Physical activity and environment perception among older adults: a population study in Florianópolis, Brazil.
To estimate the prevalence of the practice of leisure-time physical activity in older adults and to analyze its association with environment perception. Cross-sectional population study conducted from September 2009 to June 2010 with 1.656 individuals aged 60 years or older, living in the urban zone of the city of Florianópolis, Southern Brazil. Leisure-time physical activity was measured using the long version of the International Physical Activity Questionnaire. Environment perception variables were measured by means of a modified version of the Neighborhood Environment Walkability Scale. Crude and adjusted analyzes were carried out using Poisson regression with a 5% significance level. The prevalence of leisure-time physical activity was 29.7% (95% CI: 26.0; 33.3); 35.6% (95%CI: 29.7; 41.6) among men and 26.3% (95%CI: 23.1; 29.4) among women. The elderly who reported the existence of sidewalks, bike lanes, pedestrian paths and trails in the neighborhood, as well as those who reported receiving support from friends or neighbors to engage in physical activities, were more active in their leisure time. Concerning the influence of the climate, the elderly who reported that it was a barrier were rated as more active. The practice of leisure-time physical activity still has low prevalence among the elderly population of Florianópolis. Public spaces for the practice of physical activity and encouraging group activities may play a significant role in the promotion of leisure-time physical activity in older adults.


Application of microarray and functional-based screening methods for the detection of antimicrobial resistance genes in the microbiomes of healthy humans.
The aim of this study was to screen for the presence of antimicrobial resistance genes within the saliva and faecal microbiomes of healthy adult human volunteers from five European countries. Two non-culture based approaches were employed to obviate potential bias associated with difficult to culture members of the microbiota. In a gene target-based approach, a microarray was employed to screen for the presence of over 70 clinically important resistance genes in the saliva and faecal microbiomes. A total of 14 different resistance genes were detected encoding resistances to six antibiotic classes (aminoglycosides, β-lactams, macrolides, sulphonamides, tetracyclines and trimethoprim). The most commonly detected genes were erm(B), blaTEM, and sul2. In a functional-based approach, DNA prepared from pooled saliva samples was cloned into Escherichia coli and screened for expression of resistance to ampicillin or sulphonamide, two of the most common resistances found by array. The functional ampicillin resistance screen recovered genes encoding components of a predicted AcrRAB efflux pump. In the functional sulphonamide resistance screen, folP genes were recovered encoding mutant dihydropteroate synthase, the target of sulphonamide action. The genes recovered from the functional screens were from the chromosomes of commensal species that are opportunistically pathogenic and capable of exchanging DNA with related pathogenic species. Genes identified by microarray were not recovered in the activity-based screen, indicating that these two methods can be complementary in facilitating the identification of a range of resistance mechanisms present within the human microbiome. It also provides further evidence of the diverse reservoir of resistance mechanisms present in bacterial populations in the human gut and saliva. In future the methods described in this study can be used to monitor changes in the resistome in response to antibiotic therapy.


Risk factors of catheter-related bloodstream infections in parenteral nutrition catheterization.
Intravascular catheters are integral to the practice of modern medicine. Potential risk factors for catheter-related bloodstream infection (CRBSI) include underlying disease, method of catheter insertion, and duration and purpose of catheterization. The administration of parenteral nutrition (PN) through intravascular catheters increases CRBSI risks. The purpose of this study was to evaluate the risk factors of CRBSI in patients with PN administration. This study was conducted at the Karadeniz Technical University Hospital between October 2003 and November 2004. All the patients to whom PN was administered through intravascular catheters were prospectively monitored for the presence of CRBSI and risk factors. During the study period, 111 intravascular catheters through which PN was administered were monitored for a total of 1646 catheter-days. CRBSI was determined in 31 cases, a CRBSI rate of 18.8 per 1,000 catheter-days. When risk factors affecting CRBSI were investigated using logistic regression, an increase in APACHE II score (OR, 1.10; 95% CI, 1.01-1.21; p = .012), prolongation of catheterization (OR, 1.08; 95% CI, 1.02-1.14; p = .004), catheterization in emergent conditions (OR, 5.45; 95% CI, 1.20-24.82; p = .016), and poor patient hygiene (OR, 4.38; 95% CI, 1.39-13.78; p = .019) were all determined to be independent risk factors. Proper implementation of hand hygiene and maximal barrier precautions during the insertion of catheters reduced CRBSI levels (OR, 0.28; 95% CI, 0.09-0.88; p = .003 and OR, 0.26; 95% CI, 0.08-0.93; p = .017, respectively). It was concluded that the duration of catheterization should be shortened; that the intravascular catheter, which is inserted in urgent situations, should be removed as soon as possible; and that maximal sterile barrier precautions should be taken and due attention should be paid to hand hygiene.


Negative staining of proteins.
Negative staining, some closely related alternative preparation techniques and radiation stability are considered. An attempt is made to clarify the mechanism of action and ultimate resolution limit of negative staining. The results of electron diffraction investigation of thermitase microcrystals embedded in glucose and glucose + stains are presented. It is shown that at doses not exceeding 10 electrons/nm2 electron diffraction from thermitase crystals demonstrate diffraction fields up to 0.2 nm. When adding heavy-atom salts to glucose or using negative staining, the relative intensities of reflections change and electron diffraction patterns for every type of heavy-atom additive (or negative stain) have their specific features. Such characteristic changes of reflection intensities indicate specific interaction of these additives (or stains) with the object. In the case of electron diffraction from the crystals stained using the routine negative staining technique the ordering was preserved down to 0.4-0.5 nm. Increasing the dose up to the normal value results in fading of distant reflections. Thus, negative staining with radiation doses less than the critical one could yield resolution down to 0.4 nm. Yet, the structure may change due to interaction with the stain. Nevertheless, the possibility that such resolution could be obtained for a limited number of objects should not be excluded. Some examples of the application of negative staining for investigation of quaternary and domain structure of proteins (nitrogenase, glutamine synthetase, mitochondrial ATP-synthase, membrane monooxygenase enzymes), tubular and two-dimensional protein crystals (catalase, phosphorylase, HWV protein, hydrogenase), as well as ribosomes and bacteriophages are given in the review.


Clinical development of Modified Vaccinia virus Ankara vaccines.
The smallpox vaccine Vaccinia was successfully used to eradicate smallpox, but although very effective, it was a very reactogenic vaccine and responsible for the deaths of one or two people per million vaccinated. Modified Vaccinia virus Ankara (MVA) is a replication-deficient and attenuated derivative, also used in the smallpox eradication campaign and now being developed as a recombinant viral vector to produce vaccines against infectious diseases and cancer. Many clinical trials of these new vaccines have been conducted, and the findings of these trials are reviewed here. The safety of MVA is now well documented, immunogenicity is influenced by the dose and vaccination regimen, and information on the efficacy of MVA-vectored vaccines is now beginning to accumulate.


Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux.
Bleomycin is a clinically potent anticancer drug used for the treatment of germ-cell tumors, lymphomas and squamous-cell carcinomas. Unfortunately, the therapeutic efficacy of bleomycin is severely hampered by the development of pulmonary fibrosis. However, the mechanisms underlying bleomycin-induced pulmonary fibrosis, particularly the molecular target of bleomycin, remains unknown. Here, using a chemical proteomics approach, we identify ANXA2 (annexin A2) as a direct binding target of bleomycin. The interaction of bleomycin with ANXA2 was corroborated both in vitro and in vivo. Genetic depletion of anxa2 in mice mitigates bleomycin-induced pulmonary fibrosis. We further demonstrate that Glu139 (E139) of ANXA2 is required for bleomycin binding in lung epithelial cells. A CRISPR-Cas9-engineered ANXA2E139A mutation in lung epithelial cells ablates bleomycin binding and activates TFEB (transcription factor EB), a master regulator of macroautophagy/autophagy, resulting in substantial acceleration of autophagic flux. Pharmacological activation of TFEB elevates bleomycin-initiated autophagic flux, inhibits apoptosis and proliferation of epithelial cells, and ameliorates pulmonary fibrosis in bleomycin-treated mice. Notably, we observe lowered TFEB and LC3B levels in human pulmonary fibrosis tissues compared to normal controls, suggesting a critical role of TFEB-mediated autophagy in pulmonary fibrosis. Collectively, our data demonstrate that ANXA2 is a specific bleomycin target, and bleomycin binding with ANXA2 impedes TFEB-induced autophagic flux, leading to induction of pulmonary fibrosis. Our findings provide insight into the mechanisms of bleomycin-induced fibrosis and may facilitate development of optimized bleomycin therapeutics devoid of lung toxicity.


Induction of lupus-associated autoantibodies by immunization with native and recombinant Ig polypeptides expressing a cross-reactive idiotype 4B4.
A human mAb designated 4B4 with anti-Sm activity was derived from a patient with systemic lupus erythematosus. This antibody expressed a lupus-associated cross-reactive Id, partially related to the monoclonal murine anti-Sm (Y2) from MRL/lpr mice. Studies were performed to investigate the ability of 4B4 to induce lupus in nonautoimmune-prone mice. BALB/c mice immunized with 4B4 produced antibodies to dsDNA, ssDNA, Sm ribonucleoprotein, and mouse Fc fragment. There was no antibody activity against SSA/Ro, SSB/La, and hen egg lysozyme. Ag inhibition studies show that the autoantibodies were not polyreactive. Mice were also immunized with r4B4 polypeptides representing the H/L heterodimer, H chain and L chain. Autoantibodies were induced in mice immunized against the H/L and H polypeptides. No autoantibodies were induced in mice immunized with recombinant L chain. Furthermore, from 20 to 68% of antibody activity to Sm or dsDNA could be inhibited with anti-Id antiserum (either anti-4B4 or Y2). The autoantibody was initially IgM and then underwent an isotype switch to IgG. These results show that lupus-associated autoantibodies can be induced by immunization with 4B4 and that the 4B4 VH region is important in this induction process. The finding of murine IgG autoantibody expressing a cross-reactive Id similar to the immunizing 4B4 suggests a role for anti-idiotypic Th cells in this autoimmune response.


