(-)-Epigallocatechin-3-gallate inhibits RANKL-induced osteoclastogenesis via downregulation of NFATc1 and suppression of HO-1-HMGB1-RAGE pathway.
Osteoporosis disturbs the balance of bone metabolism, and excessive bone resorption causes a decrease in bone density, thus increasing the risk of fracture. (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin contained in green tea. EGCG has a variety of pharmacological activities. Recently, it was reported that EGCG inhibits osteoclast differentiation, but the details of the mechanism underlying the EGCG-mediated suppression of osteoclastogenesis are unknown. In this study, we investigated the effects of EGCG on several signaling pathways in osteoclastogenesis. EGCG suppressed the expression of the nuclear factor of activated T cells cytoplasmic-1 (NFATc1), the master regulator of osteoclastogenesis. EGCG decreased the expression of cathepsin K, c-Src, and ATP6V0d2 and suppressed bone resorption. We also found that EGCG upregulated heme oxygenase-1 (HO-1) and suppressed the extracellular release of high-mobility group box 1 (HMGB1). In addition, EGCG decreased the expression of the receptor for advanced glycation end products (RAGE), which is the receptor of HMGB1, in osteoclastogenesis. In summary, our study showed that EGCG could inhibit osteoclast differentiation through the downregulation of NFATc1 and the suppression of the HO-1-HMGB1-RAGE pathway. EGCG might have the potential to be a lead compound that suppresses bone resorption in the treatment of osteoporosis.


Prevalence of iron deficiency in 12-mo-old infants from 11 European areas and influence of dietary factors on iron status (Euro-Growth study).
A prospective longitudinal cohort study was performed to assess the prevalence of iron deficiency in European infants at 12 mo of age, and to study the influence of socio-economic status, dietary factors, growth and morbidity on iron status. The cohort consisted of 488 normal term infants from primary healthcare centres in 11 European areas. Assessed were socio-economic variables, dietary intake, anthropometry and morbidity at regular intervals from birth to 12 mo, and haemoglobin, serum ferritin, mean corpuscular volume, transferrin saturation and serum transferrin receptor concentrations at age 12 mo. The prevalence of anaemia was 9.4%, of iron deficiency 7.2%, and of iron deficiency anaemia 2.3%. More than 40% of anaemia was associated with normal iron status and associated with an increased frequency of recent infections. Iron deficiency anaemia was significantly more frequent with low (5.1%) than high socio-economic status (0%). Dietary factors accounted for most of this variation in multiple regression analysis. Early introduction of cows' milk was the strongest negative determinant of iron status. Feeding of iron-fortified formula was the main factor positively influencing iron status. Other dietary factors, including breastfeeding, did not play a significant role as determinants of iron status at age 12 mo. Conclusion. Iron deficiency anaemia is present in 2.3% of 12-mo-old European infants. The prevalence of iron deficiency anaemia varies strongly with socio-economic status. Avoidance of cows' milk feeding during the first year of life is the key measure in the prevention of iron deficiency.


Maternal affect and quality of parenting experiences are related to amygdala response to infant faces.
We examined how individual differences in mood and anxiety in the early postpartum period are related to brain response to infant stimuli during fMRI, with particular focus on regions implicated in both maternal behavior and mood/anxiety, that is, the subgenual anterior cingulate cortex (sgACC) and the amygdala. At approximately 3 months postpartum, 22 mothers completed an affect-rating task (ART) during fMRI, where their affective response to infant stimuli was explicitly probed. Mothers viewed/rated four infant face conditions: own positive (OP), own negative (ON), unfamiliar positive (UP), and unfamiliar negative (UN). Mood and anxiety were measured by the Edinburgh Postnatal Depression Scale (EDPS) and the State-Trait Anxiety Inventory-Trait Version (STAI-T); maternal factors related to parental stress and attachment were also assessed. Brain-imaging data underwent a random-effects analysis, and cluster-based statistical thresholding was applied to the following contrasts: OP-UP, ON-UN, OP-ON, and UP-UN. Our main finding was that poorer quality of maternal experience was significantly related to reduced amygdala response to OP compared to UP infant faces. Our results suggest that, in human mothers, infant-related amygdala function may be an important factor in maternal anxiety/mood, in quality of mothering, and in individual differences in the motivation to mother. We are very grateful to the staff at the Imaging Research Center of the Brain-Body Institute for their contributions to this project. This work was supported by an Ontario Mental Health Foundation operating grant awarded to Alison Fleming and a postdoctoral fellowship awarded to Jennifer Barrett.


Establishing a multidisciplinary academic cosmetic center.
The demand for cosmetic services has risen rapidly in recent years, but has slowed down with the current economic downturn. Managed care organizations and Medicare have been steadily reducing their reimbursements for physician services. The payment for reconstructive surgical procedures has been decreasing and is likely to worsen with healthcare reform, and many plastic surgery residency programs are facing fiscal challenges. An adequate volume of patients needing cosmetic services is necessary to recruit and train the best candidates to the residency programs. Self-pay patients will help ensure the fiscal viability of plastic surgery residency programs. Attracting patients to an academic healthcare center will become more difficult in a recession without the appropriate facilities, programs, and pricing strategies. Setting up a modern cosmetic services program at an academic center has some unique challenges, including funding, academic politics, and turf. The authors opened a free-standing academic multidisciplinary center at their medical school 3 years ago. The center is an off-site, 13,000-sq ft facility that includes faculty from plastic surgery, ear, nose, and throat, dermatology, and vascular surgery. In this article, the authors discuss the process of developing and executing a plan for starting an aesthetic services center in an academic setting. The financing of the center and factors in pricing services are discussed. The authors show the impact of the center on their cosmetic surgery patient volumes, resident education, and finances. They expect that their experience will be helpful to other plastic surgery programs at academic medical centers.


