half of patients readmitted after follow-up were readmitted within 24 hours of their most recent outpatient visit. Current routine follow-up does not occur early enough to detect adverse events and prevent readmission. Early outpatient care may prevent readmission in some patients, but often serves as a conduit for readmission among patients already experiencing complications. | 25,239,351 | [
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Production of polyclonal antibody to a recombinant non-structural protein Nsp1a of human astrovirus. | Human astrovirus (HAstV) are important pathogens that cause acute viral diarrhea in infants. Little is known about the mechanisms of astrovirus-induced diarrhea. Previous studies have suggested that an apoptosis inducer may be encoded in the non-structural protein (nsP1a) of astrovirus and contribute to virus-induced diarrhea. To study the biological function of nsP1a and to gain further insight into nsP1a protein-host cell interactions, good quality antibodies must be produced. The nsP1agene of HAstV-1 was cloned into a bacterial expression vector Pgex-6P-1. The recombinant plasmid Pgex-6P-nsP1a was transformed into Escherichia coli BL21 (DE3) and expressed as a fusion protein that contains N-terminal GST tags. The expressed recombinant protein was purified and used as an antigen to produce an nsP1a antiserum in rabbits. ELISA was used to detect the titer of specific antibodies. Specificity activity was detected by Western blot and immunofluorescence analysis. The titer of specific antibodies was up to 1:30,000. Western blotting and immunofluorescence analysis indicated that the polyclonal antibody could recognize specifically the HAstV-1 nsP1a protein. | 25,239,369 | [
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Initial oxygenation response to inhaled nitric oxide predicts improved outcome in congenital diaphragmatic hernia. | Pulmonary hypertension (PH) is the most important complication of congenital diaphragmatic hernia (CDH) and still has a high mortality rate. The aim of this study was to evaluate the effectiveness of inhaled nitric oxide therapy in PH due to CDH. Hospital records of children who had undergone inhaled nitric oxide therapy for PH due to CDH between June 2009 and December 2011 were reviewed. Twenty-nine patients had a diagnosis of CDH at the time of study, and eight of these patients underwent nitric oxide therapy because of failure of conventional ventilation techniques, which was successful in five of these patients. Patients who had a good overall outcome of nitric oxide therapy experienced rapid improvement (pretreatment, mean PaO2 = 44.8 mmHg; after the first hour of therapy, mean PaO2 = 96.8 mmHg), whereas patients with no response did not have a similar course (pretreatment, PaO2 = 37 mmHg; after the first hour, PaO2 = 54.6 mmHg). Inhaled nitric oxide therapy seems to increase survival in PH due to CDH. No predictive parameters to orient patient selection could be identified; however, the early response seemed to predict the overall outcome. Good results in our series were attributed to routine use of sildenafil and dopamine, along with the nitric oxide inhalation. | 25,239,432 | [
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Novel renal biomarkers to assess cardiorenal syndrome. | Renal dysfunction (RD) in heart failure portends adverse outcomes and often limits aggressive medical and decongestive therapies. Despite the high prevalence in this population, not all forms of RD are prognostically or mechanistically equivalent: RD can result from irreversible nephron loss secondary to diabetic or hypertensive kidney disease or it can develop secondary to heart failure (HF) itself, i.e., the cardiorenal syndrome. Furthermore, filtration is only one aspect of renal performance such that significant renal impairment secondary to cardiorenal syndrome can exist despite a normal glomerular filtration rate. Renal biomarkers have the potential to inform some of the intricacies involved in accurately assessing cardiorenal interactions. This article discusses novel biomarkers for cardiorenal syndrome and their utility in the prognosis, diagnosis, and targeted treatment of heart failure-induced RD. | 25,239,434 | [
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Routine use of bilateral internal thoracic artery grafts for left-sided myocardial revascularization in insulin-dependent diabetic patients: early and long-term outcomes. | Despite encouraging late outcomes, the use of bilateral internal thoracic artery (BITA) grafting for myocardial revascularization in diabetic patients remains controversial because of an increased risk of sternal complications. In the present study, early and long-term outcomes of the routine use of left-sided BITA grafting in insulin-dependent diabetic patients were reviewed retrospectively. Among the 2701 consecutive patients who underwent isolated BITA grafting at the authors' institution from 1999 throughout 2012, 188 (mean age: 67 ± 9 years) were insulin-dependent diabetic patients. The mean expected operative risk, calculated according to the European System for Cardiac Operative Risk Evaluation II, was 11 ± 10.8%. There were 6 (3.2%) hospital deaths. Prolonged invasive ventilation (17.6%), multiple transfusion (16.5%), deep sternal wound infection (DSWI, 11.7%) and acute kidney injury (10.6%) were the most frequent major postoperative complications. Chronic lung disease (P = 0.08), low cardiac output (P = 0.039), multiple transfusion (P = 0.034) and mediastinal re-exploration (P = 0.071) were risk factors for DSWI. The mean follow-up was 5.7 ± 3.6 years. The 10-year non-parametric estimates of overall survival, freedom from cardiac and cerebrovascular death, and major adverse cardiac and cerebrovascular events were 57.7 [95% confidence interval (CI): 45.1-66.2], 83.6 (95% CI: 76.6-90.7) and 55.4% (95% CI: 44.7-66.1), respectively. Predictors of decreased late survival were old age (P = 0.013), chronic lung disease (P = 0.004), renal impairment (P = 0.009) and left ventricular dysfunction (P = 0.035). Left-sided BITA grafting may be performed routinely even in insulin-dependent diabetic patients. The increased rates of postoperative complications do not prevent low early mortality and good long-term outcomes. | 25,239,446 | [
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BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development. | BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18(Ink4c) (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis. | 25,239,453 | [
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Ribosome abundance regulates the recovery of skeletal muscle protein mass upon recuperation from postnatal undernutrition in mice. | Nutritionally-induced growth faltering in the perinatal period has been associated with reduced adult skeletal muscle mass; however, the mechanisms responsible for this are unclear. To identify the factors that determine the recuperative capacity of muscle mass, we studied offspring of FVB mouse dams fed a protein-restricted diet during gestation (GLP) or pups suckled from postnatal day 1 (PN1) to PN11 (E-UN), or PN11 to PN22 (L-UN) on protein-restricted or control dams. All pups were refed under control conditions following the episode of undernutrition. Before refeeding, and 2, 7 and 21 days later, muscle protein synthesis was measured in vivo. There were no long-term deficits in protein mass in GLP and E-UN offspring, but in L-UN offspring muscle protein mass remained significantly smaller even after 18 months (P < 0.001). E-UN differed from L-UN offspring by their capacity to upregulate postprandial muscle protein synthesis when refed (P < 0.001), a difference that was attributable to a transient increase in ribosomal abundance, i.e. translational capacity, in E-UN offspring (P < 0.05); translational efficiency was similar across dietary treatments. The postprandial phosphorylation of Akt and extracellular signal-regulated protein kinases were similar among treatments. However, activation of the ribosomal S6 kinase 1 via mTOR (P < 0.02), and total upstream binding factor abundance were significantly greater in E-UN than L-UN offspring (P < 0.02). The results indicate that the capacity of muscles to recover following perinatal undernutrition depends on developmental age as this establishes whether ribosome abundance can be enhanced sufficiently to promote the protein synthesis rates required to accelerate protein deposition for catch-up growth. | 25,239,457 | [
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Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition. | GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mM by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca(2+)-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain. | 25,239,459 | [
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PET/CT before autologous stem cell transplantation predicts outcome in refractory/relapsed follicular lymphoma. | Salvage of young patients with follicular lymphoma (FL) after R-CHOP includes salvage immunochemotherapy followed by autologous stem cell transplantation (ASCT). Previous studies dealing with relapsed Hodgkin lymphoma have shown the prognostic value of PET/CT prior to ASCT. We retrospectively analysed 59 patients with refractory/relapsed FL after first-line R-CHOP who were chemosensitive (as evaluated by CT) to the salvage treatment and who proceeded to ASCT. The role of PET/CT in this setting to define chemosensitivity is not definitely established. So we focused on the prognostic value of PET/CT performed after salvage treatment, before ASCT. The estimated 3-year progression-free survival (PFS) and overall survival were 63.1% (50.9-78.3%) and 90.5% (82.8 - 98.8%), respectively, and did not differ significantly according to their Follicular Lymphoma International Prognostic Index at relapse, conditioning regimen, or type of salvage. PFS was significantly lower in PET/CT-positive patients, according to the International Harmonization Project revised response criteria, with a 3-year PFS of 45.5% (26.6 - 77.8%) versus 72.6% (58.5 - 90.0%; p = 0.039). To better refine prognosis, we applied two types of throsholds: a Deauville five-point scale positive threshold of ≥3 (3-year PFS of 74.9%, range 61.0 - 92.1% %, versus 42.8%, range 24.7 - 74.4%; p = 0.02), and a ≥70% ∆SUVmax threshold between presalvage and pre-ASCT PET/CT (3-year PFS of 72.4%, range 57.5 - 91.3% versus 13.3%, 2.2 - 81.7%; p < 10(-3)). The PET/CT findings before ASCT were independently correlated with PFS in our series. PET/CT negativity before ASCT is a desirable and achievable goal in the management of chemosensitive FL relapsing after first-line R-CHOP. | 25,239,490 | [
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Hypoxic stress induces, but cannot sustain trophoblast stem cell differentiation to labyrinthine placenta due to mitochondrial insufficiency. | Dysfunctional stem cell differentiation into placental lineages is associated with gestational diseases. Of the differentiated lineages available to trophoblast stem cells (TSC), elevated O2 and mitochondrial function are necessary to placental lineages at the maternal-placental surface and important in the etiology of preeclampsia. TSC lineage imbalance leads to embryonic failure during uterine implantation. Stress at implantation exacerbates stem cell depletion by decreasing proliferation and increasing differentiation. In an implantation site O2 is normally ~2%. In culture, exposure to 2% O2 and fibroblast growth factor 4 (FGF4) enabled the highest mouse TSC multipotency and proliferation. In contrast, hypoxic stress (0.5% O2) initiated the most TSC differentiation after 24h despite exposure to FGF4. However, hypoxic stress supported differentiation poorly after 4-7 days, despite FGF4 removal. At all tested O2 levels, FGF4 maintained Warburg metabolism; mitochondrial inactivity and aerobic glycolysis. However, hypoxic stress suppressed mitochondrial membrane potential and maintained low mitochondrial cytochrome c oxidase (oxidative phosphorylation/OxPhos), and high pyruvate kinase M2 (glycolysis) despite FGF4 removal. Inhibiting OxPhos inhibited optimum differentiation at 20% O2. Moreover, adding differentiation-inducing hyperosmolar stress failed to induce differentiation during hypoxia. Thus, differentiation depended on OxPhos at 20% O2; hypoxic and hyperosmolar stresses did not induce differentiation at 0.5% O2. Hypoxia-limited differentiation and mitochondrial inhibition and activation suggest that differentiation into two lineages of the labyrinthine placenta requires O2>0.5-2% and mitochondrial function. Stress-activated protein kinase increases an early lineage and suppresses later lineages in proportion to the deviation from optimal O2 for multipotency, thus it is the first enzyme reported to prioritize differentiation. | 25,239,494 | [
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Leukopenia predicts remission in patients with inflammatory bowel disease and Behcet's disease on thiopurine maintenance. | The thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine (6-MP) are well-established drugs for the treatment of inflammatory bowel disease (IBD). Although leukopenia is a well-recognized side effect of AZA/6-MP treatment, its association with therapeutic effects has yet to be determined. We therefore evaluated the influences of thiopurine-induced leukopenia on the long-term prognosis of IBD. We included 196 IBD patients [45 with ulcerative colitis (UC), 68 with Crohn's disease (CD), and 83 with intestinal Behçet's disease (BD)] who were treated with AZA/6-MP and achieved remission between January 2006 and December 2012. We retrospectively analyzed patient characteristics, AZA/6-MP maintenance dose (mg/kg), the lowest white blood cell (WBC) count during AZA/6-MP treatment, duration of remission, and the occurrence of relapse. We compared the clinical variables between leukopenic (n = 120, WBC count <4,000/μL) and nonleukopenic (n = 76, WBC count ≥ 4,000/μL) patients. The two groups were well matched for baseline clinical characteristics. The cumulative relapse-free survival rate was higher in the leukopenic group than the nonleukopenic group by Kaplan-Meier survival analysis (log-rank test, P < 0.001). On multivariate analysis, age, duration of AZA/6-MP treatment, presence of macrocytosis, and the presence of leukopenia were negatively associated with relapse (odds ratios 0.975, 0.988, 0.563, and 0.390, respectively). On subgroup analysis, the cumulative relapse-free survival rate was significantly higher in the leukopenic group than in the nonleukopenic group for all types of IBDs, including UC, CD, and intestinal BD (log-rank test, P = 0.032, 0.047, and 0.002, respectively). Leukopenia during thiopurine maintenance therapy was associated with prolonged remission in patients with IBD and Behcet's disease. | 25,239,495 | [