A randomized trial of normothermic preservation in liver transplantation.
Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.


Sex differences in proximal humeral outline shape: elliptical Fourier functions.
A method is presented for the numerical analysis of sex differences in size and shape of the proximal humeral outlines using elliptical Fourier functions (EFFs). A skeletal sample consisting of right and left humeri pairs of 69 individuals, 36 males and 33 females, was used. The proximal superior view in the plane of the proximo-distal axis of each humerus was photographed and then 54 boundary points were located on the two-dimensional outline tracings. These points were digitized and used to compute EFFs with 27 harmonics. From the EFFs, a set of expected points on the proximal humeral outline was generated using the centroid as an origin. Superimposition of the male and female outlines on this centroid provided a detailed picture of the relative sex differences in size and shape with respect to that center. The bounded area of the proximal humeral outline showed statistically significant sex differences. Additionally, statistical results of the amplitudes derived from the "area-standardized" EFFs and visual assessments of the mean outline plots indicated significant sex differences in shape of the proximal humeral outlines. Focusing on localized regional differences, the greater tubercle was located more postero-medially and the lesser tubercle was located more anteriorly in the males compared to the females. Sex determinations from the proximal humeri were also examined with discriminant functions based on the amplitudes, which represent shape characteristics of the outline, and the hounded area. Using a cross-validation method, predictions of the percentages of cases correctly classified with the discriminant functions were ranged from 92.8% to 95.7% for the right and left humeral data. These results suggest that differences in size and shape of the proximal humeral outlines may be better predictors of sex when compared with conventional measurements of the humerus.


A systematic review of baseline psychosocial characterisation in dietary randomised controlled trials for weight loss.
To investigate the extent of baseline psychosocial characterisation of subjects in published dietary randomised controlled trials (RCTs) for weight loss. Systematic review of adequately sized (n ≥ 10) RCTs comprising ≥ 1 diet-alone arm for weight loss were included for this systematic review. More specifically, trials included overweight (body mass index >25 kg/m(2)) adults, were of duration ≥ 8 weeks and had body weight as the primary outcome. Exclusion criteria included specific psychological intervention (for example, Cognitive Behaviour Therapy (CBT)), use of web-based tools, use of supplements, liquid diets, replacement meals and very-low calorie diets. Physical activity intervention was restricted to general exercise only (not supervised or prescribed, for example, VO2 maximum level). Of 176 weight-loss RCTs published during 2008-2010, 15 met selection criteria and were assessed for reported psychological characterisation of subjects. All studies reported standard characterisation of clinical and biochemical characteristics of subjects. Eleven studies reported no psychological attributes of subjects (three of these did exclude those taking psychoactive medication). Three studies collected data on particular aspects of psychology related to specific research objectives (figure scale rating, satiety and quality-of-life). Only one study provided a comprehensive background on psychological attributes of subjects. Better characterisation in behaviour-change interventions will reduce potential confounding and enhance generalisability of such studies.


The number of recent sex partners among bisexual men in the United States.
Little is known regarding bisexual men's number of recent sex partners, a risk factor for HIV and other STDs. Furthermore, it is unclear if bisexual men have more partners than heterosexual or homosexual men, and whether partner number varies by measures of sexual behavior, identity and attraction. Sexual orientation-defined separately by sexual behavior during the past year, identity and attraction-was assessed for 3,875 sexually active men aged 15-44 who had participated in the 2002 National Survey of Family Growth. Chi-square and t tests examined differences in background characteristics, behavioral risk factors and number of past-year sex partners by sexual orientation according to each definition. Multivariate ordinary least-squares regression was used to assess predictors of the number of partners. When sexual identity and attraction were controlled for, behaviorally bisexual men were predicted to have had 3.1 more past-year partners than behaviorally heterosexual men and 2.6 more than behaviorally homosexual men. After controlling for sexual identity and behavior, bisexual-attracted men had had 0.7 fewer partners than homosexual-attracted men. In a model including background characteristics and behavioral risk factors, behaviorally bisexual men were predicted to have had 2.5-2.6 more partners than others. Neither bisexual identity nor bisexual attraction independently predicted the number of recent partners. The way in which bisexuality relates to men's number of recent sex partners depends on how sexual orientation is measured. Interventions to reduce behaviorally bisexual men's number of partners will likely lessen their risk for HIV and other STDs.


Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats.
N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that have an important role in long-term potentiation and memory processing in the central nervous system. The aims in this study were to determine whether NMDA receptors are expressed in the peripheral nervous system and identify their role in mediating behavioral pain responses to colonic distention in the normal gut. Immunohistochemical localization of the NR1 subunit showed that NMDA receptors are expressed on the cell bodies and peripheral terminals of primary afferent nerves innervating the colon. Dorsal root ganglia neurons retrogradely labeled from the colon in short-term culture responded to addition of NMDA with increased intracellular [Ca2+]. Activation of peripheral NMDA receptors in colonic tissue sections caused Ca2+-dependent release of the proinflammatory neuropeptides, calcitonin gene-related peptide and substance P. Behavioral pain responses to noxious mechanical stimulation were inhibited in a reversible, dose-dependent manner by intravenous administration of memantine, a noncompetitive antagonist of the NMDA receptor. Single fiber recordings of decentralized pelvic nerves showed that colorectal distention responsive afferent nerve activity was inhibited by memantine. Peripheral NMDA receptors are important in normal visceral pain transmission, and may provide a novel mechanism for development of peripheral sensitization and visceral hyperalgesia.


Effects of guanine nucleotide depletion on cell cycle progression in human T lymphocytes.
Depletion of guanine nucleotide pools after inhibition of inosine monophosphate dehydrogenase (IMPDH) potently inhibits DNA synthesis by arresting cells in G1 and has been shown to induce the differentiation of cultured myeloid and erythroid cell lines, as well as chronic granulocytic leukemic cells after blast transformation. Inhibitors of IMPDH are also highly effective as immunosuppressive agents. The mechanism underlying these pleiotropic effects of depletion of guanine nucleotides is unknown. We have examined the effects of mycophenolic acid (MPA), a potent IMPDH inhibitor, on the cell cycle progression of activated normal human T lymphocytes. MPA treatment resulted in the inhibition of pRb phosphorylation and cell entry into S phase. The expression of cyclin D3, a major component of the cyclin-dependent kinase (CDK) activity required for pRb phosphorylation, was completely abrogated by MPA treatment of T cells activated by interleukin-2 (IL-2) and leucoagglutinin (PHA-L), whereas the expression of cyclin D2, CDK6, and CDK4 was more mildly attenuated. The direct kinase activity of a complex immunoprecipitated with anti-CDK6 antibody was also inhibited. In addition, MPA prevented the IL-2-induced elimination of p27(Kip1), a CDK inhibitor, and resulted in the retention of high levels of p27(Kip1) in IL-2/PHA-L-treated T cells bound to CDK2. These results indicate that inhibition of the de novo synthesis of guanine nucleotides blocks the transition of normal peripheral blood T lymphocytes from G0 to S phase in early- to mid-G1 and that this cell cycle arrest results from inhibition of the induction of cyclin D/CDK6 kinase and the elimination of p27(Kip1) inhibitory activity.


Breathing and oscillating growth of solid-electrolyte-interphase upon electrochemical cycling.
We report the first direct experimental evidence of the dynamic behavior of the solid-electrolyte-interphase (SEI) on copper electrodes upon electrochemical cycling. Synchrotron-based soft X-ray absorption spectroscopy (sXAS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) consistently show that both the chemical composition and the thickness of the SEI change with electrochemical potential throughout the slow formation process. In particular, sXAS results show that the nascent carbonate species in SEI show redox reversibility and decompose during the delithiation (oxidation) process, which leads to a significant shrinking of the SEI thickness as confirmed by TOF-SIMS. Meanwhile, the carbonates also matures and become more and more inactive at every lithiation (reduction) process. These experimental observations reveal unambiguously that SEI formation is much more complicated than a simple and monotonous deposition of electrolyte decomposition product; instead, it could be an oscillating process with a breathing growth.


Targeted deletion of the lens fiber cell-specific intermediate filament protein filensin.
To determine the function of the lens fiber cell-specific cytoskeletal protein, filensin, in lens biology. Targeted genomic deletion was used to delete exon 1 and the transcriptional start site of the filensin gene. Resultant chimeric animals were bred to homozygosity for the mutant allele. These animals were outbred to mice bearing the wild-type CP49 alleles to eliminate the mutant CP49 gene carried by the 129 strain of mice. Animals homozygous for the mutated filensin gene and wild-type CP49 gene were compared with wild-type and heterozygous animals by Northern and Western blot analyses, light and electron microscopy, and slit lamp microscopy. Disruption of the filensin gene successfully blocked production of filensin mRNA, reduced levels of filensin's assembly partner CP49, and prevented the assembly of beaded filaments. Despite the absence of beaded filaments, lenses did not show obvious changes in fetal development, nor in the differentiation of epithelial cells into mature fiber cells, as judged by light microscopic analysis. Filensin knockouts began to show evidence of light-scattering by 2 months and worsened with age. Heterozygous animals exhibited an intermediate phenotype, showing a reduction in filensin transcript and moderate light-scattering at 5 months. The lens fiber cell-specific intermediate filament protein filensin is essential for beaded filament assembly. However, although beaded filaments are not needed for normal lens fetal development or fiber cell differentiation, they appear to be necessary for the long-term maintenance of optical clarity. The mechanism by which the absence of filensin and the beaded filament affects optical clarity has yet to be defined.