Regulation of antioxidant enzymes: a significant role for melatonin.
Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.


A fluorescence nanosensor for glycoproteins with activity based on the molecularly imprinted spatial structure of the target and boronate affinity.
Glycoproteins are closely associated with the occurrence of diverse diseases, and they have been used as biomarkers and therapeutic targets in clinical diagnostics. Currently, mass spectrometry has proven to be a powerful tool for glycoprotein analysis, but it is almost impossible to directly identify glycoproteins without the preparation and pretreatment of samples. Furthermore, biological samples, especially proteins, are damaged by this process. Herein, we describe a novel fluorescence nanosensor based on a molecularly imprinted spatial structure and boronate affinity that is well-suited for monitoring glycoproteins selectively. Results showed that the recognition performance of the nanosensor for glycoproteins was regulated by controlling the pH value and temperature. Moreover, the nanosensor was successfully applied to the detection of HRP in biological fluids. This study provides a facile and efficient fluorescence tool for glycoprotein detection in clinical diagnostics.


HPO2GO: prediction of human phenotype ontology term associations for proteins using cross ontology annotation co-occurrences.
Analysing the relationships between biomolecules and the genetic diseases is a highly active area of research, where the aim is to identify the genes and their products that cause a particular disease due to functional changes originated from mutations. Biological ontologies are frequently employed in these studies, which provides researchers with extensive opportunities for knowledge discovery through computational data analysis. In this study, a novel approach is proposed for the identification of relationships between biomedical entities by automatically mapping phenotypic abnormality defining HPO terms with biomolecular function defining GO terms, where each association indicates the occurrence of the abnormality due to the loss of the biomolecular function expressed by the corresponding GO term. The proposed HPO2GO mappings were extracted by calculating the frequency of the co-annotations of the terms on the same genes/proteins, using already existing curated HPO and GO annotation sets. This was followed by the filtering of the unreliable mappings that could be observed due to chance, by statistical resampling of the co-occurrence similarity distributions. Furthermore, the biological relevance of the finalized mappings were discussed over selected cases, using the literature. The resulting HPO2GO mappings can be employed in different settings to predict and to analyse novel gene/protein-ontology term-disease relations. As an application of the proposed approach, HPO term-protein associations (i.e., HPO2protein) were predicted. In order to test the predictive performance of the method on a quantitative basis, and to compare it with the state-of-the-art, CAFA2 challenge HPO prediction target protein set was employed. The results of the benchmark indicated the potential of the proposed approach, as HPO2GO performance was among the best (Fmax = 0.35). The automated cross ontology mapping approach developed in this work may be extended to other ontologies as well, to identify unexplored relation patterns at the systemic level. The datasets, results and the source code of HPO2GO are available for download at: https://github.com/cansyl/HPO2GO.


Waste incineration of Polytetrafluoroethylene (PTFE) to evaluate potential formation of per- and Poly-Fluorinated Alkyl Substances (PFAS) in flue gas.
In recent years, concerns over some per- and polyfluorinated alkyl substances (PFAS) have grown steadily. PFAS are a large group of chemical substances with widely differing properties. While one class of PFAS, fluoropolymers, have been demonstrated to meet the OECD criteria for polymers of low concern during the in use phase of their lifecycle, questions remain regarding waste handling at the end of useful life for products containing fluoropolymers. To show that polytetrafluoroethylene (PTFE) can be almost fully transformed into fluorine (F) (as hydrofluoric acid (HF)) and to study the possible generation of low molecular weight per- and polyfluorinated alkyl substances (PFAS), PTFE combustion under typical waste incineration conditions at the BRENDA (German acronym for "Brennkammer mit Dampfkessel") pilot plant at Karlsruhe Institute of Technology (KIT) was investigated. Results indicate that, within procedural quantitation limits, no statistically significant evidence was found that the PFAS studied were created during the incineration of PTFE. Therefore, municipal incineration of PTFE using best available technologies (BAT) is not a significant source of the studied PFAS and should be considered an acceptable form of waste treatment.


Coffee Consumption and the Risk of All-Cause and Cause-Specific Mortality in the Korean Population.
There is a dearth of information regarding the association between coffee consumption and its health effects with respect to mortality among Korean people. The aim of this study was to examine the association between coffee consumption and all-cause mortality and cause-specific mortality risks in the Korean population. This prospective cohort study had a median follow-up period of 9.1 years. In total, 173,209 participants aged 40 years and older from the Health Examinees study were enrolled between 2004 and 2013. The analytic sample included 110,920 participants without diabetes, cardiovascular disease (CVD), or cancer at baseline who could be linked with their death information. Deaths of participants until December 31, 2018 were ascertained using the death certificate database of the National Statistical Office. Cause of death was classified according to the International Classification of Diseases, 10th Revision. Participants were categorized according to the amount and type of coffee consumed. Cox proportional hazards regression analysis was performed to estimate the hazard ratio (HR) and 95%CI of all-cause mortality and cause-specific mortality, such as CVD and cancer mortality. Compared with nonconsumers of coffee, participants who consumed > 3 cups/day had a reduced risk of all-cause mortality (HR 0.79, 95% CI 0.66 to 0.95). Participants who consumed ≤1 cup/day and 1 to 3 cups/day had a reduced risk of CVD mortality (≤1 cup/day: HR 0.58, 95% CI 0.69 to 0.94; 1 to 3 cups/day: HR 0.62, 95% CI 0.41 to 0.96). This study provides evidence that greater coffee consumption is associated with a decreased risk of all-cause mortality and moderate coffee consumption (approximately 3 cups/day) is associated with a decreased risk of CVD mortality, regardless of the type of coffee, in a Korean population.