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Prevalence and genomic characterization of G2P[4] group A rotavirus strains during monovalent vaccine introduction in Brazil. | This study aims to: estimate the prevalence of G2P[4] rotaviruses in Brazil between 2001-2011 from patients with acute gastroenteritis; perform phylogenetic analyses of G2P[4] Brazilian strains (from vaccinated and non-vaccinated children) based on VP7 and VP8(∗) encoding genes and analyze the antigenic regions of these proteins comparing with RV1; and assess the full genetic background of eleven selected Brazilian strains. The G2P[4] detection rate among RVA positive samples was 0/157 in 2001, 3/226 (1.3%) in 2002, 0/514 in 2003, 0/651 in 2004, 31/344 (9%)/2005, 112/227 (49%)/2006, 139/211 (66%)/2007, 240/284 (85%)/2008, 66/176 (37.5%)/2009, 367/422 (87%)/2010 and 75/149 (50%)/2011. For the VP7 and VP8(∗) encoding genes, 52 sequences were analyzed and shared up to 99% nucleotide identity with other contemporary G2P[4] strains detected worldwide, grouping into different clusters. Most differences inside antigenic epitopes of VP7 and VP8(∗) have been maintained in the G2P[4] Brazilian strains along the years, and all were present before RV1 introduction. Eleven G2P[4] strains (4-vaccinated/7-non-vaccinated) were completely characterized and possessed the typical DS-1-like genotype constellation (G2-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2) sharing up to 99% of nucleotide identity with contemporary worldwide strains. Reassortments between Brazilian G2P[4] human strains were observed. In conclusion, the data obtained in the current study suggests that implementation of RV1 vaccination might not influence the genetic diversity observed in G2P[4] analyzed strains. Several factors might have contributed to the increased prevalence of this genotype in Brazil since 2005: the introduction of RV1 into the Brazilian National Immunization Program has resulted in a decrease in the relative prevalence of predominant Wa-like RVA strains facilitating the increase of the heterotypic (DS-1-like) RVA strain G2P[4] in the Brazilian population; the genetic diversity found in different geographical regions throughout the years before, and after the introduction of RV1; the long period of low or no circulation of this genotype in Brazil previous to RV1 introduction could have created favorable conditions for the accumulation of immunological susceptible individuals. | 25,239,525 | [
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Association between SNPs in miRNA-machinery genes and chronic hepatitis B in the Chinese Han population. | Single nucleotide polymorphisms (SNPs) in miRNA-machinery genes can influence their generation and maturation, then expression and structure. To explore the relationship between three SNPs (rs3757 in DGCR8, rs636832 in AGO1, rs7813 in GEMIN4) in miRNA-machinery genes and chronic hepatitis B, we genotyped the SNPs by high resolution melting method (HRM) in a case-control study of 332 unrelated chronic hepatitis B patients and 352 unrelated healthy controls in Western China. Interestingly, the rs636832 was significantly associated with the susceptibility of CHB (genotype: AA/GA/GG: p=0.010; allele: A/G: OR=0.727, 95% CI=0.575-0.920, p=0.008). The minor allele A of rs636832 was significantly associated with a decreased risk of CHB. Additionally, the dominant model AG+GG vs. AA showed a risk of 1.442-fold (p=0.018) with CHB. Further exploration for the association between rs636832 and HBV-DNA load in 329 cases showed no significant difference (genotype: p=0.321; allele: p=0.148). Neither did the association between rs636832 and the status of HBsAg and HbeAg (HBsAg: genotype p=0.337, allele p=0.436; HBeAg: genotype p=0.861, allele p=0.822). Our study first provided the evidence that rs636832 in AGO1 was associated with chronic HBV infection susceptibility in Chinese Han population. Further epidemiological and functional studies in larger populations are warranted to verify our results. | 25,239,527 | [
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Evaluation of 3 analyte-specific reagents for detection of Bordetella pertussis and Bordetella parapertussis in clinical specimens. | The performance of 3 analyte-specific reagents (ASRs), Elitech Biosciences, EraGen Biosciences, and Focus Diagnostic, was evaluated for detection of Bordetella pertussis (BP) and Bordetella parapertussis (BPP) in nasopharyngeal swab specimens. A total of 104 frozen, leftover clinical specimens obtained from pediatric patients during 2011-2012 were included in this study. Performance was compared to the Bordetella real-time polymerase chain reaction (PCR) laboratory-developed test (LDT). The positive percent agreement for detection of BP by Elitech was 96% (95% confidence interval [CI]: 85.14-99.30); EraGen and Focus was 98% (95% CI: 87.99-99.89) in comparison to LDT PCR assay. The negative percent agreement of Elitech, EraGen, and Focus in comparison to LDT was 96% (95% CI: 85.14-99.30), 92% (95% CI: 79.89-97.41), and 96% (95% CI: 85.14-99.30), respectively. Limit of detection (LOD) for BP was 0.1 CFU/reaction by both Focus and EraGen and 1.0 CFU/reaction by Elitech. However, LOD for BPP was lower by EraGen (0.1 CFU/reaction) compared to Focus (1.0 CFU/reaction) and Elitech (1.0 CFU/reaction). These results demonstrate that all 3 ASRs tested are comparable and reliable for routine clinical diagnosis of pertussis and parapertussis. | 25,239,539 | [
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Evaluation of two flexible colonoscopy simulators and transfer of skills into clinical practice. | Surgical residents have learned flexible endoscopy by practicing on patients in hospital settings under the strict guidance of experienced surgeons. Simulation is often used to "pretrain" novices on endoscopic skills before real clinical practice; nonetheless, the optimal method of training remains unknown. The purpose of this study was to compare endoscopic virtual reality and physical model simulators and their respective roles in transferring skills to the clinical environment. At the beginning of a skills development rotation, 27 surgical postgraduate year 1 residents performed a baseline screening colonoscopy on a real patient under faculty supervision. Their performances were scored using the Global Assessment of Gastrointestinal Endoscopic Skills (GAGES). Subsequently, interns completed a 3-week flexible endoscopy curriculum developed at our institution. One-third of the residents were assigned to train with the GI Mentor simulator, one-third trained with the Kyoto simulator, and one-third of the residents trained using both simulators. At the end of their rotations, each postgraduate year 1 resident performed one posttest colonoscopy on a different patient and was again scored using GAGES by an experienced faculty. A statistically significant improvement in the GAGES total score (p < 0.001) and on each of its subcomponents (p = 0.001) was observed from pretest to posttest for all groups combined. Subgroup analysis indicated that trainees in the GI Mentor or both simulators conditions showed significant improvement from pretest to posttest in terms of GAGES total score (p = 0.017 vs 0.024, respectively). This was not observed for those exclusively using the Kyoto platform (p = 0.072). Nonetheless, no single training condition was shown to be a better training modality when compared to others in terms of total GAGES score or in any of its subcomponents. Colonoscopy simulator training with the GI Mentor platform exclusively or in combination with a physical model simulator improves skill performance in real colonoscopy cases when measured with the GAGES tool. | 25,239,553 | [
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[Obesity and the severity of asthma crisis]. | Obesity is associated with inflammatory processes, which could influence the airway inflammation that is found in patients with asthma. Obesity may thus have a role in the development of asthma. However, the role of obesity in the severity of acute asthma has not been well described. We performed a retrospective study, which included 77 patients hospitalized for acute asthma. Two groups of patients were formed according to their body mass index (BMI): group 1 consisting of 59 patients with a BMI inferior to 30 kg/m(2) and group 2 consisting of 18 patients with a BMI superior or equal to 30 kg/m(2). These two groups were compared according to demographic factors, clinical features and the spirometric severity of asthma. The mean age was 43 ± 17.4 years with a sex-ratio 0.57 (28 men/49 women). Thirty-one percent of these patients had a severe asthma attack requiring hospitalization in intensive care in four patients with the use of mechanical ventilation in two patients. The comparison between obese and non-obese patients did not show a significant difference in the severity of asthma. Although a contribution of obesity to the manifestation and severity of asthma is commonly recognized, the present data to not confirm the impact of obesity on the severity of acute attacks. | 25,239,583 | [
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[An unusual mediastinal mass]. | Primary mediastinal tumors are rare diseases including a broad spectrum of pathologies ranging from the well-known, such as lymphoma, thymoma or germ-line tumors to some very unusual presentations. We describe a solitary mediastinal mass compressing the bronchial and vascular system in a patient suffering from chronic dyspnea. Diagnosis, obtained by means of a CT-guided biopsy, was a melanoma without any sign of a primary cutaneous lesion which harbored the BRAF V600E mutation. An exclusive mediastinal presentation of a malignant melanoma is exceptional and, in the context of BRAF mutation needs to be considered and diagnosed given the potential therapeutic impact. | 25,239,585 | [
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Time course of motor and cognitive functions after chronic cerebral ischemia in rats. | Cerebral ischemia is one of the leading causes of death and long-term disability in aging populations, due to the frequent occurrence of irreversible brain damage and subsequent loss of neuronal function which lead to cognitive impairment and some motor dysfunction. In the present study, the real time course of motor and cognitive functions were evaluated following the chronic cerebral ischemia induced by permanent, bilateral occlusion of the common carotid arteries (PBOCCA). Male Sprague Dawley rats (200-300g) were subjected to PBOCCA or sham-operated surgery and tested 1, 2, 3 and 4 weeks following the ischemic insult. The results showed that PBOCCA significantly reduced step-through latency in a passive avoidance task at all time points when compared to the sham-operated group. PBOCCA rats also showed significant increase in escape latencies during training in the Morris water maze, as well as a reduction of the percentage of times spend in target quadrant of the maze at all time points following the occlusion. Importantly, there were no significant changes in locomotor activity between PBOCCA and sham-operated groups. The BDNF expression in the hippocampus was 29.3±3.1% and 40.1±2.6% on day 14 and 28 post PBOCCA, respectively compared to sham-operated group. Present data suggest that the PBOCCA procedure effectively induces behavioral, cognitive symptoms associated with cerebral ischemia and, consequently, provides a valuable model to study ischemia and related neurodegenerative disorder such as Alzheimer's disease and vascular dementia. | 25,239,606 | [
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Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases. | To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases. Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response. Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response. Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort. | 25,239,609 | [
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Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. | Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9. We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were determined by ELISAs or automated immunoassay. By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was observed in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P < 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P < 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P < 0.05). The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC. | 25,239,611 | [
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Implementation of a consent for chart review and contact and its impact in one clinical centre. | Informed consent and protection of patient confidentiality are central to the conduction of clinical research. Consent for chart review and contact (CCRC) allows a patient chart to be screened for research by persons outside the direct circle-of-care and for the patient to be contacted regarding potential studies. This study describes the process of implementation and benefits of such a consent. We present a descriptive report of a CCRC document that was created and presented to patients over a 3.5-year period at a tertiary care Endocrinology and Metabolism centre. To assess the potential impact of such a document on patient recruitment, the basic demographics of patients who did and did not consent were compared. In addition, we compared the recruitment rate at our centre, using our novel approach, with that at other centres for an ongoing study of patients with type 1 diabetes. A large proportion (6501/8025, or 81%) of patients gave their consent for chart review. Patients who denied consent were more likely to be women and older. Compared with other centres, our centre recruited at the highest rate for a known study of patients with type 1 diabetes. The majority (46/60, or 76.7%) of patients were recruited via the novel approach. Consent for chart review and contact addresses several important ethical issues regarding the use of patient clinical information for research purposes. Our study demonstrated how such a process can be implemented. | 25,239,620 | [