Interaction of peptide substrates of fibroblast collagenase with divalent cations: Ca2+ binding by substrate as a suggested recognition signal for collagenase action.
To correlate structural data on substrates of human fibroblast collagenase with their interaction with the enzyme, we have studied: Ac-PLG-s-LLG-O-ethyl ester (I), Dnp-PLGLWA(d-Arg)-NH2 (II), AcGPEGLRVG-O-ethyl ester (III) and Succ-GPLGP-O-amidomethylcoumaryl ester (IV). Peptides I and II represent collagenase cleavage sequences in collagen, peptide III is a mimic for the cleavage site in alpha 2-macroglobulin and peptide IV represents a non-substrate model. Kinetic data showed that peptides I, II and III were substrates of the enzyme. In contrast, peptide IV was not acted upon by the enzyme. Circular dichroism data on the peptides showed that the peptides assume ordered structures in water and trifluoroethanol. In the latter solvent, peptides I and III bound Ca2+ and Zn2+ while peptide II bound Ca2+ but not Zn2+. Peptide IV did not bind either cation in this solvent. Together with the kinetic data, the results suggest that the collagenase cleavage segments in collagen and non-collagen substrates of collagenase could interact with Ca2+ and the enzyme to form a ternary complex. This, in turn, would imply a cofactor role for Ca2+ in collagenase action in addition to the solely structural role ascribed so far to this cation.


JunD/AP-1 Antagonizes the Induction of DAPK1 To Promote the Survival of v-Src-Transformed Cells.
The increase in AP-1 activity is a hallmark of cell transformation by tyrosine kinases. Previously, we reported that blocking AP-1 using the c-Jun dominant negative mutant TAM67 induced senescence, adipogenesis, or apoptosis in v-Src-transformed chicken embryo fibroblasts (CEFs) whereas inhibition of JunD by short hairpin RNA (shRNA) specifically induced apoptosis. To investigate the role of AP-1 in Src-mediated transformation, we undertook a gene profiling study to characterize the transcriptomes of v-Src-transformed CEFs expressing either TAM67 or the JunD shRNA. Our study revealed a cluster of 18 probe sets upregulated exclusively in response to AP-1/JunD impairment and v-Src transformation. Four of these probe sets correspond to genes involved in the interferon pathway. One gene in particular, death-associated protein kinase 1 (DAPK1), is a C/EBPβ-regulated mediator of apoptosis in gamma interferon (IFN-γ)-induced cell death. Here, we show that inhibition of DAPK1 abrogates cell death in v-Src-transformed cells expressing the JunD shRNA. Chromatin immunoprecipitation data indicated that C/EBPβ was recruited to the DAPK1 promoter while the expression of a dominant negative mutant of C/EBPβ abrogated the induction of DAPK1 in response to the inhibition of AP-1. In contrast, as determined by chromatin immunoprecipitation (ChIP) assays, JunD was not detected on the DAPK1 promoter under any conditions, suggesting that JunD promotes survival by indirectly antagonizing the expression of DAPK1 in v-Src transformed cells. Transformation by the v-Src oncoprotein causes extensive changes in gene expression in primary cells such as chicken embryo fibroblasts. These changes, determining the properties of transformed cells, are controlled in part at the transcriptional level. Much attention has been devoted to transcription factors such as AP-1 and NF-κB and the control of genes associated with a more aggressive phenotype. In this report, we describe a novel mechanism of action determined by the JunD component of AP-1, a factor enhancing cell survival in v-Src-transformed cells. We show that the loss of JunD results in the aberrant activation of a genetic program leading to cell death. This program requires the activation of the tumor suppressor death-associated protein kinase 1 (DAPK1). Since DAPK1 is phosphorylated and inhibited by v-Src, these results highlight the importance of this kinase and the multiple mechanisms controlled by v-Src to antagonize the tumor suppressor function of DAPK1.


Further improvement in reducing superficial contamination in NIRS using double short separation measurements.
Near-Infrared Spectroscopy (NIRS) allows the recovery of the evoked hemodynamic response to brain activation. In adult human populations, the NIRS signal is strongly contaminated by systemic interference occurring in the superficial layers of the head. An approach to overcome this difficulty is to use additional NIRS measurements with short optode separations to measure the systemic hemodynamic fluctuations occurring in the superficial layers. These measurements can then be used as regressors in the post-experiment analysis to remove the systemic contamination and isolate the brain signal. In our previous work, we showed that the systemic interference measured in NIRS is heterogeneous across the surface of the scalp. As a consequence, the short separation measurement used in the regression procedure must be located close to the standard NIRS channel from which the evoked hemodynamic response of the brain is to be recovered. Here, we demonstrate that using two short separation measurements, one at the source optode and one at the detector optode, further increases the performance of the short separation regression method compared to using a single short separation measurement. While a single short separation channel produces an average reduction in noise of 33% for HbO, using a short separation channel at both source and detector reduces noise by 59% compared to the standard method using a general linear model (GLM) without short separation. For HbR, noise reduction of 3% is achieved using a single short separation and this number goes to 47% when two short separations are used. Our work emphasizes the importance of integrating short separation measurements both at the source and at the detector optode of the standard channels from which the hemodynamic response is to be recovered. While the implementation of short separation sources presents some difficulties experimentally, the improvement in noise reduction is significant enough to justify the practical challenges.


Does doxorubicin survive thermal ablation? Results of an ex vivo bench top study.
We aimed to test the hypothesis that doxorubicin (DOX) survives thermal ablative heating in an ex vivo model of combined transarterial chemoembolization (TACE) and thermal ablation. Fresh porcine psoas major muscle (3 samples, 15×10×3 cm) was submerged in aqueous DOX solution (60 µg/mL, 0.1 M) for 24 hours to passively saturate tissue. DOX-infused tissue was then dried and treated with microwave ablation (MWA) using a 2.45 GHz antenna at 65 W for 2, 5, and 10 minutes. Ablations were repeated in triplicate (9 total). Tissue was then sampled at both ablated and unablated control sites, and DOX concentration was quantified via ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS), with samples analyzed in triplicate. Tissue DOX levels in ablation and control groups were compared using one-way ANOVA. Homogeneous DOX uptake into porcine tissue was evident in all three samples. Mean DOX concentration in unablated tissue was 8.0±2.2 µg/mL. MWA was technically successful in all 9 procedures (100%), with tissue heating to 95-100°C. Mean tissue DOX concentration showed progressive reduction with increasing ablation time, measuring 6.7±1.3, 4.9±0.9, and 4.8±1.3 µg/mL in MWA-treated tissue after 2, 5, and 10 minutes, respectively. Differences in tissue DOX levels between unablated tissue and MWA groups were statistically significant (P < 0.001). Contrary to the initial hypothesis, tissue DOX concentration progressively decreased after MWA of longer ablation times. These results suggest that TACE followed by ablation may result in lower intratumoral DOX than would otherwise be anticipated for TACE alone.


Spach Transformer: Spatial and Channel-wise Transformer Based on Local and Global Self-attentions for PET Image Denoising.
Position emission tomography (PET) is widely used in clinics and research due to its quantitative merits and high sensitivity, but suffers from low signal-to-noise ratio (SNR). Recently convolutional neural networks (CNNs) have been widely used to improve PET image quality. Though successful and efficient in local feature extraction, CNN cannot capture long-range dependencies well due to its limited receptive field. Global multi-head self-attention (MSA) is a popular approach to capture long-range information. However, the calculation of global MSA for 3D images has high computational costs. In this work, we proposed an efficient spatial and channel-wise encoder-decoder transformer, Spach Transformer, that can leverage spatial and channel information based on local and global MSAs. Experiments based on datasets of different PET tracers, i.e., 18F-FDG, 18F-ACBC, 18F-DCFPyL, and 68Ga-DOTATATE, were conducted to evaluate the proposed framework. Quantitative results show that the proposed Spach Transformer framework outperforms state-of-the-art deep learning architectures.


Pressure stabilizer for reproducible picoinjection in droplet microfluidic systems.
Picoinjection is a promising technique to add reagents into pre-formed emulsion droplets on chip however, it is sensitive to pressure fluctuation, making stable operation of the picoinjector challenging. We present a chip architecture using a simple pressure stabilizer for consistent and highly reproducible picoinjection in multi-step biochemical assays with droplets. Incorporation of the stabilizer immediately upstream of a picoinjector or a combination of injectors greatly reduces pressure fluctuations enabling reproducible and effective picoinjection in systems where the pressure varies actively during operation. We demonstrate the effectiveness of the pressure stabilizer for an integrated platform for on-demand encapsulation of bacterial cells followed by picoinjection of reagents for lysing the encapsulated cells. The pressure stabilizer was also used for picoinjection of multiple displacement amplification (MDA) reagents to achieve genomic DNA amplification of lysed bacterial cells.