Antibiotic resistance genes in municipal wastewater treatment systems and receiving waters in Arctic Canada.
Domestic wastewater discharges may adversely impact arctic ecosystems and local indigenous people, who rely on being able to hunt and harvest food from their local environment. Therefore, there is a need to develop efficient wastewater treatment plants (WWTPs), which can be operated in remote communities under extreme climatic conditions. WWTPs have been identified as reservoirs of antibiotic resistance genes (ARGs). The objective of this work was to quantify the presence of nine different ARG markers (int1, sul1, sul2, tet(O), erm(B), mecA, blaCTX-M, blaTEM, and qnr(S)) in two passive systems (waste stabilization ponds [WSPs]) and one mechanical filtration plant operating in two smaller and one large community, respectively, in Nunavut, Canada. Measurement of water quality parameters (carbonaceous oxygen demand, ammonia, total suspended solids, Escherichia coli and total coliforms) showed that the WWTPs provided only primary treatment. Low levels of the ARGs (2logcopies/mL) were observed in the effluent, demonstrating that bacteria residing in three northern WWTPs harbour ARGs conferring resistance to multiple clinically-relevant classes of antibiotics. Our results indicate that long-term storage in WSPs benefitted removal of organic material and some ARGs. However, one WSP system showed evidence of the enrichment of sul1, sul2, mecA, tet(O) and qnr(S). Further research is needed to fully understand if these ARG releases pose a risk to human health, especially in the context of traditional hunting and fishing activities.


High-throughput cell and tissue analysis with enhanced molecular coverage by laser ablation electrospray ionization mass spectrometry using ion mobility separation.
Ambient ionization methods, such as laser ablation electrospray ionization (LAESI), facilitate the direct analysis of unperturbed cells and tissues in their native states. However, the lack of a separation step in these ionization techniques results in limited molecular coverage due to interferences, ion suppression effects, and the lack of ability to differentiate between structural isomers and isobaric species. In this contribution, LAESI mass spectrometry (MS) coupled with ion mobility separation (IMS) is utilized for the direct analysis of protein mixtures, megakaryoblast cell pellets, mouse brain sections, and Arabidopsis thaliana leaves. We demonstrate that the collision cross sections of ions generated by LAESI are similar to the ones obtained by ESI. In various applications, LAESI-IMS-MS allows for the high-throughput separation and mass spectrometric detection of biomolecules on the millisecond time scale with enhanced molecular coverage. For example, direct analysis of mouse brain tissue without IMS had yielded ∼300 ionic species, whereas with IMS over 1 100 different ions were detected. Differentiating between ions of similar mass-to-charge ratios with dissimilar drift times in complex biological samples removes some systematic distortions in isotope distribution patterns and improves the fidelity of molecular identification. Coupling IMS with LAESI-MS also expands the dynamic range by increasing the signal-to-noise ratio due to the separation of isobaric or other interfering ionic species. We have also shown that identification of potential biomarkers by LAESI can be enhanced by using the drift times of individual ions as an additional parameter in supervised orthogonal projections to latent structures discriminant analysis. Comparative analysis of drift time versus mass-to-charge ratio plots was performed for similar tissue samples to pinpoint significant metabolic differences.


Measurement of the incorporation and repair of exogenous 5-hydroxymethyl-2'-deoxyuridine in human cells in culture using gas chromatography-negative chemical ionization-mass spectrometry.
The DNA of all organisms is constantly damaged by oxidation. Among the array of damage products is 5-hydroxymethyluracil, derived from oxidation of the thymine methyl group. Previous studies have established that HmU can be a sensitive and valuable marker of DNA damage. More recently, the corresponding deoxynucleoside, 5-hydroxymethyl-2'-deoxyuridine (HmdU), has proven to be valuable for the introduction of controlled amounts of a single type of damage lesion into the DNA of replicating cells, which is subsequently repaired by the base excision repair pathway. Complicating the study of HmU formation and repair, however, is the known chemical reactivity of the hydroxymethyl group of HmU under conditions used to hydrolyze DNA. In the work reported here, this chemical property has been exploited by creating conditions that convert HmU to the corresponding methoxymethyluracil (MmU) derivative that can be further derivatized to the 3,5-bis-(trifluoromethyl)benzyl analogue. This derivatized compound can be detected by gas chromatography-negative chemical ionization-mass spectrometry (GC-NCI-MS) with good sensitivity. Using isotopically enriched exogenous HmdU and human osteosarcoma cells (U2OS) in culture, we demonstrate that this method allows for the measurement of HmU in DNA formed from the incorporation of exogenous HmdU. We further demonstrate that the addition of isotopically enriched uridine to the culture medium allows for the simultaneous measurement of DNA replication and repair kinetics. This sensitive and facile method should prove valuable for studies on DNA oxidation damage and repair in living cells.


Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
Developmental dynamics of neural stem/progenitor cells (NSPCs) are crucial for embryonic and adult neurogenesis, but its regulatory factors are not fully understood. By differential subtractive screening with NSPCs versus their differentiated progenies, we identified the radmis (radial fiber and mitotic spindle)/ckap2l gene, a novel microtubule-associated protein (MAP) enriched in NSPCs. Radmis is a putative substrate for the E3-ubiquitin ligase, anaphase promoting complex/cyclosome (APC/C), and is degraded via the KEN box. Radmis was highly expressed in regions of active neurogenesis throughout life, and its distribution was dynamically regulated during NSPC division. In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes) of dividing NSPCs. As central nervous system development proceeded, radmis expression was lost in most brain regions, except for several neurogenic regions. In adult brain, radmis expression persisted in the mitotic spindles of both slowly-dividing stem cells and rapid amplifying progenitors. Overexpression of radmis in vitro induced hyper-stabilization of microtubules, severe defects in mitotic spindle formation, and mitotic arrest. In vivo gain-of-function using in utero electroporation revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone. Besides, radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei. These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs.


Changing expression and subcellular distribution of karyopherins during murine oogenesis.
Mammalian oocyte growth and development is driven by a strict program of gene expression that relies on the timely presence of transcriptional regulators via nuclear pores. By targeting specific cargos for nucleo-cytoplasmic transport, karyopherin (KPN) proteins are key to the relocation of essential transcription factors and chromatin-remodelling factors into and out of the nucleus. Using multiple complementary techniques, here we establish that KPNA genes and proteins are dynamically expressed and relocalised throughout mouse oogenesis and folliculogenesis. Of the KPNAs examined (Kpna1, Kpna2, Kpna3, Kpna4, Kpna6, Kpna7, Kpnb1, Ipo5 and Xpo1), all were expressed in the embryonic ovary with up-regulation of protein levels concomitant with meiotic entry for KPNA2, accompanied by the redistribution of the cellular localisation of KPNA2 and XPO1. In contrast, postnatal folliculogenesis revealed significant up-regulation of Kpna1, Kpna2, Kpna4, Kpna6 and Ipo5 and down-regulation of Kpnb1, Kpna7 and Xpo1 at the primordial to primary follicle transition. KPNAs exhibited different localisation patterns in both oocytes and granulosa cells during folliculogenesis, with three KPNAs--KPNA1, KPNA2 and IPO5--displaying marked enrichment in the nucleus by antral follicle stage. Remarkably, varied subcellular expression profiles were also identified in isolated pre-ovulatory oocytes with KPNAs KPNA2, KPNB1 and IPO5 detected in the cytoplasm and at the nuclear rim and XPO1 in cytoplasmic aggregates. Intriguingly, meiotic spindle staining was also observed for KPNB1 and XPO1 in meiosis II eggs, implying roles for KPNAs outside of nucleo-cytoplasmic transport. Thus, we propose that KPNAs, by targeting specific cargoes, are likely to be key regulators of oocyte development.


Integrating landscape genomics and spatially explicit approaches to detect loci under selection in clinal populations.
Uncovering the genetic basis of adaptation hinges on the ability to detect loci under selection. However, population genomics outlier approaches to detect selected loci may be inappropriate for clinal populations or those with unclear population structure because they require that individuals be clustered into populations. An alternate approach, landscape genomics, uses individual-based approaches to detect loci under selection and reveal potential environmental drivers of selection. We tested four landscape genomics methods on a simulated clinal population to determine their effectiveness at identifying a locus under varying selection strengths along an environmental gradient. We found all methods produced very low type I error rates across all selection strengths, but elevated type II error rates under "weak" selection. We then applied these methods to an AFLP genome scan of an alpine plant, Campanula barbata, and identified five highly supported candidate loci associated with precipitation variables. These loci also showed spatial autocorrelation and cline patterns indicative of selection along a precipitation gradient. Our results suggest that landscape genomics in combination with other spatial analyses provides a powerful approach for identifying loci potentially under selection and explaining spatially complex interactions between species and their environment.


Putative odour receptors localize in cilia of olfactory receptor cells in rat and mouse: a freeze-substitution ultrastructural study.
Two different polyclonal antibodies were raised to synthetic peptides corresponding to distinct putative odour receptors of rat and mouse. Both antibodies selectively labelled olfactory cilia as seen with cryofixation and immunogold ultrastructural procedures. Regions of the olfactory organ where label was detected were consistent with those found at LM levels. Immunopositive cells were rare; only up to about 0.4% of these receptor cells were labelled. Despite chemical, species, and topographic differences both antibodies behaved identically in their ultrastructural labelling patterns. For both antibodies, labelling was very specific for olfactory cilia; both bound amply to the thick proximal and the thinner and long distal parts of the cilia. Dendritic knobs showed little labelling if any. Dendritic receptor cell structures below the knobs, supporting cell structures, and respiratory cilia did not immunolabel. There were no obvious differences in morphology between labelled and unlabelled receptor cells and their cilia. Labelling could be followed up to a distance of about 15 microns from the knobs along the distal parts of the cilia. When labelled cells were observed, this signal was detectable in two, sometimes three, sections taken through these cells while being consistently absent in neighbouring cells. This pattern argues strongly for the specificity of the labelling. In conclusion, very few receptor cells labelled with the antibodies to putative odour receptors. Additionally the olfactory cilia, the cellular regions that first encounter odour molecules and that are thought to transduce the odorous signal, displayed the most intense labelling with both antibodies. Consequently, the results showed these cilia as having many copies of the putative receptors. Finally, similar patterns of subcellular labelling were displayed in two different species, despite the use of different antibodies. Thus, this study provides compelling evidence that the heptahelical putative odour receptors localize in the olfactory cilia.