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Neuropeptide Y family-degrading metallopeptidases in the Tityus serrulatus venom partially blocked by commercial antivenoms. | Accidents caused by scorpions represent a relevant public health issue in Brazil, being more recurring than incidents with snakes and spiders. The main species responsible for this situation is the yellow scorpion, Tityus serrulatus, due especially to the great frequency with which accidents occur and the potential of its venom to induce severe clinical manifestations, even death, mainly among children. Although neurotoxins are well characterized, little information is known about other components of scorpion venoms, such as peptidases, and their effect on envenomation. Previous results from our group showed that the metallopeptidases present in this venom are capable of hydrolyzing the neuropeptide dynorphin 1-13 in vitro, releasing Leu-enkephalin, which may interact with ion channels and promote indirect neurotoxicity. Thus, this study aims to get more information about the effect of toxic peptidase activity present in the venom on biologically active peptides, and to evaluate the in vitro neutralizing potential of commercial antivenoms produced by the Butantan Institute. A set of human bioactive peptides were studied as substrates for the peptidases, and the members of the neuropeptide Y family were found to be the most susceptible ones. All new substrate hydrolyses were totally inhibited by ethylenediaminetetracetic and not blocked by phenylmethanesulfonylfluoride, indicating that metallopeptidases were responsible for the peptidase activity. Also, peptidase activities were only partially inhibited by therapeutic Brazilian scorpion antivenom (SAV) and arachnid antivenom (AAV). The dose-response inhibition by both antivenoms indicates that AAV neutralizes better than SAV at the used doses. These characterizations, unpublished until now, can contribute to the improvement of our knowledge about the venom and envenomation processes by T. serrulatus. | 25,239,630 | [
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Developmental exposure to organophosphate flame retardants elicits overt toxicity and alters behavior in early life stage zebrafish (Danio rerio). | Organophosphate flame retardants (OPFRs) are common replacements for the phased-out polybrominated diphenyl ethers (PBDEs) and have been detected at high concentrations in environmental samples. OPFRs are structurally similar to organophosphate pesticides and may adversely affect the developing nervous system. This study evaluated the overt toxicity, uptake, and neurobehavioral effects of tris (1,3-dichloro-2-propyl) phosphate (TDCPP), tris (2-chloroethyl) phosphate (TCEP), tris (1-chloro-2-propyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP) in early life stage zebrafish. Chlorpyrifos was used as a positive control. For overt toxicity and neurobehavioral assessments, zebrafish were exposed from 0 to 5 days postfertilization (dpf). Hatching, death, or malformations were evaluated daily. Teratogenic effects were scored by visual examination on 6 dpf. To evaluate uptake and metabolism, zebrafish were exposed to 1 µM of each organophosphate (OP) flame retardant and collected on 1 and 5 dpf to monitor accumulation. Larval swimming activity was measured in 6 dpf larvae to evaluate neurobehavioral effects of exposures below the acute toxicity threshold. TDBPP elicited the greatest toxicity at >1 µM. TDCPP and chlorpyrifos were overtly toxic at concentrations ≥10 µM, TCEP, and TCPP were not overtly toxic at the doses tested. Tissue concentrations increased with increasing hydrophobicity of the parent chemical after 24 h exposures. TDCPP and TDBPP and their respective metabolites were detected in embryos on 5 dpf. For all chemicals tested, developmental exposures that were not overtly toxic significantly altered larval swimming activity. These data indicate that OPFRs adversely affect development of early life stage zebrafish. | 25,239,634 | [
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Predictors of senior center use among older adults in New York City public housing. | Despite agreement among stakeholders that senior centers can promote physical and mental health, research on senior center use in urban populations is limited. Our objective was to describe demographic and health factors associated with senior center use among urban, low-income older adults in order to inform programming and outreach efforts. We used data from a 2009 telephone survey of 1036 adults randomly selected from rosters of New York City public housing residents aged 65 and older. We analyzed senior center use by race/ethnicity, age, gender, health, housing type, and income, and used a forward selection approach to build best-fit models predicting senior center use. Older adults of all ages and of both genders reported substantial use of senior centers, with nearly one third (31.3%) reporting use. Older adults living alone, at risk of depression, or living in specialized senior housing had the greatest use of centers. Senior center use varied by race/ethnicity, and English-speaking Hispanics had a higher prevalence of use than Spanish-speaking Hispanics (adjusted prevalence ratio [PR]=1.69, 95% CI: 1.11-2.59). Spanish-speaking communities and older adults living in non-senior congregate housing are appropriate targets for increased senior center outreach efforts. | 25,239,639 | [
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A comparison between respondent-driven sampling and time-location sampling among men who have sex with men in Shenzhen, China. | Men who have sex with men (MSM) are a key population for HIV control and prevention in China. It is difficult to acquire representative samples of this hidden population. Respondent-driven sampling (RDS), based on peer referral, and time-location sampling (TLS) based on random selection of venue-day-time periods, are among the most commonly used sampling methods. However, differences in HIV-related characteristics of MSM recruited by these two methods have not been fully evaluated. We compared sociodemographics, risk behaviors, utilization of HIV-related intervention services, and HIV/syphilis infection rates between samples of 621 RDS MSM and 533 TLS MSM in Shenzhen, China in 2010. We found that the HIV prevalence was comparable in RDS and TLS MSM. TLS recruited larger proportions of more marginalized MSM than RDS: MSM recruited by TLS were older, less educated and more likely to be migrants (without Shenzhen hukou registration), to be non-gay identified and to engage in risky sexual behaviors. On the other hand, MSM recruited by TLS were more likely to have been covered by HIV-related intervention services. To conclude, in Shenzhen, TLS is more effective to reach the marginalized population of MSM. But because TLS can only reach MSM who physically attend venues and HIV-related intervention services are already commonly available at gay venues in Shenzhen, RDS is more informative for allocating prevention efforts than TLS. Furthermore, researchers and public health authorities should take into account the different sample compositions of RDS and TLS and apply sampling methods consistently when evaluating trends over time. | 25,239,658 | [
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Induction and imaging of photothrombotic stroke in conscious and freely moving rats. | In experimental stroke research, anesthesia is common and serves as a major reason for translational failure. Real-time cerebral blood flow (CBF) monitoring during stroke onset can provide important information for the prediction of brain injury; however, this is difficult to achieve in clinical practice due to various technical problems. We created a photothrombotic focal ischemic stroke model utilizing our self-developed miniature headstage in conscious and freely moving rats. In this model, a high spatiotemporal resolution imager using laser speckle contrast imaging technology was integrated to acquire real-time two-dimensional CBF information during thrombosis. The feasibility, stability, and reliability of the system were tested in terms of CBF, behavior, and T2-weighted magnetic resonance imaging (MRI) findings. After completion of occlusion, the CBF in the targeted cortex of the stroke group was reduced to 16 ± 9% of the baseline value. The mean infarct volume measured by MRI 24 h postmodeling was 77 ± 11 mm3 and correlated well with CBF (R2 = 0.74). This rodent model of focal cerebral ischemia and real-time blood flow imaging opens the possibility of performing various fundamental and translational studies on stroke without the influence of anesthetics. | 25,239,673 | [
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Intramural hematoma of the esophagus after thrombolysis for ischemic stroke. | Intramural dissecting hematoma is an unusual esophageal condition with a threatening presentation but excellent prognosis when managed conservatively.We report the case of an 88-year-old woman who developed an intramural hematoma of the esophagus after intravenous thrombolysis for an acute ischemic stroke. Before thrombolysis, nasogastric intubation was attempted unsuccessfully. She was kept on nil by mouth, intravenous hydration, proton pump inhibitor, antiemetics,and an antibiotic initiated 2 days before for periodontal disease. The esophageal hematoma regressed, and she resumed oral diet asymptomatically.To our knowledge, this is the first report of this type of lesion after thrombolysis for an ischemic stroke. A brief discussion and literature review are presented. | 25,239,697 | [
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The "sweet" side of ion channels. | Ion channels play a crucial role in cell functioning, contributing to transmembrane potential and participating in cell signalling and homeostasis. To fulfil highly specialised functions, cells have developed various mechanisms to regulate channel expression and activity at particular subcellular loci, and alteration of ion channel regulation can lead to serious disorders. Glycosylation, one of the most common forms of co- and post-translational protein modification, is rapidly emerging as a fundamental mechanism not only controlling the proper folding of nascent channels but also their subcellular localisation, gating and function. Moreover, studies on various channel subtypes have revealed that glycosylation represents an important determinant by which other signalling pathways modulate channel activity. The discovery of detailed mechanisms of regulation of ion channels by glycosylation provides new insights in the physiology of ion channels and may allow developing new pharmaceutics for the treatment of ion channel-related disorders. | 25,239,698 | [
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Three-column intermittent simulated moving bed chromatography: 2. Experimental implementation for the separation of Tröger's Base. | The three-column intermittent simulated moving bed (3C-ISMB) process has been presented in the first part of this series [1]. A theoretical comparative analysis of the new process to intermittent simulated moving bed (I-SMB) demonstrated successfully the potential of the 3C-ISMB technology. Particularly, 3C-ISMB was shown to substantially outperform I-SMB in terms of productivity whilst maintaining high purity specifications and without significantly sacrificing solvent consumption. Moreover, we demonstrated the applicability of Triangle Theory for 3C-ISMB design, which is an important advantage compared to other modified SMB schemes. In the present work we report on the experimental implementation of the 3C-ISMB technology demonstrating the simplicity of retrofitting an existing SMB or I-SMB plant. Moreover, we perform an experimental comparative analysis studying the well-known separation of Tröger's Base enantiomers in pure ethanol on Chiralpak AD™. In a comprehensive series of experimental runs, each examining three different modes of operation, applying total feed concentrations ranging from 5 g/l to 17.4 g/l, we assess and compare the separation performances of both conventional I-SMB and 3C-ISMB. This series of experiments successfully demonstrates that 3C-ISMB delivers the same high purity levels as conventional I-SMB whilst significantly outperforming the conventional process in terms of productivity; in fact an increase of more than 80% is achieved. | 25,239,701 | [
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Reducing healthcare-associated infections in an ambulatory dialysis unit: Identification and alignment of work system factors. | Patients undergoing hemodialysis have experienced a 43% increase in rate of hospitalization due to infection during the past 20 years. Research in other industries has shown that safe systems are achieved by considering the entire system to enable performance specifications to be met. A sociotechnical systems framework was applied through the Macroergonomic Analysis and Design method to evaluate a 54-chair ambulatory dialysis unit to decrease healthcare-associated infections. Fifty-seven system discrepancies across 6 healthcare-associated infection risk factors were identified. A multicomponent intervention was developed to address 44 of the variances across 4 of the risk factors. Access-related bloodstream infections and access site infections did not improve. Bacterial surface contamination decreased. Process measures for the individual components of the intervention demonstrated varying adherence to the intervention. Inconsistent compliance with interventions is hypothesized to be due to organizational and external environment factors. | 25,239,723 | [
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Recombineering linear BACs. | Recombineering is a powerful genetic engineering technique based on homologous recombination that can be used to accurately modify DNA independent of its sequence or size. One novel application of recombineering is the assembly of linear BACs in E. coli that can replicate autonomously as linear plasmids. A circular BAC is inserted with a short telomeric sequence from phage N15, which is subsequently cut and rejoined by the phage protelomerase enzyme to generate a linear BAC with terminal hairpin telomeres. Telomere-capped linear BACs are protected against exonuclease attack both in vitro and in vivo in E. coli cells and can replicate stably. Here we describe step-by-step protocols to linearize any BAC clone by recombineering, including inserting and screening for presence of the N15 telomeric sequence, linearizing BACs in vivo in E. coli, extracting linear BACs, and verifying the presence of hairpin telomere structures. Linear BACs may be useful for functional expression of genomic loci in cells, maintenance of linear viral genomes in their natural conformation, and for constructing innovative artificial chromosome structures for applications in mammalian and plant cells. | 25,239,740 | [