A PLSPM-based test statistic for detecting gene-gene co-association in genome-wide association study with case-control design.
For genome-wide association data analysis, two genes in any pathway, two SNPs in the two linked gene regions respectively or in the two linked exons respectively within one gene are often correlated with each other. We therefore proposed the concept of gene-gene co-association, which refers to the effects not only due to the traditional interaction under nearly independent condition but the correlation between two genes. Furthermore, we constructed a novel statistic for detecting gene-gene co-association based on Partial Least Squares Path Modeling (PLSPM). Through simulation, the relationship between traditional interaction and co-association was highlighted under three different types of co-association. Both simulation and real data analysis demonstrated that the proposed PLSPM-based statistic has better performance than single SNP-based logistic model, PCA-based logistic model, and other gene-based methods.


Adamantinoma: metastatic disease masquerading as a gynaecological malignancy.
Adamantinoma is a rare low-grade malignancy of the appendicular skeleton with unclear histogenesis. We present the case of a 65-year-old woman with known recurrent and metastatic right tibial disease despite clear resection margins. On further investigation, a positron emission tomography-CT scan identified a primary breast lesion and an 11 cm mass in the right iliac fossa of suspected ovarian malignancy amenable to surgical resection. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and resection of a retroperitoneal mass arising from the pelvic sidewall encompassing the iliac vasculature. The patient made an uneventful recovery with histology confirming disease metastasising to the pelvis. Currently, clinical management guidelines are not available. We present an overview of adamantinoma and highlight a previously undocumented gynaecological oncology surgical approach to this novel disease location. Regarding metastases, we acknowledge the challenges of investigation pertaining to disease site and origin as well as a paucity of recommendations for surveillance and follow-up.


Continued colonization of the human genome by mitochondrial DNA.
Integration of mitochondrial DNA fragments into nuclear chromosomes (giving rise to nuclear DNA sequences of mitochondrial origin, or NUMTs) is an ongoing process that shapes nuclear genomes. In yeast this process depends on double-strand-break repair. Since NUMTs lack amplification and specific integration mechanisms, they represent the prototype of exogenous insertions in the nucleus. From sequence analysis of the genome of Homo sapiens, followed by sampling humans from different ethnic backgrounds, and chimpanzees, we have identified 27 NUMTs that are specific to humans and must have colonized human chromosomes in the last 4-6 million years. Thus, we measured the fixation rate of NUMTs in the human genome. Six such NUMTs show insertion polymorphism and provide a useful set of DNA markers for human population genetics. We also found that during recent human evolution, Chromosomes 18 and Y have been more susceptible to colonization by NUMTs. Surprisingly, 23 out of 27 human-specific NUMTs are inserted in known or predicted genes, mainly in introns. Some individuals carry a NUMT insertion in a tumor-suppressor gene and in a putative angiogenesis inhibitor. Therefore in humans, but not in yeast, NUMT integrations preferentially target coding or regulatory sequences. This is indeed the case for novel insertions associated with human diseases and those driven by environmental insults. We thus propose a mutagenic phenomenon that may be responsible for a variety of genetic diseases in humans and suggest that genetic or environmental factors that increase the frequency of chromosome breaks provide the impetus for the continued colonization of the human genome by mitochondrial DNA.


Focal DNA copy number changes in neuroblastoma target MYCN regulated genes.
Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17~92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17~92 regulatory network controlling TGFß signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17~92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment.


A Drosophila resource of transgenic RNAi lines for neurogenetics.
Conditional expression of hairpin constructs in Drosophila is a powerful method to disrupt the activity of single genes with a spatial and temporal resolution that is impossible, or exceedingly difficult, using classical genetic methods. We previously described a method (Ni et al. 2008) whereby RNAi constructs are targeted into the genome by the phiC31-mediated integration approach using Vermilion-AttB-Loxp-Intron-UAS-MCS (VALIUM), a vector that contains vermilion as a selectable marker, an attB sequence to allow for phiC31-targeted integration at genomic attP landing sites, two pentamers of UAS, the hsp70 core promoter, a multiple cloning site, and two introns. As the level of gene activity knockdown associated with transgenic RNAi depends on the level of expression of the hairpin constructs, we generated a number of derivatives of our initial vector, called the "VALIUM" series, to improve the efficiency of the method. Here, we report the results from the systematic analysis of these derivatives and characterize VALIUM10 as the most optimal vector of this series. A critical feature of VALIUM10 is the presence of gypsy insulator sequences that boost dramatically the level of knockdown. We document the efficacy of VALIUM as a vector to analyze the phenotype of genes expressed in the nervous system and have generated a library of 2282 constructs targeting 2043 genes that will be particularly useful for studies of the nervous system as they target, in particular, transcription factors, ion channels, and transporters.


mTORC1 and CK2 coordinate ternary and eIF4F complex assembly.
Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation.


Three-year follow-up after presymptomatic testing for Huntington's disease in tested individuals and partners.
The 3-year psychological effects of presymptomatic DNA diagnosis for Huntington's disease are described in 20 identified carriers of the Huntington's disease gene (mean age = 31 years), 29 noncarriers (mean age = 32 years), and 37 partners. The Intrusion and Avoidance subscales of the Impact of Event Scale (M. J. Horowitz, N. Wilner, & W. Alvarez, 1979) and the Beck Hopelessness Scale (A. T. Beck, 1986; A. T. Beck, A. Weissman, D. Lester, & L. Trexler, 1974) measured psychological distress at 4 time points: baseline (before disclosure of test results) and 1 week, 6 months, and 3 years after testing. Multivariate testing on course of distress revealed similar patterns of intrusive thoughts about Huntington's disease over the 3-year follow-up in carriers and noncarriers but showed opposite patterns of avoidance at the 6-month assessment. One week after disclosure, carriers had increased and noncarriers had decreased levels of hopelessness. These effects disappeared after 6 months and did not recur. Carrier partners followed the same course of distress as carriers. Carrier partners with children were significantly more distressed than those without offspring. Noncarrier partners were significantly less distressed than noncarriers after 3 years.


Reliability and validity of a self-efficacy instrument specific to sickle cell disease.
The psychometric properties of a new, 9-item scale measuring disease-specific perceptions of self-efficacy were investigated in a community-based sample of adults (N = 83) with sickle cell disease (SCD). The Sickle Cell Self-Efficacy Scale (SCSES) was comprised of nine questions relating to participants' perceptions of their ability to function on a day-to-day basis and to manage SCD symptomatology (e.g. episodes of pain). The SCSES demonstrated good internal consistency, discriminant validity, and convergent and predictive validity, both with previously validated measures of related constructs as well as with reported SCD symptomatology. Overall, the instrument appears to be reliable and valid for assessing clients' self-efficacy for engaging successfully in day-to-day activities despite having SCD. Future investigators may wish to examine temporal and causal links between alterations in self-efficacy and changes in adjustment to sickle cell disease; the SCSES provides a psychometrically sound tool with which to investigate these phenomena.


Origin and evolution of the RIG-I like RNA helicase gene family.
The DExD/H domain containing RNA helicases such as retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are key cytosolic pattern recognition receptors (PRRs) for detecting nucleotide pathogen associated molecular patterns (PAMPs) of invading viruses. The RIG-I and MDA5 proteins differentially recognise conserved PAMPs in double stranded or single stranded viral RNA molecules, leading to activation of the interferon system in vertebrates. They share three core protein domains including a RNA helicase domain near the C terminus (HELICc), one or more caspase activation and recruitment domains (CARDs) and an ATP dependent DExD/H domain. The RIG-I/MDA5 directed interferon response is negatively regulated by laboratory of genetics and physiology 2 (LGP2) and is believed to be controlled by the mitochondria antiviral signalling protein (MAVS), a CARD containing protein associated with mitochondria. The DExD/H containing RNA helicases including RIG-I, MDA5 and LGP2 were analysed in silico in a wide spectrum of invertebrate and vertebrate genomes. The gene synteny of MDA5 and LGP2 is well conserved among vertebrates whilst conservation of the gene synteny of RIG-I is less apparent. Invertebrate homologues had a closer phylogenetic relationship with the vertebrate RIG-Is than the MDA5/LGP2 molecules, suggesting the RIG-I homologues may have emerged earlier in evolution, possibly prior to the appearance of vertebrates. Our data suggest that the RIG-I like helicases possibly originated from three distinct genes coding for the core domains including the HELICc, CARD and ATP dependent DExD/H domains through gene fusion and gene/domain duplication. Furthermore, presence of domains similar to a prokaryotic DNA restriction enzyme III domain (Res III), and a zinc finger domain of transcription factor (TF) IIS have been detected by bioinformatic analysis. The RIG-I/MDA5 viral surveillance system is conserved in vertebrates. The RIG-I like helicase family appears to have evolved from a common ancestor that originated from genes encoding different core functional domains. Diversification of core functional domains might be fundamental to their functional divergence in terms of recognition of different viral PAMPs.


Enhanced piezoelectric effect at the edges of stepped molybdenum disulfide nanosheets.
The development of piezoelectric layered materials may be one of the key elements enabling expansion of nanotechnology, as they offer a solution for the construction of efficient transducers for a wide range of applications, including self-powered devices. Here, we investigate the piezoelectric effect in multilayer (ML) stepped MoS2 flakes obtained by liquid-phase exfoliation, which is especially interesting because it may allow the scalable fabrication of electronic devices using large area deposition techniques (e.g. solution casting, spray coating, inkjet printing). By using a conductive atomic force microscope we map the piezoelectricity of the MoS2 flakes at the nanoscale. Our experiments demonstrate the presence of electrical current densities above 100 A cm-2 when the flakes are strained in the absence of bias, and the current increases proportional to the bias. Simultaneously collected topographic and current maps demonstrate that the edges of stepped ML MoS2 flakes promote the piezoelectric effect, where the largest currents are observed. Density functional theory calculations are consistent with the ring-like piezoelectric potential generated when the flakes are strained, as well as the enhanced piezoelectric effect at edges. Our results pave the way to the design of piezoelectric devices using layered materials.