External validation of a mammographic texture marker for breast cancer risk in a case-control study.
Purpose: The pattern of dense tissue on a mammogram appears to provide additional information than overall density for risk assessment, but there has been little consistency in measures of texture identified. The purpose of this study is thus to validate a mammographic texture feature developed from a previous study in a new setting. Approach: A case-control study (316 invasive cases and 1339 controls) of women in Virginia, USA was used to validate a mammographic texture feature (MMTEXT) derived in a independent previous study. Analysis of predictive ability was adjusted for age, demographic factors, questionnaire risk factors (combined through the Tyrer-Cuzick model), and optionally BI-RADS breast density. Odds ratios per interquartile range (IQ-OR) in controls were estimated. Subgroup analysis assessed heterogeneity by mode of cancer detection (94 not detected by mammography). Results: MMTEXT was not a significant risk factor at 0.05 level after adjusting for classical risk factors ( IQ - OR = 1.16 , 95%CI 0.92 to 1.46), nor after further adjustment for BI-RADS density ( IQ - OR = 0.92 , 95%CI 0.76 to 1.10). There was weak evidence that MMTEXT was more predictive for cancers that were not detected by mammography (unadjusted for density: IQ - OR = 1.46 , 95%CI 0.99 to 2.15 versus 1.03, 95%CI 0.79 to 1.35, Phet 0.10; adjusted for density: IQ - OR = 1.11 , 95%CI 0.70 to 1.77 versus 0.76, 95%CI 0.55 to 1.05, Phet 0.21). Conclusions: MMTEXT is unlikely to be a useful imaging marker for invasive breast cancer risk assessment in women attending mammography screening. Future studies may benefit from a larger sample size to confirm this as well as developing and validating other measures of risk. This negative finding demonstrates the importance of external validation.


Modeling visual search using three-parameter probability functions in a hierarchical Bayesian framework.
In this study, we applied Bayesian-based distributional analyses to examine the shapes of response time (RT) distributions in three visual search paradigms, which varied in task difficulty. In further analyses we investigated two common observations in visual search-the effects of display size and of variations in search efficiency across different task conditions-following a design that had been used in previous studies (Palmer, Horowitz, Torralba, & Wolfe, Journal of Experimental Psychology: Human Perception and Performance, 37, 58-71, 2011; Wolfe, Palmer, & Horowitz, Vision Research, 50, 1304-1311, 2010) in which parameters of the response distributions were measured. Our study showed that the distributional parameters in an experimental condition can be reliably estimated by moderate sample sizes when Monte Carlo simulation techniques are applied. More importantly, by analyzing trial RTs, we were able to extract paradigm-dependent shape changes in the RT distributions that could be accounted for by using the EZ2 diffusion model. The study showed that Bayesian-based RT distribution analyses can provide an important means to investigate the underlying cognitive processes in search, including stimulus grouping and the bottom-up guidance of attention.


Calcium and inorganic phosphate transport in rat colon: dissociated response to 1,25-dihydroxyvitamin D3.
In the small intestine, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] stimulates both calcium (Ca) and inorganic phosphate (Pi) absorption. This is mediated through an increase in mucosal-to-serosal flux (Jms) whereas the serosal-to-mucosal flux (Jsm) remains unchanged. We now report that in rat proximal colon, 1,25(OH)(2)D(3) produces active Ca absorption without affecting Pi transport, and that this induced active Ca absorption is associated with alterations in kinetics of both Jms and Jsm so that both processes demonstrate saturable components. Vitamin D-deficient rats were given daily injections of solvent (-D) or 270 ng 1,25(OH)(2)D(3) (+D) for 3 d. (45)Ca and [(32)P]phosphate fluxes were measured employing the Ussing technique using a modified Krebs-Ringer-HCO(3) buffer ([Ca] 1.25, [Pi] 1.18, [glucose] 11 mM). In -D rats there was no net flux (Jnet) of either Ca or Pi. In +D rats net active Ca absorption was observed (-D = 3.3 nmol/cm(2) per h +/-3.4 (SEM); +D = 27.3 +/-3.8, n = 11, P < 0.001) whereas Pi transport was unchanged, i.e., still no Jnet. Pi Jms was not different from Pi Jsm measured at the following buffer [Pi]: 0.0118, 0.118, 1.18, and 2.36 mM. Ca saturation kinetics were estimated using buffer [Ca] from 0.0125 to 5.0 mM. Saturable processes were demonstrated for both Jms and Jsm. Jnet for Ca across colon from +D rats exhibited saturation at [Ca] > 3 mM, with an estimated V(max) of 44.0 nmol/cm(2) per h and a K(m) of 0.9 mM. This colonic model may provide a useful system for studying 1,25(OH)(2)D(3)-induced molecular events related to Ca but not Pi transport. The apparent action of 1,25(OH)(2)D(3) on Ca secretory process may furnish new insights into the mechanism of action of vitamin D.