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Herpesvirus mutagenesis facilitated by infectious bacterial artificial chromosomes (iBACs). | A critical factor in the study of herpesviruses, their genes and gene functions is the capacity to derive mutants that harbor deletions, truncations, or insertions within the genetic elements of interest. Once constructed the impact of the introduced mutation on the phenotypic properties of the rescued virus can be determined in either in vitro or in vivo systems. However, the construction of such mutants by traditional virological mutagenesis techniques can be a difficult and laborious undertaking. The maintenance of a viral genome as an infectious bacterial artificial chromosome (iBAC), however, endows the capacity to manipulate the viral genome for mutagenesis studies with relative ease. Here, the construction and characterization of two gene deletion mutants of an alphaherpesvirus maintained as iBAC in combination with an inducible homologous recombination system in Escherichia coli is detailed. The methodology is generally applicable to any iBAC and is demonstrated to be a highly efficient and informative approach for mutant virus construction. | 25,239,746 | [
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Deviations of inorganic and organic carbon content in hypomineralised enamel. | The purpose of this study was to discriminate hypomineralised enamel of permanent first molars from normal enamel by means of spectroscopic methods. The present study was conducted using Multi spot Raman Fourier Transform Spectroscopy, Diffuse Reflectance Infrared Fourier Transform Spectroscopy (FTIR) and X-ray diffraction (XRD). Raman spectroscopy indicated significantly more B-type carbonate and hydrocarbons in hypomineralised enamel diagnosed as MIH (Molar Incisor Hypomineralisation). From XRD analysis, no changes in crystallinity of the enamel apatite could be found. Using multi spot Raman-spectroscopy, a significant molecular discrimination between normal and hypomineralised enamel could be made. Detailed surface studies are needed in order to achieve better restorative materials, specifically designed for restoration of hypomineralised enamel, and are also needed in order to understand and predict the clinical consequences of hypomineralised enamel with the condition MIH. | 25,239,769 | [
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Tilted versus axially placed dental implants: a meta-analysis. | The purpose of the present review was to test the null hypothesis of no difference in the implant failure rate, marginal bone loss, and postoperative infection for patients being rehabilitated by tilted or by axially placed dental implants, against the alternative hypothesis of a difference. An electronic search without time or language restrictions was undertaken in July 2014. Eligibility criteria included clinical human studies, either randomised or not, interventional or observational. The estimates of an intervention were expressed in risk ratio (RR) and mean difference (MD) in millimetres. The search strategy resulted in 44 publications. A total of 5029 dental implants were tilted (82 failures; 1.63%), and 5732 implants were axially placed (104 failures; 1.81%). The difference between the procedures did not significantly affect the implant failure rates (P=0.40), with a RR of 1.14 (95% CI 0.84-1.56). A statistically significant difference was found for implant failures when studies evaluating implants inserted in maxillae only were pooled (RR 1.70, 95% CI 1.05-2.74; P=0.03), the same not happening for the mandible (RR 0.77, 95% CI 0.39-1.52; P=0.45). There were no apparent significant effects of tilted dental implants on the occurrence of marginal bone loss (MD 0.03, 95% CI -0.03 to 0.08; P=0.32). Due to lack of satisfactory information, meta-analysis for the outcome 'postoperative infection' was not performed. It is suggested that the differences in angulation of dental implants might not affect the implant survival or the marginal bone loss. The reliability and validity of the data collected and the potential for biases and confounding factors are some of the shortcomings of the present study. The question whether tilted implants are more at risk for failure than axially placed implants has received increasing attention in the last years. As the philosophies of treatment alter over time, a periodic review of the different concepts is necessary to refine techniques and eliminate unnecessary procedures. This would form a basis for optimum treatment. | 25,239,770 | [
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Late surgical repair of a traumatic ventricular septal defect. | Ventricular Septal Defect (VSD) complicates approximately 1-5% of patients presenting with penetrating chest trauma, however not all VSDs are evident at the time of initial presentation to the emergency department. Acute closure of traumatic VSDs is indicated in patients with a large defect and haemodynamic compromise, however closure may be delayed in smaller defects in order to minimise operative time, reduce operative mortality and allow for recovery from the initial trauma. We describe the case of a previously healthy 23 year-old Caucasian man who presented in extremis following stab wounds to the precordium. After emergency cardiopulmonary bypass and closure of lacerations to both the left and right ventricles, postoperative trans-thoracic echocardiography (TTE) noted a restrictive intramuscular VSD with a high velocity left to right shunt, initially managed conservatively. Elective surgical closure was performed 10 months after the initial injury through a right ventriculotomy using 4-0 Proline sutures reinforced with Teflon pledgets. Despite excellent clinical recovery, 3-month follow-up TTE noted a residual VSD in the mid apical septum. However, given the presence of minimal left to right shunt and the small size of the defect, the patient was managed conservatively with annual review and repeat transthoracic echo. This case highlights the potential pitfalls in both the diagnosis and management of traumatic VSDs particularly where the patient presents in extremis with other life-threatening injuries. Furthermore, it exemplifies the importance of a multidisciplinary approach when planning any elective intervention. Regardless of the management strategy, repeated re-assessment and re-evaluation is vital following penetrating cardiac trauma, and vigilant long-term follow-up is of paramount importance in these cases. | 25,239,775 | [
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Long-term urine biobanking: storage stability of clinical chemical parameters under moderate freezing conditions without use of preservatives. | To examine the long-term stability and validity of analyte concentrations of 21 clinical biochemistry parameters in 24-h urine samples stored for 12 or 15 yr at -22°C and preservative free. Healthy children's 24-h urine samples in which the respective analytes had been measured shortly after sample collection (baseline) were reanalyzed. Second measurement was performed after 12 yr (organic acids) and 15 yr (creatinine, urea, osmolality, iodine, nitrogen, anions, cations, acid-base parameters) with the same analytical methodology. Paired comparisons and correlations between the baseline and repeated measurements were done. Recovery rates were calculated. More than half of the analytes (creatinine, urea, iodine, nitrogen, sodium, potassium, magnesium, calcium, ammonium, bicarbonate, citric & uric acid) showed measurement values after >10 yr of storage not significantly different from baseline. 15 of the 21 parameters were highly correlated (r=0.99) between baseline and second measurement. Poorest correlation was r=0.77 for oxalate. Recovery ranged from 73% (oxalate) to 105% (phosphate). Our results suggest high long-term stability and measurement validity for numerous clinical chemistry parameters stored at -22°C without addition of any urine preservative. Prospective storage of urine aliquots at -22°C for periods even exceeding 10 yr, appears to be an acceptable and valid tool in epidemiological settings for later quantification of several urine analytes. | 25,239,781 | [
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Production, separation and applications of phenolic-rich bio-oil--a review. | This paper provides an overview of current research trends in the production and separation of phenolic-rich bio-oils, as well as their applications. The first part of this paper highlights the strong dependency of the phenolic content of bio-oil on the kinds of biomass feedstock, reaction system, reaction conditions, and the type of catalysts used in their production. More recent separation technologies are also discussed in the second part of the paper. The final part of the paper deals with recent experimental results from applications of phenolic-rich bio-oils in the synthesis of phenolic resins. The paper suggests that the microwave-assisted pyrolysis of palm residues is a promising route for phenolic-rich bio-oil production, and that the use of supercritical CO2 and switchable hydrophilicity solvents during extraction, as well as molecular distillation techniques, can be applied to increase the recovery of phenolic compounds from bio-oils. | 25,239,785 | [
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β-Adrenergic receptor blockade impairs coronary exercise hyperemia in young men but not older men. | Patients with coronary artery disease have attenuated coronary vasodilator responses to physiological stress, which is partially attributed to a β-adrenergic receptor (β-AR)-mediated mechanisms. Whether β-ARs contribute to impaired coronary vasodilation seen with healthy aging is unknown. The purpose of this study was to investigate the role of β-ARs in coronary exercise hyperemia in healthy humans. Six young men (26 ± 1 yr) and seven older men (67 ± 4 yr) performed isometric handgrip exercise at 30% maximal voluntary contraction for 2 min after receiving intravenous propranolol, a β-AR antagonist, and no treatment. Isoproterenol, a β-AR agonist, was infused to confirm the β-AR blockade. Blood pressure and heart rate were monitored continuously, and coronary blood flow velocity (CBV, left anterior descending artery) was measured by transthoracic Doppler echocardiography. Older men had an attenuated ΔCBV to isometric exercise (3.8 ± 1.3 vs. 9.7 ± 2.1 cm/s, P = 0.02) compared with young men. Propranolol decreased the ΔCBV at peak handgrip exercise in young men (9.7 ± 2.1 vs. 2.7 ± 0.9 cm/s, P = 0.008). However, propranolol had no effect on ΔCBV in older men (3.8 ± 1.3 vs. 4.2 ± 1.9 cm/s, P = 0.9). Older men also had attenuated coronary hyperemia to low-dose isoproterenol. These data indicate that β-AR control of coronary blood flow is impaired in healthy older men. | 25,239,806 | [
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Evaluation of anti-HIV-1 activity of a new iridoid glycoside isolated from Avicenna marina, in vitro. | This study was carried out to check the efficacy of methanol seed extract of Avicenna marina and its column chromatographic fractions on Peripheral Blood Mono nuclear Cells (PBMCs) toxicity and HIV-1 replication. The anti-HIV-1 activities of crude methanol extract and its fractions were performed by use of real-time polymerase chain reaction (PCR) assay and HIV-1 p24 antigen kit. A time of drug addiction approach was also done to identify target of anti-HIV compound. The activity of the extracts on CD4, CD3, CD19 and CD45 expression in lymphocytes population was performed by use of flow cytometry. The most active anti-HIV agent was detected by spectroscopic analysis as 2'-O-(4-methoxycinnamoyl) mussaenosidic acid. The apparent effective concentrations for 50% virus replication (EC50) of methanol extract and iridoid glycoside were 45 and 0.1 μg/ml respectively. The iridoid glycoside also did not have any observable effect on the proportion of CD4, CD3, CD19 and CD45 cells or on the intensity of their expressions on PBMCs. In addition, the expression level of C-C chemokine receptor type 5 (CCR5) and chemokine receptor type 4 (CXCR4) on CD4(+) T cells were decreased in cells treated with this iridoid glycoside. The reduction of these two HIV coreceptors and the result of time of addition study demonstrated that this iridoid glycoside restricts HIV-1 replication on the early stage of HIV infection. | 25,239,814 | [
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Detection of cyclic di-AMP using a competitive ELISA with a unique pneumococcal cyclic di-AMP binding protein. | Cyclic di-AMP (c-di-AMP) is a recently recognized bacterial signaling molecule. In this study, a competitive enzyme-linked immunosorbent assay (ELISA) for the quantification of c-di-AMP was developed using a novel pneumococcal c-di-AMP binding protein (CabP). With this method, c-di-AMP concentrations in biological samples can be quickly and accurately quantified. | 25,239,824 | [
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In vitro and in vivo characterization of the actin polymerizing compound chondramide as an angiogenic inhibitor. | Inhibiting angiogenesis is a major approach in tumour therapy. To combat angiogenesis, the tubulin cytoskeleton has emerged as an interesting target in many pre- and clinical studies. Contrarily, the actin cytoskeleton has been largely neglected as a potential drug target in angiogenesis. However, due to the development of drug resistances, new therapeutic strategies are always needed in tumour treatment. Therefore, the therapeutic potential of actin-binding small molecules is of particular interest. We investigate the impact of chondramide (Ch), an actin polymerizing myxobacterial compound, on angiogenesis and underlying signalling. Chondramide treatment not only reduces the migration of endothelial cells but also the maturation of endothelial tube networks on matrigel. These observations can partly be explained by a disintegration of stress fibres due to aggregation and subsequent accumulation of actin in cellular structures known as 'aggresomes'. Chondramide treatment impairs the maturation of focal adhesions and reduces the amount of active β1 integrin at the cell surface. Accordingly, signalling events downstream of focal adhesions are reduced. Thus, we observed that the activity of Src and downstream factors Rho-GTPases Rac1 and Rho is reduced upon Ch treatment. In vivo, Ch was well tolerated in mice and vascularization of a tumour xenograft as well as of the developing retina was significantly reduced. Chondramide diminishes angiogenesis via two ways: (i) the disintegration of stress fibres and (ii) the reduction of promigratory signals. Our findings highlight Ch as a novel class of therapeutic lead compound with anti-angiogenic potential. | 25,239,826 | [