Mouse NK cell-mediated rejection of bone marrow allografts exhibits patterns consistent with Ly49 subset licensing.
Natural killer (NK) cells can mediate the rejection of bone marrow allografts and exist as subsets based on expression of inhibitory/activating receptors that can bind MHC. In vitro data have shown that NK subsets bearing Ly49 receptors for self-MHC class I have intrinsically higher effector function, supporting the hypothesis that NK cells undergo a host MHC-dependent functional education. These subsets also play a role in bone marrow cell (BMC) allograft rejection. Thus far, little in vivo evidence for this preferential licensing across mouse strains with different MHC haplotypes has been shown. We assessed the intrinsic response potential of the different Ly49(+) subsets in BMC rejection by using β2-microglobulin deficient (β2m(-/-)) mice as donors. Using congenic and allogeneic mice as recipients and depleting the different Ly49 subsets, we found that NK subsets bearing Ly49s, which bind "self-MHC" were found to be the dominant subset responsible for β2m(-/-) BMC rejection. This provides in vivo evidence for host MHC class I-dependent functional education. Interestingly, all H2(d) strain mice regardless of background were able to resist significantly greater amounts of β2m(-/-), but not wild-type BMC than H2(b) mice, providing evidence that the rheostat hypothesis regarding Ly49 affinities for MHC and NK-cell function impacts BMC rejection capability.


Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy.
Metronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynamic mathematical model that identifies in silico the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5-1 mg/kg gemcitabine as an optimal protocol to maximize antitumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation in vivo, while standard gemcitabine did not. Furthermore, metronomic gemcitabine yielded a 40%-50% decrease in tumor mass at the end of treatment as compared with control mice (P = 0.002; ANOVA on ranks with Dunn test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67%-72% reduction in tumor growth at study conclusion, P < 0.001; ANOVA on ranks with Dunn test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors in vivoCancer Res; 77(17); 4723-33. ©2017 AACR.


Vibration analysis of logs with electronic speckle pattern interferometry.
Electronic speckle pattern interferometry combined with phase-shifting techniques for vibration analysis of logs is presented. Changes in the vibration pattern were followed on a television monitor at the video rate. We determined resonant vibrations by scanning through the frequency range of interest and by changing the point of excitation. We observed bending and torsional modes of vibration by changing the support and point of excitation. The vibrational modes reflect the structural properties of the material. The longitudinal modulus of elasticity and the shear modulus were calculated, giving valuable information for the strength grading of logs.


Estimating end-use emissions factors for policy analysis: the case of space cooling and heating.
This paper provides the first estimates of end-use specific emissions factors, which are estimates of the amount of a pollutant that is emitted when a unit of electricity is generated to meet demand from a specific end-use. In particular, this paper provides estimates of emissions factors for space cooling and heating, which are two of the most significant end-uses. The analysis is based on a novel two-stage regression framework that estimates emissions factors that are specific to cooling or heating by exploiting variation in cooling and heating demand induced by weather variation. Heating is associated with similar or greater CO2 emissions factor than cooling in all regions. The difference is greatest in the Midwest and Northeast, where the estimated CO2 emissions factor for heating is more than 20% larger than the emissions factor for cooling. The minor differences in emissions factors in other regions, combined with the substantial difference in the demand pattern for cooling and heating, suggests that the use of overall regional emissions factors is reasonable for policy evaluations in certain locations. Accurately quantifying the emissions factors associated with different end-uses across regions will aid in designing improved energy and environmental policies.


What do computer scientists tweet? Analyzing the link-sharing practice on Twitter.
Twitter communication has permeated every sphere of society. To highlight and share small pieces of information with possibly vast audiences or small circles of the interested has some value in almost any aspect of social life. But what is the value exactly for a scientific field? We perform a comprehensive study of computer scientists using Twitter and their tweeting behavior concerning the sharing of web links. Discerning the domains, hosts and individual web pages being tweeted and the differences between computer scientists and a Twitter sample enables us to look in depth at the Twitter-based information sharing practices of a scientific community. Additionally, we aim at providing a deeper understanding of the role and impact of altmetrics in computer science and give a glance at the publications mentioned on Twitter that are most relevant for the computer science community. Our results show a link sharing culture that concentrates more heavily on public and professional quality information than the Twitter sample does. The results also show a broad variety in linked sources and especially in linked publications with some publications clearly related to community-specific interests of computer scientists, while others with a strong relation to attention mechanisms in social media. This refers to the observation that Twitter is a hybrid form of social media between an information service and a social network service. Overall the computer scientists' style of usage seems to be more on the information-oriented side and to some degree also on professional usage. Therefore, altmetrics are of considerable use in analyzing computer science.


Molecular Cloning and Ethylene Induction of mRNA Encoding a Phytoalexin Elicitor-Releasing Factor, beta-1,3-Endoglucanase, in Soybean.
Soybean (Glycine max) beta-1,3-endoglucanase (EC 3.2. 1.39) is involved in one of the earliest plant-pathogen interactions that may lead to active disease resistance by releasing elicitor-active carbohydrates from the cell walls of fungal pathogens. Ethylene induced beta-1,3-endoglucanase activity to 2- to 3-fold higher levels in cotyledons of soybean seedlings. A specific polyclonal antiserum raised against purified soybean beta-1,3-endoglucanase was used to immunoprecipitate in vitro translation products, demonstrating that ethylene induction increased translatable beta-1,3-endoglucanase mRNA. Several cDNA clones for the endoglucanase gene were obtained by antibody screening of a lambda-gt11 expression library prepared from soybean cotyledons. Hybrid-select translation experiments indicated that the cloned cDNA encoded a 36-kilodalton precursor protein product that was specifically immunoprecipitated with beta-1,3-endoglucanase antiserum. Escherichia coli cells expressing the cloned cDNA also synthesized an immunologically positive protein. Nucleotide sequence of three independent clones revealed a single uninterrupted open reading frame of 1041 nucleotides, corresponding to a polypeptide of 347 residue long. The primary amino acid sequence of beta-1,3-endoglucanase as deduced from the nucleotide sequence was confirmed by direct amino acid sequencing of trypsin digests of the glucanase. The soybean beta-1,3-endoglucanase exhibited 53% amino acid homology to a beta-1,3-glucanase cloned from cultured tobacco cells and 48% homology to a beta-(1,3-1,4)-glucanase from barley. Utilizing the largest cloned cDNA (pEG488) as a hybridization probe, it was found that the increase in translatable beta-1,3-endoglucanase mRNA seen upon ethylene treatment of soybean seedlings was due to 50- to 100-fold increase in steady state mRNA levels, indicating that ethylene regulates gene expression of this enzyme important in disease resistance at the level of gene transcription.


The Canadian Trial of Carbohydrates in Diabetes (CCD), a 1-y controlled trial of low-glycemic-index dietary carbohydrate in type 2 diabetes: no effect on glycated hemoglobin but reduction in C-reactive protein.
The optimal source and amount of dietary carbohydrate for managing type 2 diabetes (T2DM) are unknown. We aimed to compare the effects of altering the glycemic index or the amount of carbohydrate on glycated hemoglobin (HbA1c), plasma glucose, lipids, and C-reactive protein (CRP) in T2DM patients. Subjects with T2DM managed by diet alone (n=162) were randomly assigned to receive high-carbohydrate, high-glycemic-index (high-GI), high-carbohydrate, low-glycemic-index (low-GI), or low-carbohydrate, high-monounsaturated-fat (low-CHO) diets for 1 y. The high-GI, low-GI, and low-CHO diets contained, respectively, 47%, 52%, and 39% of energy as carbohydrate and 31%, 27%, and 40% of energy as fat; they had GIs of 63, 55, and 59, respectively. Body weight and HbA1c did not differ significantly between diets. Fasting glucose was higher (P=0.041), but 2-h postload glucose was lower (P=0.010) after 12 mo of the low-GI diet. With the low-GI diet, overall mean triacylglycerol was 12% higher and HDL cholesterol 4% lower than with the low-CHO diet (P<0.05), but the difference in the ratio of total to HDL cholesterol disappeared by 6 mo (time x diet interaction, P=0.044). Overall mean CRP with the low-GI diet, 1.95 mg/L, was 30% less than that with the high-GI diet, 2.75 mg/L (P=0.0078); the concentration with the low-CHO diet, 2.35 mg/L, was intermediate. In subjects with T2DM managed by diet alone with optimal glycemic control, long-term HbA1c was not affected by altering the GI or the amount of dietary carbohydrate. Differences in total:HDL cholesterol among diets had disappeared by 6 mo. However, because of sustained reductions in postprandial glucose and CRP, a low-GI diet may be preferred for the dietary management of T2DM.