Both Granulocytic and Non-Granulocytic Blood Cells Are Affected in Patients with Severe Congenital Neutropenia and Their Non-Neutropenic Family Members: An Evaluation of Morphology, Function, and Cell Death
To examine granulocytic and non-granulocytic cells in children with severe congenital neutropenia (SCN) and their non-neutropenic parents. Fifteen patients with SCN and 21 non-neutropenic parents were evaluated for a) CD95, CD95 ligand, annexin V, propidium iodide, cell cycle, and lymphocyte subsets by flow cytometry; b) rapid cell senescence (of leukocytes) by senescence-associated β-galactosidase stain; c) aggregation tests by aggregometer; d) in vitro bleeding time by PFA-100 instrument; e) mepacrine-labeled dense granule number of thrombocytes by fluorescence microscope; and f) hematomorphology by light and electron microscope. HAX1, ELANE, G6PC3, CSF3R, and JAGN1 mutations associated with SCN were studied in patients and several parents. Significant increase in apoptosis and secondary necrosis in monocytes, lymphocytes, and granulocytes of the patients and parents was detected, irrespective of the mutation type. CD95 and CD95 ligand results implied that apoptosis was non-CD95-mediated. Leukocytes of 25%, 12.5%, and 0% of patients, parents, and controls showed rapid cell senescence. The cell cycle analysis testable in four cases showed G1 arrest and apoptosis in lymphocytes of three. The patients had HAX1 (n=6), ELANE (n=2), G6PC3 (n=2), and unidentified (n=5) mutations. The CD3, CD4, and NK lymphocytes were below normal levels in 16.6%, 8.3%, and 36.4% of the patients and in 0%, 0%, and 15.4% of the parents (controls: 0%, 0%, 5.6%). The thrombocytes aggregated at low rates, dense granule number/thrombocyte ratio was low, and in vitro bleeding time was prolonged in 37.5%-66.6% of patients and 33.3%-63.2% of parents (vs. 0% in controls). Under electron and/or light microscope, the neutrophils, monocytes, lymphocytes, and thrombocytes in the peripheral blood of both patients and parents were dysplastic and the bone marrow of patients revealed increased phagocytic activity, dysmegakaryopoiesis, and necrotic and apoptotic cells. Ultrastructurally, thrombocyte adhesion, aggregation, and release were inadequate. In cases of SCN, patients' pluripotent hematopoietic stem cells and their non-neutropenic parents are both affected irrespective of the genetic defect.


Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense.
Microbial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced RegIIIγ expression is IL-22 dependent, but how TLR signaling leads to IL-22 expression is incompletely defined. By using conditional depletion of lamina propria dendritic cell (LPDC) subsets, we demonstrated that CD103(+)CD11b(+) LPDCs, but not monocyte-derived CD103(-)CD11b(+) LPDCs, expressed high amounts of IL-23 after bacterial flagellin administration and drove IL-22-dependent RegIIIγ production. Maximal expression of IL-23 subunits IL-23p19 and IL-12p40 occurred within 60 min of exposure to flagellin. IL-23 subsequently induced a burst of IL-22 followed by sustained RegIIIγ expression. Thus, CD103(+)CD11b(+) LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.


South African clinical practice guidelines: A landscape analysis.
South Africa (SA) is in the process of implementing National Health Insurance (NHI), which will require co-ordination of health provision across sectors and levels of care. Clinical practice guidelines (CPGs) are tools for standardising and implementing care, and are intended to influence clinical decision-making with consequences for patient outcomes, health system costs and resource use. Under NHI, CPGs will be used to guide the provision of healthcare for South Africans. It is therefore important to explore the current landscape of CPG developers and development. To identify and describe all CPGs available in the public domain produced by SA developers for the SA context. We conducted a cross-sectional evaluation using a two-part search process: an iterative, electronic search of grey literature and relevant websites (161 websites searched), and a systematic search for peer-reviewed literature (PubMed) after publication year 2000. CPGs were identified, and data were extracted and categorised by two independent reviewers. Any discrepancies were referred to a third reviewer. Data extracted included a description of the developer, condition, and reporting of items associated with CPG quality. A search conducted in May 2017 identified 285 CPGs published after January 2000. Of those, 171 had been developed in the past 5 years. Developers included the national and provincial departments of health (DoH), professional societies and associations, ad hoc collaborations of clinicians, and the Council for Medical Schemes. Topics varied by developer; DoH CPGs focused on high-burden conditions (HIV/AIDS, tuberculosis and malaria), and other developers focused on non-communicable diseases. A conflict of interest statement was included in 23% of CPGs developed by societies or clinicians, compared with 4% of DoH CPGs. Accessing CPGs was challenging and required extensive searching. SA has many contributors to CPG development from the public and private sectors and across disciplines, but there is no formal co-ordination or prioritisation of topics for CPG development. Different versions of the CPGs were identified and key quality items were poorly reported, potentially affecting the usability and credibility of those available. There was substantial variation in CPG comprehensiveness and methodological approach. Establishing a national CPG co-ordinating unit responsible for developing standards for CPG development along with clinical quality standards, and supporting high-quality CPG development, is one essential step for moving forward with NHI.