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Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium. | Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylphosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in ICAM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p38 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and corresponding age-related inflammatory activation of endothelium. | 25,239,871 | [
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hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. | Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) or GDF15 is a divergent member of the transforming growth factor beta (TGF-β) superfamily and mice expressing hNAG-1/hGDF15 have been shown to be resistant to HFD-induced obesity and inflammation. This study investigated if hNAG-1 increases lifespan in mice and its potential mechanisms. Here we report that female hNAG-1 mice had significantly increased both mean and median life spans in two transgenic lines, with a larger difference in life spans in mice on a HFD than on low fat diet. hNAG-1 mice displayed significantly reduced body and adipose tissue weight, lowered serum IGF-1, insulin and glucose levels, improved insulin sensitivity, and increased oxygen utilization, oxidative metabolism and energy expenditure. Gene expression analysis revealed significant differences in conserved gene pathways that are important regulators of longevity, including IGF-1, p70S6K, and PI3K/Akt signaling cascades. Phosphorylation of major components of IGF-1/mTOR signaling pathway was significantly lower in hNAG-1mice. Collectively, hNAG-1 is an important regulator of mammalian longevity and may act as a survival factor. Our study suggests that hNAG-1 has potential therapeutic uses in obesity-related diseases where life span is frequently shorter. | 25,239,873 | [
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The genetics of rheumatoid arthritis: risk and protection in different stages of the evolution of RA. | There is now a general consensus that RA has a spectrum of disease stages that can begin many years before the onset of clinical symptoms. It is widely thought that understanding the complex interplay between genetics and environment, and their role in pathogenesis, is essential in gaining further insight into the mechanisms that drive disease development and progression. More than 100 genetic susceptibility loci have now been identified for RA through studies that have focused on patients with established RA compared with healthy controls. Studying the early preclinical phases of disease will provide valuable insights into the biological events that precede disease and could potentially identify biomarkers to predict disease onset and future therapeutic targets. In this review we will cover recent advances in the knowledge of genetic and environmental risk factors and speculate on how these factors may influence the transition from one stage of disease to another. | 25,239,882 | [
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GSK3β-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury. | Although AMP-activated protein kinase (AMPK) is involved in regulating carbohydrate and lipid metabolism, activated AMPK also plays an anti-inflammatory role in many cell populations. However, despite the ability of AMPK activation to diminish the severity of inflammatory responses, previous studies have found that AMPK activity is diminished in LPS-treated neutrophils and also in lungs of mice with LPS-induced acute lung injury (ALI). Since GSK3β participates in regulating AMPK activity, we examined potential roles for GSK3β in modulating LPS-induced activation of neutrophils and macrophages and in influencing severity of ALI. We found that GSK3β-dependent phosphorylation of T479-AMPK was associated with pT172 dephosphorylation and inactivation of AMPK following TLR4 engagement. GSK3β inhibitors BIO (6-bromoindirubin-3'-oxime), SB216763, or siRNA knockdown of GSK3β, but not the PI3K/AKT inhibitor LY294002, prevented Thr172-AMPK dephosphorylation. Exposure to LPS resulted in rapid binding between IKKβ and AMPKα, and phosphorylation of S485-AMPK by IKKβ. These results suggest that IKKβ-dependent phosphorylation of S485-AMPK was an essential step in subsequent phosphorylation and inactivation AMPK by GSK3β. Inhibition of GSK3β activity delayed IκBα degradation and diminished expression of the proinflammatory TNF-α in LPS-stimulated neutrophils and macrophages. In vivo, inhibition of GSK3β decreased the severity of LPS-induced lung injury as assessed by development of pulmonary edema, production of TNF-α and MIP-2, and release of the alarmins HMGB1 and histone 3 in the lungs. These results show that inhibition of AMPK by GSK3β plays an important contributory role in enhancing LPS-induced inflammatory responses, including worsening the severity of ALI. | 25,239,914 | [
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Calcineurin upregulates local Ca(2+) signaling through ryanodine receptor-1 in airway smooth muscle cells. | Local Ca(2+) signals (Ca(2+) sparks) play an important role in multiple cellular functions in airway smooth muscle cells (ASMCs). Protein kinase Cϵ is known to downregulate ASMC Ca(2+) sparks and contraction; however, no complementary phosphatase has been shown to produce opposite effects. Here, we for the first time report that treatment with a specific calcineurin (CaN) autoinhibitory peptide (CAIP) to block CaN activity decreases, whereas application of nickel to activate CaN increases, Ca(2+) sparks in both the presence and absence of extracellular Ca(2+). Treatment with xestospogin-C to eliminate functional inositol 1,4,5-trisphosphate receptors does not prevent CAIP from inhibiting local Ca(2+) signaling. However, high ryanodine treatment almost completely blocks spark formation and prevents the nickel-mediated increase in sparks. Unlike CAIP, the protein phosphatase 2A inhibitor endothall has no effect. Local Ca(2+) signaling is lower in CaN catalytic subunit Aα gene knockout (CaN-Aα(-/-)) mouse ASMCs. The effects of CAIP and nickel are completely lost in CaN-Aα(-/-) ASMCs. Neither CAIP nor nickel produces an effect on Ca(2+) sparks in type 1 ryanodine receptor heterozygous knockout (RyR1(-/+)) mouse ASMCs. However, their effects are not altered in RyR2(-/+) or RyR3(-/-) mouse ASMCs. CaN inhibition decreases methacholine-induced contraction in isolated RyR1(+/+) but not RyR1(-/+) mouse tracheal rings. Supportively, muscarinic contractile responses are also reduced in CaN-Aα(-/+) mouse tracheal rings. Taken together, these results provide novel evidence that CaN regulates ASMC Ca(2+) sparks specifically through RyR1, which plays an important role in the control of Ca(2+) signaling and contraction in ASMCs. | 25,239,916 | [
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Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits. | The development of new growth hormone (GH) agonists and growth hormone antagonists (GHAs) requires animal models for pre-clinical testing. Ideally, the effects of treatment are monitored using the same pharmacodynamic marker that is later used in clinical practice. However, intact rodents are of limited value for this purpose because serum IGF-I, the most sensitive pharmacodynamic marker for the action of GH in humans, shows no response to treatment with recombinant human GH and there is little evidence for the effects of GHAs, except when administered at very high doses or when overexpressed. As an alternative, more suitable model, we explored pharmacodynamic markers of GH action in intact rabbits. We performed the first validation of an IGF-I assay for the analysis of rabbit serum and tested precision, sensitivity, linearity and recovery using an automated human IGF-I assay (IDS-iSYS). Furthermore, IGF-I was measured in rabbits of different strains, age groups and sexes, and we monitored IGF-I response to treatment with recombinant human GH or the GHA Pegvisomant. For a subset of samples, we used LC-MS/MS to measure IGF-I, and quantitative western ligand blot to analyze IGF-binding proteins (IGFBPs). Although recovery of recombinant rabbit IGF-I was only 50% in the human IGF-I assay, our results show that the sensitivity, precision (1.7-3.3% coefficient of variation) and linearity (90.4-105.6%) were excellent in rabbit samples. As expected, sex, age and genetic background were major determinants of IGF-I concentration in rabbits. IGF-I and IGFBP-2 levels increased after single and multiple injections of recombinant human GH (IGF-I: 286±22 versus 434±26 ng/ml; P<0.01) and were highly correlated (P<0.0001). Treatment with the GHA lowered IGF-I levels from the fourth injection onwards (P<0.01). In summary, we demonstrated that the IDS-iSYS IGF-I immunoassay can be used in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on sex, age and genetic background. Unlike in rodents, the IGF-I response to treatment with recombinant human GH or a GHA closely mimics the pharmacodynamics seen in humans, suggesting that rabbits are a suitable new model to test human GH agonists and antagonists. | 25,239,917 | [
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Rac1--a novel regulator of contraction-stimulated glucose uptake in skeletal muscle. | Muscle contraction stimulates muscle glucose uptake by facilitating translocation of glucose transporter 4 from intracellular locations to the cell surface, which allows for diffusion of glucose into the myofibres. The intracellular mechanisms regulating this process are not well understood. The GTPase Rac1 has, until recently, been investigated only with regard to its involvement in insulin-stimulated glucose uptake. However, we recently found that Rac1 is activated during muscle contraction and exercise in mice and humans. Remarkably, Rac1 seems to be necessary for exercise and contraction-stimulated glucose uptake in skeletal muscle, because muscle-specific Rac1 knockout mice display reduced ex vivo contraction- and in vivo exercise-stimulated glucose uptake. The molecular mechanism by which Rac1 regulates glucose uptake is presently unknown. However, recent studies link Rac1 to the actin cytoskeleton, the small GTPase RalA and/or free radical production, which have previously been shown to be regulators of glucose uptake in muscle. We propose a model in which Rac1 is activated by contraction- and exercise-induced mechanical stress signals and that Rac1 in conjunction with other signalling regulates glucose uptake during muscle contraction and exercise. | 25,239,922 | [
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In vitro and in vivo interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib in non-Hodgkin lymphoma cells. | Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib were examined in non-Hodgkin lymphoma (NHL) models, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2-M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with carfilzomib and ricolinostat increased reactive oxygen species (ROS), whereas the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34(+) cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by carfilzomib. shRNA knockdown of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced carfilzomib-ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to carfilzomib and ricolinostat also markedly downregulated the cargo-loading protein HR23B. Moreover, HR23B knockdown significantly increased carfilzomib- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with carfilzomib and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that carfilzomib and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL. | 25,239,935 | [
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Efficacy of RG7787, a next-generation mesothelin-targeted immunotoxin, against triple-negative breast and gastric cancers. | The RG7787 mesothelin-targeted recombinant immunotoxin (RIT) consists of an antibody fragment targeting mesothelin (MSLN) fused to a 24-kD fragment of Pseudomonas exotoxin A for cell killing. Compared with prior RITs, RG7787 has improved properties for clinical development including decreased nonspecific toxicity and immunogenicity and resistance to degradation by lysosomal proteases. MSLN is a cell surface glycoprotein highly expressed by many solid tumor malignancies. New reports have demonstrated that MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triple-negative breast and gastric cancer cell lines were tested for surface MSLN expression, and for sensitivity to RG7787 in vitro and in animal models. RG7787 produced >95% cell killing of the HCC70 and SUM149 breast cancer cell lines in vitro with IC50 < 100 pmol/L. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 in vitro, with subnanomolar IC50s. In a nude mouse model, RG7787 treatment (2.5 mg/kg i.v. qod ×3-4) resulted in a statistically significant 41% decrease in volumes of HCC70 xenograft tumors (P < 0.0001) and an 18% decrease in MKN28 tumors (P < 0.0001). Pretreatment with paclitaxel (50 mg/kg i.p.) enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (P < 0.0001 for both). RG7787 merits clinical testing for triple-negative breast and gastric cancers. | 25,239,937 | [
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The prevalence of loneliness among U.S. Chinese older adults. | Loneliness is an important indicator of well-being. However, we have limited understanding of loneliness in minority aging populations. This study aims to identify the prevalence of loneliness among U.S. Chinese older adults. Data were drawn from the PINE study, a population-based study of 3,159 U.S. Chinese older adults in the Greater Chicago area. Our findings indicated that the prevalence of loneliness was 26.2%. Older adults with older age, female gender, and living alone reported higher prevalence of loneliness. Older adults with worsened health status, poorer quality of life, and negative health changes over the past year were also more likely to experience loneliness. Loneliness is common among U.S. Chinese older adults in the Greater Chicago area. Future longitudinal studies are needed to improve the understanding of risk factors and outcomes associated with loneliness in Chinese older adults. | 25,239,972 | [