Subclinical Changes in Deceased Donor Kidney Proteomes Are Associated With 12-month Allograft Function Posttransplantation-A Preliminary Study.
Cerebral injury during donation after brain death may induce systemic damage affecting long-term kidney function posttransplantation. Conventional evaluation of donor organ quality as a triage for transplantation is of limited utility. We compared donor kidneys yielding opposing extremes of the continuum of posttransplantation outcomes by several common kidney biopsy evaluation techniques, including Kidney Donor Profile Index and Remuzzi scoring, and analyzed tissue from a minimal sample cohort using label-free quantitation mass spectrometry. Further assessment of the proteomic results was performed by orthogonal quantitative comparisons of selected key proteins by immunoblotting. We show that common evaluation techniques of kidney biopsies were not predictive for posttransplantation outcomes. In contrast, despite the limited cohort size, the proteomic analysis was able to clearly differentiate between kidneys yielding extreme posttransplantation outcome differences. Pathway analysis of the proteomic data suggested that outcome-related variance in protein abundance associated with profibrotic, apoptosis, and antioxidant proteins. Immunoblotting confirmation further supported this observation. We present preliminary data indicating that there is scope for existing evaluation approaches to be supplemented by the analysis of proteomic differences. Furthermore, the observed outcome-related variance in a limited cohort was supported by immunoblotting and is consistent with mechanisms previously implicated in the development of injury and cytoprotection in kidney transplantation.


Adolescent sexual offenders: a total survey of referrals to Social Services in Sweden and subgroup characteristics.
Sampling methodology (e.g. population-based vs. clinical samples, anonymous self-reports vs. data collected as part of mandated treatment) affects the validity of conclusions drawn from research addressing the etiology of adolescent sexual offending. Studies of unselected samples allow testing of the generalizability of etiological models suggested from investigation of selected clinical or forensic populations. Further, representative epidemiological data on adolescent sexual offending is needed for policy-making and the planning of services. We conducted a national survey of all adolescent sexual offenders (ASOs, 12-17 years) referred to Social Services during 2000. Social workers at all child and adolescent units in Social Service authorities throughout Sweden (N=285, 99% response rate) completed a questionnaire about new ASO referrals in 2000. The National Board of Health and Welfare commissioned the survey and questionnaire items tapped offender, offence, and victim characteristics. A total of 197 boys and 2 girls aged 12-17 years were referred to Social Services because of sexually abusive behavior in 2000. Focusing specifically on males, this yielded a one-year incidence of .060% (95% confidence interval = .052-.068). Forty-six percent of male ASOs abused at least one child younger than age 12 years (child offenders) whereas the rest had abused peer or adult victims (peer offenders). Forty-two percent of male ASOs had ever committed sexual offences together with at least one other offender (group offenders). Child- vs. peer offenders and group vs. single offenders, suggested typologies in the literature, were compared to explore potential subtype-specific risk factors and correlates. The results suggested a higher proportion of group ASOs than previously reported and stronger support for subdividing ASOs into child vs. peer offenders than into group vs. single ASOs.


Expression of extracellular matrix metalloproteinase inducer and matrix metalloproteinase-2 and -9 in horses with chronic airway inflammation.
OBJECTIVE To examine whether expression of extracellular matrix metalloproteinase inducer (EMMPRIN) can be detected in equine lungs and whether it correlates with matrix metalloproteinase (MMP)-2 and -9 expression in bronchoalveolar lavage fluid (BALF) of horses with chronic inflammation of the lungs (ie, lower airway inflammation [LAI]). ANIMALS 29 horses with signs of chronic respiratory tract disease, which were classified as the LAI (n = 17) and LAI with respiratory distress (RDLAI [12]) groups, and 15 control horses. PROCEDURES BALF, tracheal aspirate, and blood samples were obtained, and EMMPRIN expression was determined from BALF cells and RBCs by use of western blotting. Activities of MMP-2 and -9 were determined with zymography. RESULTS Expression of EMMPRIN protein was identified in BALF cells of all horses. Expression of EMMPRIN protein was highest for the RDLAI group and was correlated with MMP-2 and -9 protein expression, MMP-9 gelatinolytic activity, and airway neutrophilia. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that EMMPRIN was involved in the pathophysiologic processes of asthma in horses. However, additional studies of horses and other species are warranted to elucidate the regulation of EMMPRIN expression in asthmatic lungs.


Pseudoautosomal Region 1 Overdosage Affects the Global Transcriptome in iPSCs From Patients With Klinefelter Syndrome and High-Grade X Chromosome Aneuploidies.
Klinefelter syndrome (KS) is the most prevalent aneuploidy in males and is characterized by a 47,XXY karyotype. Less frequently, higher grade sex chromosome aneuploidies (HGAs) can also occur. Here, using a paradigmatic cohort of KS and HGA induced pluripotent stem cells (iPSCs) carrying 49,XXXXY, 48,XXXY, and 47,XXY karyotypes, we identified the genes within the pseudoautosomal region 1 (PAR1) as the most susceptible to dosage-dependent transcriptional dysregulation and therefore potentially responsible for the progressively worsening phenotype in higher grade X aneuploidies. By contrast, the biallelically expressed non-PAR escape genes displayed high interclonal and interpatient variability in iPSCs and differentiated derivatives, suggesting that these genes could be associated with variable KS traits. By interrogating KS and HGA iPSCs at the single-cell resolution we showed that PAR1 and non-PAR escape genes are not only resilient to the X-inactive specific transcript (XIST)-mediated inactivation but also that their transcriptional regulation is disjointed from the absolute XIST expression level. Finally, we explored the transcriptional effects of X chromosome overdosage on autosomes and identified the nuclear respiratory factor 1 (NRF1) as a key regulator of the zinc finger protein X-linked (ZFX). Our study provides the first evidence of an X-dosage-sensitive autosomal transcription factor regulating an X-linked gene in low- and high-grade X aneuploidies.


Elliptic flow in Au+Au collisions at square root(S)NN = 130 GeV.
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at square root(S)NN = 130 GeV using the STAR Time Projection Chamber at the Relativistic Heavy Ion Collider. The elliptic flow signal, v2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.


Breast-conservative surgery with and without radiotherapy in patients aged 55-75 years with early-stage breast cancer: a prospective, randomized, multicenter trial analysis after 108 months of median follow-up.
Breast-conserving therapy (BCT), including postoperative whole breast irradiation (WBI), is generally accepted as the treatment of choice for most patients with early-stage breast cancer. The question whether WBI is mandatory in all patients remains one of the most controversial issues in BCT. To answer this question, a randomized, prospective, multicentre study was launched in January 2001. Primary endpoints of the study were to assess the cumulative incidence of in-breast-recurrences (IBR) and overall survival (OAS) after conservative surgery (BCS) with or without WBI. From January 2001 until December 2005, 749 patients with unifocal infiltrating breast cancer up to 25 mm, 0-3 positive axillary lymph nodes, no extensive intraductal component or lymphvascular invasion from 11 centres in Italy, were randomly assigned to BCS+WBI (arm 1:373 patients) or BCS alone (arm 2:376 patients). Treatment arms were well balanced in terms of baseline characteristics. Systemic adjuvant therapy was administered according to the institutional policies. Kaplan-Meier method was used for survival analysis and log-rank test to evaluate the difference between the two arms. RESULTS (Last analysis 31.12.2012): After median follow-up of 108 months, 12 (3.4%) IBR were observed in arm 1 and 16 (4.4%) in arm 2. OAS was 81.4% in arm 1 and 83.7% in arm 2. There was no statistically significant difference regarding IBR and death in the two treatment groups. These data are promising and suggest that WBI after BCS can be omitted in selected patients with early stage breast cancer without exposing them to an increased risk of local recurrence and death. Longer follow-up is needed to further consolidate these results.


Gene interaction at HLA-DQ enhances autoantibody production in primary Sjögren's syndrome.
Primary Sjögren's syndrome is an autoimmune disorder characterized by dryness of the mouth and eyes. The human leukocyte antigen (HLA) locus DQ is related to the primary Sjögren's syndrome autoantibodies that bind the RNA proteins Ro/SSA and La/SSB. Both DQ1 and DQ2 alleles are associated with high concentrations of these autoantibodies. An analysis of all possible combinations at DQ has shown that the entire effect was due to heterozygotes expressing the DQ1 and DQ2 alleles. These data suggest that gene interaction between DQ1 and DQ2 (or alleles at associated loci), possibly from gene complementation of trans-associated surface molecules, influences the autoimmune response in primary Sjögren's syndrome.


[Diagnostic value of electroencephalography and evoked potentials in monitoring brain maturation in children with febrile convulsions].
A group of 31 children aged 4-14 was presented with clinical manifestations of febrile convulsions, which after clinical examination, were followed--up in outpatient clinics during 1-12 year period. Together with continuous electroencephalographic monitoring, visual and somatosensory potentials were measured with the aim to stress a diagnostic significance of these neurophysiological methods for cerebral maturation assessment in children with febrile convulsions. Results reveal that electroencephalography (EEG) and somatosensory potentials (SEP) have higher diagnostic sensitivity compared to the visual ones (VEP). In 25 children (80.64%) SEP changes were registered in the form of prolonged central conductivity time (CCT) and EEG revealed changes in the form of slower cerebral activity and posterior theta activities fr. 4-7 Hz (P-O bilaterally) in 10 children (32.26%). Registered SEP changes, particularly prolonged CVP, as well as changes in the form of slower basic cerebral activity or posterior theta rhythm could be explained by slower maturation of some CNS regions. EEG and SEP findings show positive correlation with clinical findings and different diagnostic sensitivity, therefore their use in clinical follow-up of children with febrile convulsions is important.