Homeopathic potentization based on nanoscale domains.
The objectives of this study were to present a simple descriptive and quantitative model of how high potencies in homeopathy arise. The model begins with the mechanochemical production of hydrogen and hydroxyl radicals from water and the electronic stabilization of the resulting nanodomains of water molecules. The life of these domains is initially limited to a few days, but may extend to years when the electromagnetic characteristic of a homeopathic agent is copied onto the domains. This information is transferred between the original agent and the nanodomains, and also between previously imprinted nanodomains and new ones. The differential equations previously used to describe these processes are replaced here by exponential expressions, corresponding to simplified model mechanisms. Magnetic stabilization is also involved, since these long-lived domains apparently require the presence of the geomagnetic field. Our model incorporates this factor in the formation of the long-lived compound. Numerical simulation and graphs show that the potentization mechanism can be described quantitatively by a very simplified mechanism. The omitted factors affect only the fine structure of the kinetics. Measurements of pH changes upon absorption of different electromagnetic frequencies indicate that about 400 nanodomains polymerize to form one cooperating unit. Singlet excited states of some compounds lead to dramatic changes in their hydrogen ion dissociation constant, explaining this pH effect and suggesting that homeopathic information is imprinted as higher singlet excited states. A simple description is provided of the process of potentization in homeopathic dilutions. With the exception of minor details, this simple model replicates the results previously obtained from a more complex model. While excited states are short lived in isolated molecules, they become long lived in nanodomains that form coherent cooperative aggregates controlled by the geomagnetic field. These domains either slowly emit biophotons or perform specific biochemical work at their target.


Comparison of the safety, vaccine virus shedding, and immunogenicity of influenza virus vaccine, trivalent, types A and B, live cold-adapted, administered to human immunodeficiency virus (HIV)-infected and non-HIV-infected adults.
Fifty-seven human immunodeficiency virus (HIV)-infected (CDC class A1-2) and 54 non-HIV-infected adults, not prescreened for influenza susceptibility, were randomized to receive trivalent live attenuated influenza vaccine (LAIV) or placebo intranasally. LAIV was safe and well tolerated with no serious adverse events attributable to vaccine. Reactogenicity rates were similar in LAIV and placebo recipients except that runny nose/nasal congestion was significantly more common in LAIV recipients regardless of HIV status. No prolonged shedding of LAIV was observed in HIV-infected participants. HIV RNA levels were not increased and CD4 counts were not decreased in HIV-infected LAIV recipients compared with placebo recipients after immunization. Shedding of LAIV and increases in antibody titers were infrequent, consistent with prior experience in unscreened adults. The data suggest that inadvertent vaccination with LAIV in relatively asymptomatic HIV-infected adults would not be associated with frequent significant adverse events.


Improving survival rate of patients with in-hospital cardiac arrest: five years of experience in a single center in Korea.
The aim of this study was to describe the cause of the recent improvement in the outcomes of patients who experienced in-hospital cardiac arrest. We retrospectively analyzed the in-hospital arrest registry of a tertiary care university hospital in Korea between 2005 and 2009. Major changes to the in-hospital resuscitation policies occurred during the study period, which included the requirement of extensive education of basic life support and advanced cardiac life support, the reformation of cardiopulmonary resuscitation (CPR) team with trained physicians, and the activation of a medical emergency team. A total of 958 patients with in-hospital cardiac arrest were enrolled. A significant annual trend in in-hospital survival improvement (odds ratio = 0.77, 95% confidence interval 0.65-0.90) was observed in a multivariate model. The adjusted trend analysis of the return of spontaneous circulation, six-month survival, and survival with minimal neurologic impairment upon discharge and six-months afterward revealed similar results to the original analysis. These trends in outcome improvement throughout the study were apparent in non-ICU (Intensive Care Unit) areas. We report that the in-hospital survival of cardiac arrest patients gradually improved. Multidisciplinary hospital-based efforts that reinforce the Chain of Survival concept may have contributed to this improvement.


Treatment of lupus-induced thrombocytopenia with recombinant human interleukin-11.
Autoimmune thrombocytopenia can be a serious manifestation of systemic lupus erythematosus (SLE) which necessitates treatment with immunosuppressive agents and platelet transfusions. Interleukin-11 (IL-11) is a unique thrombopoietic growth factor which causes proliferation of megakaryocyte progenitors as well as induces megakaryocytic maturation. To our knowledge, this agent has not been used in the treatment of autoimmune thrombocytopenia, since theoretically there is a danger of IL-11 stimulating the immune system by up-regulating the lymphoid stem cells. We describe a 36-year-old splenectomized woman with known SLE who presented with pulmonary hemorrhage, acute renal failure, change in mental status, and severe thrombocytopenia (platelet count 2,000/mm3). Her pulmonary, renal, and central nervous system complications responded to intensive therapy with intravenous (IV) pulse methylprednisone and cyclophosphamide along with hemodialysis. The thrombocytopenia remained refractory to the above treatment plus daily multiple platelet transfusions and IV immunoglobulin. Treatment with recombinant human IL-11 (25 microg/kg/day subcutaneously) was initiated and continued for 5 days. Her platelet count improved to 25,000/mm3 within 48 hours, and she experienced no adverse effects.


Biomonitoring data for 2,4-dichlorophenoxyacetic acid in the United States and Canada: interpretation in a public health risk assessment context using Biomonitoring Equivalents.
Several extensive studies of exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) using urinary concentrations in samples from the general population, farm applicators, and farm family members are now available. Reference doses (RfDs) exist for 2,4-D, and Biomonitoring Equivalents (BEs; concentrations in urine or plasma that are consistent with those RfDs) for 2,4-D have recently been derived and published. We reviewed the available biomonitoring data for 2,4-D from the United States and Canada and compared them with BE values to draw conclusions regarding the margin of safety for 2,4-D exposures within each population group. Data on urinary 2,4-D excretion in general and target populations from recent published studies are tabulated and the derivation of BE values for 2,4-D summarized. The biomonitoring data indicate margins of safety (ratio of BE value to biomarker concentration) of approximately 200 at the central tendency and 50 at the extremes in the general population. Median exposures for applicators and their family members during periods of use appear to be well within acute exposure guidance values. Biomonitoring data from these studies indicate that current exposures to 2,4-D are below applicable exposure guidance values. This review demonstrates the value of biomonitoring data in assessing population exposures in the context of existing risk assessments using the BE approach. Risk managers can use this approach to integrate the available biomonitoring data into an overall assessment of current risk management practices for 2,4-D.