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Hemorrhagic collision metastasis in a cerebral arteriovenous malformation. | A 26-year-old patient with recurrent choriocarcinoma of the testis presented with headache and progressive left homonymous hemianopsia. On initial MRI a grade 4 arteriovenous malformation (AVM) was identified in the right occipital lobe, which was further characterized by catheter angiography. Continued worsening of the headache in the following days prompted a follow-up MRI, which revealed a new T2 hypointense nodule and adjacent vasogenic edema in the periphery of the AVM. A follow-up MRI showed a marked increase in the size of the nodule with intrinsic enhancement and worsening perilesional edema. Based on the imaging evolution, the nodule was diagnosed as a metastasis and the patient was started on chemotherapy and radiotherapy. One week after the MRI he developed a sudden hemorrhage within the mass requiring decompression craniectomy and resection of both AVM and tumor. The histopathology of the resected mass confirmed the diagnosis of choriocarcinoma metastasis to the AVM. | 25,239,982 | [
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Central alarin ameliorated insulin resistance of adipocytes in type 2 diabetic rats. | Alarin, a regulatory peptide, belongs to the galanin family and plays the same regulatory roles as galanin in orexigenic activity and energy metabolism. Our previous studies had found that galanin might facilitate insulin sensitivity via activation of its central receptors. To date, little is known about whether central alarin may exert similar effects on insulin sensitivity. In order to investigate this, alarin and its specific antagonist, alarin 6-25Cys, were administered into the cerebral ventricles of type 2 diabetic rats (T2DR) to evaluate the changes in insulin resistance. The results indicated that central treatment with alarin significantly increased the body weight of animals, the 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake, the plasma adiponectin levels, the glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, the vesicle-associated membrane protein 2 as well as glucose transporter 4 (GLUT4 (SLC2A4)) protein and mRNA levels, and the ratios of GLUT4 contents in plasma membranes to total cell membranes in adipocytes, but reduced blood glucose and plasma retinol-binding protein 4 levels. These effects of alarin may be inhibited by pretreatment with alarin 6-25Cys. The above-mentioned results suggest that the central alarin projective system may facilitate insulin sensitivity and glucose uptake via the increase in GLUT4 content and GLUT4 translocation from intracellular pools to plasma membranes in T2DR. | 25,240,061 | [
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Derivation and validation of simple equations to predict total muscle mass from simple anthropometric and demographic data. | Muscle mass reflects and influences health status. Its reliable estimation would be of value for epidemiology. The aim of the study was to derive and validate anthropometric prediction equations to quantify whole-body skeletal muscle mass (SM) in adults. The derivation sample included 423 subjects (227 women) aged 18-81 y with a body mass index (BMI; in kg/m(2)) of 15.9-40.8. The validation sample included 197 subjects (105 women) aged 19-83 y with a BMI of 15.7-36.4. Both samples were of mixed ethnic/racial groups. All underwent whole-body magnetic resonance imaging to quantify SM (dependent variable for multiple regressions) and anthropometric variables (independent variables). Two prediction equations with high practicality and optimal derivation correlations with SM were further investigated to assess agreement and bias by using Bland-Altman plots and validated in separate data sets. Including race as a variable increased R(2) by only 0.1% in men and by 8% in women. For men: SM (kg) = 39.5 + 0.665 body weight (BW; kg) - 0.185 waist circumference (cm) - 0.418 hip circumference (cm) - 0.08 age (y) (derivation: R(2) = 0.76, SEE = 2.7 kg; validation: R(2) = 0.79, SEE = 2.7 kg). Bland-Altman plots showed moderate agreement in both derivation and validation analyses. For women: SM (kg) = 2.89 + 0.255 BW (kg) - 0.175 hip circumference (cm) - 0.038 age (y) + 0.118 height (cm) (derivation: R(2) = 0.58, SEE = 2.2 kg; validation: R(2) = 0.59, SEE = 2.1 kg). Bland-Altman plots had a negative slope, indicating a tendency to overestimate SM among women with smaller muscle mass and to underestimate SM among those with larger muscle mass. Anthropometry predicts SM better in men than in women. Equations that include hip circumference showed agreement between methods, with predictive power similar to that of BMI to predict fat mass, with the potential for applications in groups, as well as epidemiology and survey settings. | 25,240,071 | [
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Added sugars and periodontal disease in young adults: an analysis of NHANES III data. | Added sugar consumption seems to trigger a hyperinflammatory state and may result in visceral adiposity, dyslipidemia, and insulin resistance. These conditions are risk factors for periodontal disease. However, the role of sugar intake in the cause of periodontal disease has not been adequately studied. We evaluated the association between the frequency of added sugar consumption and periodontal disease in young adults by using NHANES III data. Data from 2437 young adults (aged 18-25 y) who participated in NHANES III (1988-1994) were analyzed. We estimated the frequency of added sugar consumption by using food-frequency questionnaire responses. We considered periodontal disease to be present in teeth with bleeding on probing and a probing depth ≥3 mm at one or more sites. We evaluated this outcome as a discrete variable in Poisson regression models and as a categorical variable in multinomial logistic regression models adjusted for sex, age, race-ethnicity, education, poverty-income ratio, tobacco exposure, previous diagnosis of diabetes, and body mass index. A high consumption of added sugars was associated with a greater prevalence of periodontal disease in middle [prevalence ratio (PR): 1.39; 95% CI: 1.02, 1.89] and upper (PR: 1.42; 95% CI: 1.08, 1.85) tertiles of consumption in the adjusted Poisson regression model. The upper tertile of added sugar intake was associated with periodontal disease in ≥2 teeth (PR: 1.73; 95% CI: 1.19, 2.52) but not with periodontal disease in only one tooth (PR: 0.85; 95% CI: 0.54, 1.34) in the adjusted multinomial logistic regression model. A high frequency of consumption of added sugars is associated with periodontal disease, independent of traditional risk factors, suggesting that this consumption pattern may contribute to the systemic inflammation observed in periodontal disease and associated noncommunicable diseases. | 25,240,081 | [
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Thromboembolism incidence and prophylaxis during vaginal delivery hospitalizations. | Although major international guidelines recommend venous thromboembolism (VTE) prophylaxis during vaginal delivery hospitalization for women with additional risk factors, US guidelines recommend prophylaxis for a very small number of women who are at particularly high risk for an event. The purpose of this study was to characterize practice patterns of VTE prophylaxis in the United States during vaginal delivery hospitalizations and to determine VTE incidence in this population. A population-level database was used to analyze VTE incidence and use of VTE prophylaxis during vaginal delivery hospitalizations in the United States between 2006 and 2012 (n = 2,673,986). We evaluated whether patients received either pharmacologic or mechanical prophylaxis. Hospital-level factors and patient characteristics were included in multivariable regression analysis that evaluated prophylaxis administration. We identified 2,673,986 women who underwent vaginal delivery. Incidence of VTE increased during the study period from 15.6-29.8 events per 100,000 delivery hospitalizations. Within the cohort, 2.6% of patients (n = 68,835) received VTE prophylaxis. Pharmacologic prophylaxis was rare; <1% of women received unfractionated or low-molecular-weight heparin. Although patients with thrombophilia or a previous VTE event were likely to receive prophylaxis (60.8% and 72.8%, respectively), patients with risk factors for VTE such as obesity, smoking, and heart disease were unlikely to receive prophylaxis (rates of 5.9%, 3.3%, and 6.2%, respectively). Our findings demonstrate that the administration of VTE prophylaxis outside a small group of women at extremely high risk for VTE is rare during vaginal delivery hospitalization. Given that VTE incidence is rising in this population, further research to determine whether broadening prophylaxis for VTE may reduce severe maternal morbidity and death is indicated. | 25,240,092 | [
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Design, synthesis and antimycobacterial activity of various 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole derivatives. | In this communication, we synthesized a series of twenty four novel 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole analogues, characterized using various spectroscopic techniques and evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The titled compounds exhibited Minimum inhibitory concentration (MIC) between 3.125 and >50 μg/mL. Among the tested compounds, 5c, 6a, 6j and 6p exhibited moderate activity (MIC = 12.5 μg/mL), while 5a and 6i exhibited good activity (MIC = 6.25 μg/mL) and 6b (MIC = 3.125 μg/mL) exhibited very good anti-tubercular activity. In addition, the analogues 5a, 5c, 6a, 6b, 6i, 6j and 6p were subjected to toxicity studies against mouse macrophage (RAW 264.7) cell lines to analyse the selectivity profile of the newly synthesized compounds and selectivity index of the most active compound was found to be >130 indicating suitability of the compound for further drug development. Structure of 6b was further substantiated through single crystal XRD. | 25,240,097 | [
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A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy. | This study explored the efficacy and safety of transcutaneous vagus nerve stimulation (t-VNS) in patients with pharmacoresistant epilepsy. A total of 60 patients were randomly divided into two groups based on the stimulation zone: the Ramsay-Hunt zone (treatment group) and the earlobe (control group). Before and after the 12-month treatment period, all patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), and the Quality of Life in Epilepsy Inventory (QOLIE-31). Seizure frequency was determined according to the patient's seizure diary. During our study, the antiepileptic drugs were maintained at a constant level in all subjects. After 12 months, the monthly seizure frequency was lower in the treatment group than in the control group (8.0 to 4.0; P=0.003). This reduction in seizure frequency was correlated with seizure frequency at baseline and duration of epilepsy (both P>0.05). Additionally, all patients showed improved SAS, SDS, LSSS, and QOLIE-31 scores that were not correlated with a reduction in seizure frequency. The side effects in the treatment group were dizziness (1 case) and daytime drowsiness (3 cases), which could be relieved by reducing the stimulation intensity. In the control group, compared with baseline, there were no significant changes in seizure frequency (P=0.397), SAS, SDS, LESS, or QOLIE-31. There were also no complications in this group. | 25,240,121 | [
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Improving the mental health of adolescents with epilepsy through a group cognitive behavioral therapy program. | The threat of unpredictable seizures makes epilepsy unique among childhood chronic illnesses. One consequence is that people who have childhood-onset epilepsy often have poor social adjustment and competence in adulthood. Better emotional and social functioning could improve long-term outcomes. Thirty-four adolescents with epilepsy participated in a group cognitive behavioral therapy program designed to enhance their level of psychosocial functioning. Baseline Strength and Difficulty Questionnaire scores suggested that many participants had difficulties with emotions, concentration, and social functioning, with parent-reported Impact scores significantly worse than adolescent-reported scores (p=0.005). Four months after the intervention, adolescent-reported Prosocial Behavior scores significantly improved (p=0.03). Parent-reported scores improved significantly at follow-up, compared with baseline, in Peer Problems (p=0.04), Impact (p=0.001), and Prosocial Behavior (p=0.004) scores. Adolescents with lower socioeconomic status reported the greatest improvements (p=0.01). A brief CBT intervention was effective and resulted in improved mental health indices and social functioning for adolescents with epilepsy. | 25,240,125 | [
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Highly selective colorimetric detection and estimation of Hg2+ at nano-molar concentration by silver nanoparticles in the presence of glutathione. | The present study investigated the colorimetric detection of mercury (Hg(2+)) ions by using silver nanoparticles (Ag NPs) in the presence of glutathione. The nanoparticles used in the study were synthesized biologically by using Polyalthia longifolia leaf extract. The synthesized nanoparticles were characterized by UV-visible spectrophotometer, transmission electron microscope, X-ray diffraction, particle size analyzer and zeta sizer. The particles were spherical in shape and it possesses the effective diameter of 5 nm. The zeta potential of the particles was determined to be -28.6 mV. Ag NPs-glutathione conjugates were able to detect Hg(2+) in nanomolar level. Ag NPs-glutathione conjugates upon interaction with Hg(2+) changes from yellowish brown to pale yellow and finally colorless. The study may be applied for the qualitative and quantitative estimation of mercury at very low concentration. | 25,240,142 | [