Asthma during Pregnancy: Exacerbations, Management, and Health Outcomes for Mother and Infant.
One in 10 pregnant women worldwide has asthma and of these, 10% will have a severe exacerbation requiring oral corticosteroids (OCSs) in pregnancy. This review of recent publications in the field will describe the effects of exacerbation on maternal and neonatal health, the use of asthma medications during pregnancy, and will suggest novel management approaches for asthma in pregnancy. Pregnancy results in unpredictable changes in the disease; therefore, regular monitoring of symptoms is recommended. Uncontrolled asthma is frequently described in cohorts of pregnant women with asthma, and some recent studies show associations with adverse perinatal outcomes, as previously demonstrated with exacerbations. Guidelines for the management of asthma recommend the continued use of inhaled corticosteroids (ICSs) in pregnancy, with budesonide having a particularly good safety profile. Recent data suggest small effects of asthma and/or asthma medication use on congenital malformations; however, there is less data available on the safety of ICS/long-acting β agonist combinations, which are increasingly used for maintenance treatment. Novel management strategies are needed to address the complex needs of pregnant women with asthma. These include medication nonadherence and the presence of numerous comorbidities which can affect asthma, such as rhinitis, cigarette smoking, obesity, and mental health issues. Inflammation-based management has been shown to be effective in reducing exacerbations in pregnancy and may also improve perinatal outcomes. The involvement of a multidisciplinary team and the assessment of comorbidities have potential to improve the health of mothers and their offspring.


Efficacy of exposure-based cognitive behaviour therapy for post-traumatic stress disorder in emergency service personnel: a randomised clinical trial.
Although emergency service personnel experience markedly elevated the rates of post-traumatic stress disorder (PTSD), there are no rigorously conducted trials for PTSD in this population. This study assessed the efficacy of cognitive behaviour therapy (CBT) for PTSD in emergency service personnel, and examined if brief exposure (CBT-B) to trauma memories is no less efficacious as prolonged exposure (CBT-L). One hundred emergency service personnel with PTSD were randomised to either immediate CBT-L, CBT-B or wait-list (WL). Following post-treatment assessment, WL participants were randomised to an active treatment. Participants randomised to CBT-L or CBT-B were assessed at baseline, post-treatment and at 6-month follow-up. Both CBT conditions involved 12 weekly individual sessions comprising education, CBT skills building, imaginal exposure, in vivo exposure, cognitive restructuring and relapse prevention. Imaginal exposure occurred for 40 min per session in CBT-L and for 10 min in CBT-B. At post-treatment, participants in WL had smaller reductions in PTSD severity (Clinician Administered PTSD Scale), depression, maladaptive appraisals about oneself and the world, and smaller improvements on psychological and social quality of life than CBT-L and CBT-B. There were no differences between CBT-L and CBT-B at follow-up on primary or secondary outcome measures but both CBT-L and CBT-B had large baseline to follow-up effect sizes for reduction of PTSD symptoms. This study highlights that CBT, which can include either long or brief imaginal exposure, is efficacious in reducing PTSD in emergency service personnel.


Effects of reward on spatial working memory in schizophrenia.
Reward processing and cognition are disrupted in schizophrenia (SCZ), yet how these processes interface is unknown. In SCZ, deficits in reward representation may affect motivated, goal-directed behaviors. To test this, we examined the effects of monetary reward on spatial working memory (WM) performance in patients with SCZ. To capture complimentary effects, we tested biophysically grounded computational models of neuropharmacologic manipulations onto a canonical fronto-parietal association cortical microcircuit capable of WM computations. Patients with SCZ (n = 33) and healthy control subjects (HCS; n = 32) performed a spatial WM task with 2 reward manipulations: reward cues presented prior to each trial, or contextually prior to a block of trials. WM performance was compared with cortical circuit models of WM subjected to feed-forward glutamatergic excitation, feed-forward GABAergic inhibition, or recurrent modulation strengthening local connections. Results demonstrated that both groups improved WM performance to reward cues presented prior to each trial (HCS d = -0.62; SCZ d = -1.0), with percent improvement correlating with baseline WM performance (r = .472, p < .001). However, rewards presented contextually before a block of trials did not improve WM performance in patients with SCZ (d = 0.01). Modeling simulations achieved improved WM precision through strengthened local connections via neuromodulation, or feed-forward inhibition. Taken together, this work demonstrates that patients with SCZ can improve WM performance to short-term, but not longer-term rewards-thus, motivated behaviors may be limited by strength of reward representation. A potential mechanism for transiently improved WM performance may be strengthening of local fronto-parietal microcircuit connections via neuromodulation or feed-forward inhibitory drive. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Bovine milk fatty acid profiles produced by feeding diets containing solin, flax and canola.
Fatty acid profiles with emphasis on linoleic, linolenic, oleic, and conjugated linoleic acid (CLA) were compared in milk from dairy cows fed diets containing 3.25% supplemental fat and a control diet containing no supplemented fat. The fat was supplied by either whole ground solin, flax, or canola oilseed. Solin (linola) is a new cultivar of flax that contains 28% linoleic acid in the seed, Twelve multiparous Holstein cows were assigned to one of four dietary treatments. The experimental design was a 4 x 4 Latin square with each period consisting of 16 d for adjustment to the diet followed by a 5-d sampling period. Feed intake, milk yield, milk fat yield, and milk fat percentage were not affected by treatment. Adding solin, flax, or canola oilseed to lactation diets produced the highest proportions of linoleic (C18:2), linolenic (C18:3), and oleic (C18:1) acids, respectively, in the lipid fraction of the milk of the cows consuming these diets. The proportions of C6:0 to C16:1 were depressed in the milk fat of cows fed the oilseed diets, compared with the control diet. Increasing the lactation diet levels of C18:2, by using different oilseeds, increased CLA to 1.5% of milk fatty acids. The content of CLA in milk fatty acids, however, did not increase with the solin-supplemented diet compared with the canola-supplemented diet even though the C18:2 level was higher in the former diet.


Enhanced T2 contrast for MR histology of the mouse brain.
A 3D Carr-Purcell-Meiboom-Gill (CPMG) sequence was implemented to obtain enhanced T(2) contrast in actively stained (perfusion with fixative and contrast agent) mouse brains at 9.4 T. Short interecho spacing was used to minimize diffusion and susceptibility losses. The sequence produced 16 3D volumes with an interecho spacing of 7 ms for isotropic 43-mu-resolution images of the mouse brains in a scan time of 4 hr. To enhance the signal-to-noise ratio (SNR) and contrast, the multiecho frequency domain image contrast (MEFIC) method was applied, resulting in a composite image with T(2)-weighted contrast. The high SNR and contrast thus achieved revealed aspects of mouse brain morphology, such as multiple cortical layers, groups of thalamic nuclei, layers of the inferior and superior colliculus, and molecular and granular layers of the cerebellum, with a high degree of definition and contrast that was not previously achieved in T(2)-weighted acquisitions at high fields.


Aging promotes progression of IgA nephropathy: a systematic review and meta-analysis.
There has been considerable interest in whether old age is associated with IgA nephropathy (IgAN) progression, which is still controversial. We searched multiple databases for studies published from 1980 to 2012. The inclusion criteria were case-control, cohort studies published in any language. The included studies needed to have an older group. IgAN was proven by biopsy. We included 9 studies with a total of 6,543 patients. The meta-analyses of other risk factors between the older group (>50 years old) and the non-older group (15-50 years old) found significant differences in the presence of hypertension, proteinuria, serum cholesterol levels and baseline renal function. In the overall analysis, compared to the non-older group, older age significantly increased the incidence of developing end-stage renal disease [ESRD; relative risk (RR) random model 1.95; 95% CI: 1.27-3.01]. In the subgroup analyses, we found the age limit and traditional risk factors of IgAN may be the sources of heterogeneity between studies. Moreover, the RR (2.56) of the Asian countries was much higher than the RR (1.11) of the European countries. This comprehensive review revealed that old age is a real risk factor for IgAN progression to ESRD. The incidence of ESRD in the older IgAN patients was 1.95 times higher than that in the non-older IgAN patients. Moreover, the risk of IgAN progression to ESRD of the older patients in Asia was higher than that of the older patients in Europe.


MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb.
MiR-150 is a microRNA (miRNA) specifically expressed in mature lymphocytes, but not their progenitors. A top predicted target of miR-150 is c-Myb, a transcription factor controlling multiple steps of lymphocyte development. Combining loss- and gain-of-function gene targeting approaches for miR-150 with conditional and partial ablation of c-Myb, we show that miR-150 indeed controls c-Myb expression in vivo in a dose-dependent manner over a narrow range of miRNA and c-Myb concentrations and that this dramatically affects lymphocyte development and response. Our results identify a key transcription factor as a critical target of a stage-specifically expressed miRNA in lymphocytes and suggest that this and perhaps other miRNAs have evolved to control the expression of just a few critical target proteins in particular cellular contexts.


Is fast food addictive?
Studies of food addiction have focused on highly palatable foods. While fast food falls squarely into that category, it has several other attributes that may increase its salience. This review examines whether the nutrients present in fast food, the characteristics of fast food consumers or the presentation and packaging of fast food may encourage substance dependence, as defined by the American Psychiatric Association. The majority of fast food meals are accompanied by a soda, which increases the sugar content 10-fold. Sugar addiction, including tolerance and withdrawal, has been demonstrated in rodents but not humans. Caffeine is a "model" substance of dependence; coffee drinks are driving the recent increase in fast food sales. Limited evidence suggests that the high fat and salt content of fast food may increase addictive potential. Fast food restaurants cluster in poorer neighborhoods and obese adults eat more fast food than those who are normal weight. Obesity is characterized by resistance to insulin, leptin and other hormonal signals that would normally control appetite and limit reward. Neuroimaging studies in obese subjects provide evidence of altered reward and tolerance. Once obese, many individuals meet criteria for psychological dependence. Stress and dieting may sensitize an individual to reward. Finally, fast food advertisements, restaurants and menus all provide environmental cues that may trigger addictive overeating. While the concept of fast food addiction remains to be proven, these findings support the role of fast food as a potentially addictive substance that is most likely to create dependence in vulnerable populations.