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Pollinia-borne chemicals that induce early postpollination effects in Dendrobium flowers move rapidly into agar blocks and include ACC and compounds with auxin activity. | The early visible effects of pollination in orchids are likely due to pollinia-borne chemicals. In Dendrobium we tested whether such compounds were water soluble and would diffuse in solid-aqueous phase, and determined both 1-aminocyclopropane-1-carboxylic acid (ACC) concentrations and auxin activity. Following pollination, the flower peduncle showed epinastic movement, followed by yellowing of the flower lip, flower senescence and ovary growth. Placing pollinia on agar blocks for 3, 6, 9 or 12h, prior to transferring them to the stigma, increased the time to these early postpollination effects or prevented them. Placing agar blocks that had been used for contact with the pollinia on the stigma also induced the early postpollination effects. The concentrations of ACC, the direct precursor of ethylene, in pollinia was lower the longer the pollinia had been in contact with the agar blocks, whilst the ACC content in the agar blocks increased with the period of contact. The auxin activity of the agar blocks also increased with the time of contact with pollinia. It is concluded that chemicals in the pollinia are responsible for the early visible postpollination effects, and that these (a) rapidly diffuse in aqueous media, and (b) comprise at least ACC and compounds with auxin activity. The idea is discussed that ACC plus auxin is adequate for the production of the early postpollination effects. | 25,240,156 | [
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Impact of preoperative serum creatinine on short- and long-term mortality after cardiac surgery: a cohort study. | Preoperative renal insufficiency is an important predictor of mortality after cardiac surgery. This retrospective cohort study was designed to identify the optimal cut-off for baseline serum creatinine (bSCr) and estimated glomerular filtration rate (eGFR) to predict survival. Furthermore, we investigated the potential confounding effect of other perioperative risk indicators on short- and long-term survival. Data of 9490 cardiac surgical patients were prospectively collected between 1997 and 2008 (follow up to 2010) at the Medical University Vienna. We identified bSCr cut-off values and calculated uni- and multivariate hazard models for short- and long-term survival and compared the results with a validation set from Zurich. The estimated survival curves defined a distinct period of increased mortality until 150 days. Cut-off values of >115 µmol litre(-1) for bSCr and ≤50 ml min(-1) for eGFR were identified. Increased bSCr, associated with higher mortality [hazard ratio (HR) 2.61, 95% confidence interval (CI) 2.43-2.80, P<0.0001], was present in 19.5% of patients and remained predictive for short- (HR 1.59, 95% CI 1.38-1.83, P=0.0027) and long-term survival (HR 1.46, 95% CI 1.32-1.62, P<0.0001) in the multivariate hazard models. A cut-off of >120 µmol litre(-1) for bSCr was determined for the validation set. Decreased eGFR was present in 23.6% (HR 2.86, 95% CI 2.67-3.06, P<0.0001). In our patients, increased bSCr was an independent predictor of mortality, which may critically influence risk evaluation and perioperative treatment guidance. | 25,240,162 | [
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A convenient synthesis of novel aza-C-disaccharide analogues. | Novel aza-C-disaccharide analogues have been conveniently synthesized by using the isoxazoline-linked C-disaccharide derivatives as the intermediates. Firstly, the C=N of isoxazoline was reduced to C-N by using DIBAL-H as reducing agent, then followed by the tandem multi-step reactions through catalytic hydrogenation with Pd(OH)2/C involving debenzylated, reductive cleavage of the N-O, condensation-cyclization of the aldehyde and the in situ generated amine group to form imine C=N and then C=N hydrogenation to form C-N, thus providing a practical and new access to the synthesis of novel aza-C-disaccharide analogues. | 25,240,179 | [
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Assessment of floating plastic debris in surface water along the Seine River. | This study is intended to examine the quality and quantity of floating plastic debris in the River Seine through use of an extensive regional network of floating debris-retention booms; it is one of the first attempts to provide reliable information on such debris at a large regional scale. Plastic debris represented between 0.8% and 5.1% of total debris collected by weight. A significant proportion consisted of food wrappers/containers and plastic cutlery, probably originating from voluntary or involuntary dumping, urban discharges and surface runoff. Most plastic items are made of polypropylene, polyethylene and, to a lesser extent, polyethylene terephthalate. By extrapolation, some 27 tons of floating plastic debris are intercepted annually by this network; corresponding to 2.3 g per Parisian inhabitant per year. Such data could serve to provide a first evaluation of floating plastic inputs conveyed by rivers. | 25,240,189 | [
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Chaperone-mediated reversible inhibition of the sarcomeric myosin power stroke. | Molecular chaperones are required for successful folding and assembly of sarcomeric myosin in skeletal and cardiac muscle. Here, we show that the chaperone UNC-45B inhibits the actin translocation function of myosin. Further, we show that Hsp90, another chaperone involved in sarcomere development, allows the myosin to resume actin translocation. These previously unknown activities may play a key role in sarcomere development, preventing untimely myosin powerstrokes from disrupting the precise alignment of the sarcomere until it has formed completely. | 25,240,199 | [
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Development and validation of bioanalytical method for simultaneous estimation of ramipril and hydrochlorothiazide in human plasma using liquid chromatography-tandem mass spectrometry. | The present study describes a novel liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the simultaneous estimation of ramipril (RAM) and hydrochlorothiazide (HCTZ) in human plasma using liquid-liquid extraction technique. This method made use of electrospray ionization in positive mode for RAM and in negative mode for HCTZ using triple quadrupole mass spectrometry where carbamazepine was used as an internal standard (IS). Analytes were recovered by methyl tertiary butyl ether:dichloromethane (85:15) subsequently separated on an Enable C18 G column (150 mm × 4.6 mm, 5 μm) using methanol:0.1% formic acid in water (85:15) as a mobile phase, at a flow rate of 0.5 mL/min. Quantification of RAM, HCTZ and IS was performed using multi-reaction monitoring mode (MRM) where transition of m/z 417.2→234.1 (RAM) and 237.0→194.0 (IS) in positive mode and 296.1→205.0 for HCTZ in negative mode. The calibration curve was linear (r(2)>0.99) over the concentration range of 2-170 ng/mL for RAM and 8-680 ng/mL for HCTZ. The intra-day and inter-day precisions were <15% and the accuracy was all within ±15% (at LLOQ level ±20%). Additionally, the LC-MS/MS method was fully validated for all the other parameters such as selectivity, matrix effect, recovery and stability as well. In conclusion, the findings of the present study revealed the selectivity and sensitivity of this method for the simultaneous estimation of RAM and HCTZ in human plasma. | 25,240,204 | [
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Routine use of ultrasound-guided access reduces access site-related complications after lower extremity percutaneous revascularization. | We sought to elucidate the risks for access site-related complications (ASCs) after percutaneous lower extremity revascularization and to evaluate the benefit of routine ultrasound-guided access (RUS) in decreasing ASCs. We reviewed all consecutive percutaneous revascularizations (percutaneous transluminal angioplasty or stent) performed for lower extremity atherosclerosis at our institution from 2002 to 2012. RUS began in September 2007. Primary outcome was any ASC (bleeding, groin or retroperitoneal hematoma, vessel rupture, or thrombosis). Multivariable logistic regression was used to determine predictors of ASC. A total of 1371 punctures were performed on 877 patients (43% women; median age, 69 [interquartile range, 60-78] years) for claudication (29%), critical limb ischemia (59%), or bypass graft stenosis (12%) with 4F to 8F sheaths. There were 72 ASCs (5%): 52 instances of bleeding or groin hematoma, nine pseudoaneurysms, eight retroperitoneal hematomas, two artery lacerations, and one thrombosis. ASCs were less frequent when RUS was used (4% vs 7%; P = .02). Multivariable predictors of ASC were age >75 years (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1-3.7; P = .03), congestive heart failure (OR, 1.9; 95% CI, 1.1-1.3; P = .02), preoperative warfarin use (OR, 2.0; 95% CI, 1.1-3.5; P = .02), and RUS (OR, 0.4; 95% CI, 0.2-0.7; P < .01). Vascular closure devices (VCDs) were not associated with lower rates of ASCs (OR, 1.1; 95% CI, 0.6-1.9; P = .79). RUS lowered ASCs in those >75 years (5% vs 12%; P < .01) but not in those taking warfarin preoperatively (10% vs 13%; P = .47). RUS did not decrease VCD failure (6% vs 4%; P = .79). We were able to decrease the rate of ASCs during lower extremity revascularization with the implementation of RUS. VCDs did not affect ASCs. Particular care should be taken with patients >75 years old, those with congestive heart failure, and those taking warfarin. | 25,240,244 | [
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Dissociation of functional and anatomical brain abnormalities in unaffected siblings of schizophrenia patients. | Schizophrenia patients and their unaffected siblings share similar brain functional and structural abnormalities. However, no study is engaged to investigate whether and how functional abnormalities are related to structural abnormalities in unaffected siblings. This study was undertaken to examine the association between functional and anatomical abnormalities in unaffected siblings. Forty-six unaffected siblings of schizophrenia patients and 46 age-, sex-, and education-matched healthy controls underwent structural and resting-state functional magnetic resonance imaging scanning. Voxel-based morphometry (VBM), amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) were utilized to analyze imaging data. The VBM analysis showed gray matter volume decreases in the fronto-temporal regions (the left middle temporal gyrus and right inferior frontal gyrus, orbital part) and increases in basal ganglia system (the left putamen). Functional abnormalities measured by ALFF and fALFF mainly involved in the fronto-limbic-sensorimotor circuit (decreased ALFF in bilateral middle frontal gyrus and the right middle cingulate gyrus, and decreased fALFF in the right inferior frontal gyrus, orbital part; and increased ALFF in the left fusiform gyrus and left lingual gyrus, and increased fALFF in bilateral calcarine cortex). No significant correlation was found between functional and anatomical abnormalities in the sibling group. A dissociation pattern of brain regions with functional and anatomical abnormalities is observed in unaffected siblings. Our findings suggest that brain functional and anatomical abnormalities might be present independently in unaffected siblings of schizophrenia patients. | 25,240,248 | [
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Integrating monitor alarms with laboratory test results to enhance patient deterioration prediction. | Patient monitors in modern hospitals have become ubiquitous but they generate an excessive number of false alarms causing alarm fatigue. Our previous work showed that combinations of frequently co-occurring monitor alarms, called SuperAlarm patterns, were capable of predicting in-hospital code blue events at a lower alarm frequency. In the present study, we extend the conceptual domain of a SuperAlarm to incorporate laboratory test results along with monitor alarms so as to build an integrated data set to mine SuperAlarm patterns. We propose two approaches to integrate monitor alarms with laboratory test results and use a maximal frequent itemsets mining algorithm to find SuperAlarm patterns. Under an acceptable false positive rate FPRmax, optimal parameters including the minimum support threshold and the length of time window for the algorithm to find the combinations of monitor alarms and laboratory test results are determined based on a 10-fold cross-validation set. SuperAlarm candidates are generated under these optimal parameters. The final SuperAlarm patterns are obtained by further removing the candidates with false positive rate>FPRmax. The performance of SuperAlarm patterns are assessed using an independent test data set. First, we calculate the sensitivity with respect to prediction window and the sensitivity with respect to lead time. Second, we calculate the false SuperAlarm ratio (ratio of the hourly number of SuperAlarm triggers for control patients to that of the monitor alarms, or that of regular monitor alarms plus laboratory test results if the SuperAlarm patterns contain laboratory test results) and the work-up to detection ratio, WDR (ratio of the number of patients triggering any SuperAlarm patterns to that of code blue patients triggering any SuperAlarm patterns). The experiment results demonstrate that when varying FPRmax between 0.02 and 0.15, the SuperAlarm patterns composed of monitor alarms along with the last two laboratory test results are triggered at least once for [56.7-93.3%] of code blue patients within an 1-h prediction window before code blue events and for [43.3-90.0%] of code blue patients at least 1-h ahead of code blue events. However, the hourly number of these SuperAlarm patterns occurring in control patients is only [2.0-14.8%] of that of regular monitor alarms with WDR varying between 2.1 and 6.5 in a 12-h window. For a given FPRmax threshold, the SuperAlarm set generated from the integrated data set has higher sensitivity and lower WDR than the SuperAlarm set generated from the regular monitor alarm data set. In addition, the McNemar's test also shows that the performance of the SuperAlarm set from the integrated data set is significantly different from that of the SuperAlarm set from the regular monitor alarm data set. We therefore conclude that the SuperAlarm patterns generated from the integrated data set are better at predicting code blue events. | 25,240,252 | [