Doppler haemodynamics of cerebral venous return.
Physiologic functioning of the cerebrovenous system is indispensable for maintaining normal brain function. However, in contrast to the cerebroarterial system, the cerebral venous return is not routinely investigated. Combined high-resolution echo-colour-Doppler (ECD) and transcranial colour coded Doppler sonography (TCCS) represents an ideal method to investigate the haemodynamics of cerebral venous return. TCCS-ECD is noninvasive, repeatable, cost-effective and permits to investigate the cerebral venous outflow in its dependence upon changes in posture and the alternating pressure gradients of the thoracic pump. Several authors reported normal parameters concerning related aspects of cerebral venous return. However, there is no ECD-TCCS standardization of what can be considered a normal venous return. The authors have summarized the current knowledge of the Doppler haemodynamics of the cerebrovenous system and propose a list of reproducible clinical parameters for its sonographic evaluation. In future, the development of this diagnostic technique could be of singular interest in iron-related inflammatory and neurodegenerative disorders like multiple sclerosis.


Self-care and anticipated transition into retirement and later life in a Nordic welfare context.
Few studies have appeared in the health care literature on the meaning of transition into retirement and later life. However, this predictable-involuntary transition may influence personal health and well-being, and studying it from a self-care perspective could be useful. The aim of this study was to illuminate aspects of self-care in a group of middle-aged individuals in relation to their anticipated transition into retirement in the Nordic welfare context. A total of 13 individuals, aged 55 to 65 years, were randomly chosen from the total number of inhabitants in three municipalities in mid-west Sweden. Conversational interviews took place, during which the informants shared important events in their lives that had occurred from early childhood until the present time, together with thoughts about their anticipated future developmental transition into later life. The interviews were tape recorded and transcribed verbatim. After content analyses and interpretation, a comprehensive picture of the phenomenon was revealed. The results showed that there were opportunities, expectations, wishes, concerns, and worries related to the transition into retirement and old age among informants from both rural and urban municipalities. Self-care, in connection with this, depended on motivating and demotivating factors. Autonomy and mature dependence seemed to be positive driving forces for reaching a successful transition into later life. Supporting autonomy should be a way of facilitating the transition into retirement and later life.


AGA Clinical Practice Update: Coagulation in Cirrhosis.
This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The intent is to evaluate the current data on mechanism of altered coagulation in patients with cirrhosis, provide guidance on the use of currently available testing of the coagulation cascade, and help practitioners use anticoagulation and pro-coagulants appropriately in patients with cirrhosis. This review is framed around the best practice points, which were derived from the most impactful publications in the area of coagulation in cirrhosis and agreed to by all authors. BEST PRACTICE ADVICE 1: Global tests of clot formation, such as rotational thromboelastometry, thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels. BEST PRACTICE ADVICE 2: In general, clinicians should not routinely correct thrombocytopenia and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation in patients with hepatic synthetic dysfunction-induced coagulation abnormalities. BEST PRACTICE ADVICE 3: Blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunization, and/or transfusion reactions. BEST PRACTICE ADVICE 4: The following transfusion thresholds for management of active bleeding or high-risk procedures may optimize clot formation in advanced liver disease: hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized thresholds for international normalized ratio correction are not supported by evidence. BEST PRACTICE ADVICE 5: Thrombopoietin agonists are a good alternative to platelet transfusion, but require time (about 10 days) to elevate platelet levels. BEST PRACTICE ADVICE 6: The large volume of fresh frozen plasma required to reach an arbitrary international normalized ratio target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the utility of this agent significantly. BEST PRACTICE ADVICE 7: The 4-factor prothrombin complex concentrate contains both pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance a disturbed hemostatic system. However, dosage is, in part, based on international normalized ratio, which is problematic in cirrhosis, and published experience in liver disease is limited. BEST PRACTICE ADVICE 8: Anti-fibrinolytic therapy may be considered in patients with persistent bleeding from mucosal oozing or puncture wound bleeding consistent with impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot dissolution. Neither is believed to generate a hypercoagulable state, although both may exacerbate pre-existing thrombi. BEST PRACTICE ADVICE 9: Desmopressin releases von Willebrand factor as its primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the agent lacks a sound evidence-based foundation, but may be useful in patients with concomitant renal failure. BEST PRACTICE ADVICE 10: Systemic heparin infusion is recommended for symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but there are unresolved issues regarding monitoring with both the anti-Xa assay and the partial thromboplastin time due to cirrhosis-related antithrombin deficiency (heparin cofactor). BEST PRACTICE ADVICE 11: Treatment of incidental portal and mesenteric vein thrombosis depends on estimated impact on transplantation surgical complexity vs risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K antagonists, and direct-acting anticoagulants improve portal vein repermeation vs observation alone. BEST PRACTICE ADVICE 12: Direct-acting anticoagulants, such as the factor Xa and thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but are in need of further study in patients with more advanced liver disease.


Obesity and the potential reduction of social inequalities in mortality: evidence from 21 European populations.
Obesity contributes considerably to the problem of health inequalities in many countries, but quantitative estimates of this contribution and to what extent it is modifiable are scarce. We identify the potential for reducing educational inequalities in all-cause and obesity-related mortality in 21 European populations, by modifying educational differences in obesity and overweight. Prevalence data and mortality data come from 21 European populations. Mortality rate ratios come from literature reviews. We use the population attributable fraction (PAF) to estimate the impact of scenario-based changes in the social distribution of obesity on educational inequalities in mortality. An elimination of differences in obesity between educational groups would decrease relative inequality in all-cause mortality between those with high and low education by up to 12% for men and 42% for women. About half of the relative inequality in mortality could be reduced for some causes of death in several countries, often in southern Europe. Absolute inequalities in all-cause mortality would be reduced by up to 69 (men) and 67 (women) deaths per 100,000 person-years. The potential reduction of health inequality by an elimination of social inequalities in obesity might be substantial. The reductions differ by country, cause of death and gender, suggesting that the priority given to obesity as an entry-point for tackling health inequalities should differ between countries and gender.


Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis.
TGF-β regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-β is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-O-sulfotransferase 2 (HS6ST2) as a critical gene for TGF-β-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-β-induced IL-11 production in MDA-MB-231(SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231(SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin-like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-β induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts.


Dynamics of hollow atom formation in intense x-ray pulses probed by partial covariance mapping.
When exposed to ultraintense x-radiation sources such as free electron lasers (FELs) the innermost electronic shell can efficiently be emptied, creating a transient hollow atom or molecule. Understanding the femtosecond dynamics of such systems is fundamental to achieving atomic resolution in flash diffraction imaging of noncrystallized complex biological samples. We demonstrate the capacity of a correlation method called "partial covariance mapping" to probe the electron dynamics of neon atoms exposed to intense 8 fs pulses of 1062 eV photons. A complete picture of ionization processes competing in hollow atom formation and decay is visualized with unprecedented ease and the map reveals hitherto unobserved nonlinear sequences of photoionization and Auger events. The technique is particularly well suited to the high counting rate inherent in FEL experiments.


A molecule-like PtAu24(SC6H13)18 nanocluster as an electrocatalyst for hydrogen production.
The theoretically predicted volcano plot for hydrogen production shows the best catalyst as the one that ensures that the hydrogen binding step is thermodynamically neutral. However, the experimental realization of this concept has suffered from the inherent surface heterogeneity of solid catalysts. It is even more challenging for molecular catalysts because of their complex chemical environment. Here, we report that the thermoneutral catalyst can be prepared by simple doping of a platinum atom into a molecule-like gold nanocluster. The catalytic activity of the resulting bimetallic nanocluster, PtAu24(SC6H13)18, for the hydrogen production is found to be significantly higher than reported catalysts. It is even better than the benchmarking platinum catalyst. The molecule-like bimetallic nanocluster represents a class of catalysts that bridge homogeneous and heterogeneous catalysis and may provide a platform for the discovery of finely optimized catalysts.


Effectiveness of intravenous immunoglobulin for children with severe COVID-19: a rapid review.
Intravenous immunoglobulin (IVIG) is usually used as supportive therapy, but the treatment of COVID-19 by IVIG is controversial. This rapid review aims to explore the clinical effectiveness and safety of IVIG in the treatment of children with severe COVID-19. We systematically searched the literature on the use of IVIG in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), including both adults and children. We assessed the risk of bias and quality of evidence and reported the main findings descriptively. A total of 1,519 articles were identified by initial literature search, and finally six studies met our inclusion criteria, included one randomized controlled trial (RCT), four case series and one case report involving 198 patients. One case series showed the survival of COVID-19 patients with acute respiratory distress syndrome (ARDS) was not improved by IVIG. One case report showed high-dose IVIG could improve the outcome of COVID-19 adults. Three observational studies showed inconsistent results of the effect of IVIG on SARS patients. One RCT showed that IVIG did not reduce mortality or the incidence of nosocomial infection in adults with severe SARS. The quality of evidence was between low and very low. The existing evidence is insufficient to support the efficacy or safety of IVIG in the treatment of COVID-19.