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The clinician in the Driver's Seat: part 1 - a drag/drop user-composable electronic health record platform. | Creating electronic health records that support the uniquely complex and varied needs of healthcare presents formidable challenges. To address some of these challenges we created a new model for healthcare information systems, embodied in MedWISE,(2) a widget-based highly configurable electronic health record (EHR) platform. Founded on the idea that providing clinician users with greater control of the EHR may result in greater fit to user needs and preferences, MedWISE allows drag/drop user configurations and the sharing of user-created elements such as custom laboratory result panels and user-created interface tabs. After reviewing the current state of EHR configurability, we describe the philosophical, theoretical and practical rationales for our model, and the specific functionality of MedWISE. The alternative approach may have several advantages for human-computer interaction, efficiency, cognition, and fit of EHR tools to different contexts and tasks. We discuss potential issues raised by this approach. | 25,240,253 | [
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... |
Reactions of methylphosphonic difluoride with human acetylcholinesterase and oximes--Possible therapeutic implications. | Highly toxic organophosphorus (OP) nerve agents are well characterized regarding chemical, biological and toxicological properties and the effectiveness of standard atropine and oxime therapy. Open literature data on the key nerve agent precursor methylphosphonic difluoride (DF) are scarce. To fill this gap the reactions of DF and its main degradation product methylphosphonofluoridic acid (MF) with human acetylcholinesterase (AChE) and the oximes obidoxime, HI-6 and 2-PAM were investigated in vitro. DF and MF were found to be weak inhibitors of human AChE being at least five orders less potent compared to the nerve agent sarin. Incubation of human AChE with millimolar DF and MF and subsequent addition of obidoxime and HI-6 resulted in a concentration-dependent decrease of AChE activity. This effect was not observed when incubating highly diluted AChE with oximes. The most likely explanation for this phenomenon is an inhibitory effect of phosphonyloximes formed by direct reaction of DF or MF with obidoxime and HI-6. These data indicate that high DF doses, resulting in millimolar blood and tissue DF/MF concentrations, are necessary to induce cholinergic signs and that under these conditions treatment with obidoxime and HI-6 may even worsen the poisoning. | 25,240,274 | [
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PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. | Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft-tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1 associated) or after radiotherapy. Using comprehensive genomic approaches, we identified loss-of-function somatic alterations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the lost PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 levels and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), both of which significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2 components, NF1 and CDKN2A highlights their critical and potentially cooperative roles in MPNST pathogenesis. | 25,240,281 | [
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Alterations in the nuclear proteome of HIV-1 infected T-cells. | Virus infection of a cell involves the appropriation of host factors and the innate defensive response of the cell. The identification of proteins critical for virus replication may lead to the development of novel, cell-based inhibitors. In this study we mapped the changes in T-cell nuclei during human immunodeficiency virus type 1 (HIV-1) at 20 hpi. Using a stringent data threshold, a total of 13 and 38 unique proteins were identified in infected and uninfected cells, respectively, across all biological replicates. An additional 15 proteins were found to be differentially regulated between infected and control nuclei. STRING analysis identified four clusters of protein-protein interactions in the data set related to nuclear architecture, RNA regulation, cell division, and cell homeostasis. Immunoblot analysis confirmed the differential expression of several proteins in both C8166-45 and Jurkat E6-1 T-cells. These data provide a map of the response in host cell nuclei upon HIV-1 infection. | 25,240,327 | [
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Intranasal immunization with DNA vaccine coexpressing Der p 1 and ubiquitin in an allergic rhinitis mouse model. | The worldwide prevalence of allergic rhinitis (AR) is increasing, whereas treatments for AR remain limited in effect. Therefore, a new type of effective drug is eagerly in demand. To create a hypoallergenic vaccine by forced ubiquitination. In the present study, we constructed a DNA vaccine coexpressing Der p 1 allergen and murine ubiquitin, which used chitosan as a carrier. Through the vitro and vivo experiments, we evaluated its protective efficacy against AR. The results indicated that the DNA vaccine pVAX1-Ub-Derp1/CS had been successfully constructed. This nanoparticle could not only transfect 293T cells in vitro but also transform cells in vivo. The inflammation of nasal mucosa in an AR murine model via immunization with pVAX1-Ub-Derp1/CS was less severe than those without treatments. Furthermore, it found that mice immunized with pVAX1-Ub-Derp1/CS generated a high level of specific IgG but a low level of specific IgE (P < .01). The significantly increased levels of interferon-γ and the significantly decreased levels of interleukins 4, 10, and 17 indicated that a TH1-type response was elicited by immunization with pVAX1-Ub-Derp1/CS (P < .01). This effect was especially stronger through intranasal immunization. Nasal mucosal immunization and ubiquitination are efficacious strategies to enhance the efficiency and safety of DNA vaccine. The nanoparticle pVAX1-Ub-Derp1/CS is expected to be a new kind of effective vaccine for AR. | 25,240,330 | [
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... |
A general time-dependent route to resonance-Raman spectroscopy including Franck-Condon, Herzberg-Teller and Duschinsky effects. | We present a new formulation of the time-dependent theory of Resonance-Raman spectroscopy (TD-RR). Particular attention has been devoted to the generality of the framework and to the possibility of including different effects (Duschinsky mixing, Herzberg-Teller contributions). Furthermore, the effects of different harmonic models for the intermediate electronic state are also investigated. Thanks to the implementation of the TD-RR procedure within a general-purpose quantum-chemistry program, both solvation and leading anharmonicity effects have been included in an effective way. The reliability and stability of our TD-RR implementation are validated against our previously proposed and well-tested time-independent procedure. Practical applications are illustrated with some closed- and open-shell medium-size molecules (anthracene, phenoxyl radical, benzyl radical) and the simulated spectra are compared to the experimental results. More complex and larger systems, not limited to organic compounds, can be also studied, as shown for the case of Tris(bipyridine)ruthenium(II) chloride. | 25,240,346 | [
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... |
Dielectric-dependent screened Hartree-Fock exchange potential and Slater-formula with Coulomb-hole interaction for energy band structure calculations. | We previously reported a screened Hartree-Fock (HF) exchange potential for energy band structure calculations [T. Shimazaki and Y. Asai, J. Chem. Phys. 130, 164702 (2009); T. Shimazaki and Y. Asai, J. Chem. Phys. 132, 224105 (2010)]. In this paper, we discuss the Coulomb-hole (COH) interaction and screened Slater-formula and determine the energy band diagrams of several semiconductors, such as diamond, silicon, AlAs, AlP, GaAs, GaP, and InP, based on the screened HF exchange potential and Slater-formula with COH interaction, to demonstrate the adequacy of those theoretical concepts. The screened HF exchange potential and Slater-formula are derived from a simplified dielectric function and, therefore, include the dielectric constant in their expressions. We also present a self-consistent calculation technique to automatically determine the dielectric constant, which is incorporated into each self-consistent field step. | 25,240,347 | [
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0.... |
Test of the interaction potential energy for Na⁺-H₂ by gaseous ion transport data. | Transport properties of Na(+) ions in gaseous hydrogen are calculated using the recently developed "beyond Monchick-Mason" (BMM) approximation and an ab initio Na(+)-H2 potential energy surface. Good agreement with the experimental data on the reduced mobility and longitudinal diffusion coefficient proves the accuracy of the surface and the adequacy of the BMM method, allowing for its optimal parameterization. | 25,240,356 | [
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0.066598... |
Topological defects around a spherical nanoparticle in nematic liquid crystal: coarse-grained molecular dynamics simulations. | We consider the applicability of coarse-grained molecular dynamics for the simulation of defects in a nematic liquid crystal around a colloidal particle. Two types of colloids are considered, a soft colloid resembling a liquid crystal dendrimer or a similar macromolecule. In addition, a decorated colloid is used which could represent a gold nanoparticle with mesogen-modified surface. For both models we consider homeotropic and tangential anchoring. Precise control of the easy axis on the colloid's surface enables us to focus on specific planar arrangements in the case of a decorated colloid. The nematic phase is modelled explicitly via soft spherocylinders interacting through a potential, suggested by Lintuvuori and Wilson [J. Chem. Phys. 128, 044906 (2008)]. Properties of the nematic phase are studied by computing the Frank elastic constants. In addition, estimates for the nematic-isotropic transition and the coherence length allow us to establish a relation between energy and length scales with respect to experimental systems. Both models exhibit similar defect topologies, namely, that of a Saturn ring and a boojum-type of defect for homeotropic and tangential surface anchoring, respectively. In the decorated colloid model we tune the anchoring strength through the density of the mesogenic shell on the surface. We also found the biaxial boojum defect for the special case of longitudinal planar anchoring. The study demonstrates the potential of coarse-grained simulation methods for studying defects in liquid crystals. | 25,240,368 | [
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Bionomic response of Aedes aegypti to two future climate change scenarios in far north Queensland, Australia: implications for dengue outbreaks. | Dengue viruses are transmitted by anthropophilic mosquitoes and infect approximately 50 million humans annually. To investigate impacts of future climate change on dengue virus transmission, we investigated bionomics of the mosquito vector, Aedes aegypti. Using a dynamic life table simulation model (the Container inhabiting mosquito simulation CIMSiM) and statistically downscaled daily values for future climate, we assessed climate change induced changes to mosquito bionomics. Simulations of Ae. aegypti populations for current (1991-2011) and future climate (2046-2065) were conducted for the city of Cairns, Queensland, the population centre with most dengue virus transmission in Australia. Female mosquito abundance, wet weight, and the extrinsic incubation period for dengue virus in these mosquitoes were estimated for current and future climate (MPI ECHAM 5 model, B1 and A2 emission scenarios). Overall mosquito abundance is predicted to change, but results were equivocal for different climate change scenarios. Aedes aegypti abundance is predicted to increase under the B1, but decrease under the A2 scenario. Mosquitoes are predicted to have a smaller body mass in a future climate. Shorter extrinsic incubation periods are projected. It is therefore unclear whether dengue risk would increase or decrease in tropical Australia with climate change. Our findings challenge the prevailing view that a future, warmer climate will lead to larger mosquito populations and a definite increase in dengue transmission. Whilst general predictions can be made about future mosquito borne disease incidence, cautious interpretation is necessary due to interaction between local environment, human behaviour and built environment, dengue virus, and vectors. | 25,240,382 | [
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Low-level laser therapy as an alternative for pulpotomy in human primary teeth. | This study aimed to evaluate the effects of low-level laser therapy (LLLT) on pulpal response of primary teeth. Twenty mandibular primary molars were randomly divided into the following groups: group I Buckley's formocresol (diluted at 1:5), group II calcium hydroxide, group III LLLT + zinc oxide/eugenol, and group IV LLLT + calcium hydroxide. LLLT parameters were set at 660-nm wavelength, 10-mW power output, and 2.5 J/cm(2) energy density for 10 s in continuous mode (InGaAlP laser, Twin Laser®, MMOptics, Sao Carlos, Sao Paulo, Brazil). The teeth were extracted at the regular exfoliation period. The dentin-pulp complex was graded by an established histopathological score system. Statistical analysis was performed by Kruskal-Wallis and chi-square test. The histopathological assessment revealed statistically significant differences among groups (P < 0.05). The lowest degree of pulpal inflammation was present in LLLT + calcium hydroxide (P = 0.0296). Calcium hydroxide showed the highest rate of hard tissue barrier (P = 0.0033), odontoblastic layer (P = 0.0033), and dense collagen fibers (P = 0.0095). On the other hand, formocresol showed the highest incidence of internal resorption (P = 0.0142). Based on this study, low-level laser therapy preceding the use of calcium hydroxide exhibited satisfactory results on pulp tissue healing. However, further clinical studies on human teeth with long-term follow-up are needed to test the low-level laser therapy efficacy. | 25,240,388 | [
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