Psychological distress in applicants for predictive DNA testing for autosomal dominant, heritable, late onset disorders. The Rotterdam/Leiden Genetics Workgroup.
In a comparative study on the effects of predictive DNA testing for late onset disorders, pre-test psychological distress was assessed in people at risk for Huntington's disease (HD, n = 41), cerebral haemorrhage (HCHWA-D, n = 9), breast and ovarian cancer (HBOC, n = 24), and polyposis coli (FAP, n = 45). Partners, if available, also participated in the study. Distress was measured with the subscales Intrusion and Avoidance of the Impact of Event Scale. People at risk for the neurodegenerative disorders reported more avoidance than those at risk for the cancer syndromes. People at risk for FAP and partners of those at risk for HBOC reported less intrusion than the others at risk and the other partners. Subjects who were more distressed reported more experiences with the disease in close relatives, the disease having a great impact on their lives, having considerations against predictive testing, expecting that being identified as a gene carrier would have adverse effects, and expecting relief after being identified as a non-carrier. Test candidates who expected an increase of personal problems showed higher avoidance, whereas those who could better anticipate future life as a carrier had higher intrusion levels. Generally, subjects with high distress levels are of more concern to the healthcare professional than those with low distress levels. However, high distress may reflect worrying as a mental preparation for the test result, whereas low distress may indicate denial-avoidance behaviour and poor anticipation of the test outcome. In pre-test counselling sessions, this should be acknowledged and addressed.


SU-E-T-296: Optimization of the Energy Selection System with Varying Magnetic Field for Laser-Accelerated Proton Beams.
Laser-based accelerated proton beams are unsuitable for clinical use because of their broad energy spectra. For this reason, it is essential to employ an energy selection system (ESS). The purpose of this study is to determine optimum parameters of the ESS which uses a varying magnetic field to generate Bragg-peak. We simulated an accelerated proton beams using radiation pressure acceleration mechanism with carbon-proton mixture target. The density ratio (n = 6) between the protons and the carbon ions is one of optimization parameters in determining the accelerating mechanisms. The ESS was implemented by the Geant4 Monte Carlo toolkit. In order to optimize the hole size and position of the energy selection collimator, and magnetic field at ESS, these parameters were simulated for acquiring energy and dose distributions by changing each values. The proton energy distributions had a poly-energetic distribution after passing through the ESS. As the magnetic field was increased, the mean energy of the proton beams also was increased. Also as the hole size was increased, the energy bandwidth of proton passed through the ESS was increased. The hole size and position of the energy selection collimator were effectively optimized to 2 cm and 5 cm from the z-axis, respectively. We simulated laser-accelerated proton beams using ESS for generation of Bragg-peak. Our results suggest that the ESS with magnetic field variation can effectively generate a Bragg-peak suitable for use in proton radiation therapy. Our ESS can be applied to pencil beam scanning proton therapy.


Factors Underlying Bench Press Performance in Elite Competitive Powerlifters.
Reya, M, Škarabot, J, Cvetičanin, B, and Šarabon, N. Factors underlying bench press performance in elite competitive powerlifters. J Strength Cond Res 35(8): 2179-2186, 2021-Previous investigations of 1 repetition maximum bench press (1RM BP) performance have been either descriptive or have explored a limited number of contributing variables. The purpose of this study was to investigate the interplay between structural, technical, and neuromuscular factors in relation to 1RM BP in competitive powerlifters. Thirteen national and international level male powerlifters (26 ± 9 years, 178 ± 6 cm, and 93.8 ± 9.9 kg) visited the laboratory twice. Anthropometric and ultrasound measures were taken on the first visit, whereas performance measures (voluntary activation level, isokinetic strength, and kinetic, kinematic, and electromyographic measurements during 1RM BP) were recorded on the second visit. Correlation and multiple regression were used to investigate the contribution of structural, technical, and neuromuscular variables to 1RM BP corrected for body mass using the Wilks coefficient. The highest degree of association was shown for structural (lean and bone mass, brachial index, arm circumference, and agonist cross-sectional area [CSA]; r = 0.58-0.74) followed by neuromuscular factors (elbow and shoulder flexion strength; r = 0.57-0.71), whereas technical factors did not correlate with 1RM BP performance (r ≤ 0.49). The multiple regression showed that lean body mass, brachial index, and isometric shoulder flexion torque predicted 59% of the common variance in 1RM BP. These data suggest that in a sample of elite competitive powerlifters, multiple factors contribute to 1RM BP with variables such as lean body mass, the agonist CSA, brachial index, and strength of the elbow and shoulder flexors being the greatest predictors of performance.


Transcriptome analysis indicates considerable divergence in alternative splicing between duplicated genes in Arabidopsis thaliana.
Gene and genome duplication events have created a large number of new genes in plants that can diverge by evolving new expression profiles and functions (neofunctionalization) or dividing extant ones (subfunctionalization). Alternative splicing (AS) generates multiple types of mRNA from a single type of pre-mRNA by differential intron splicing. It can result in new protein isoforms or downregulation of gene expression by transcript decay. Using RNA-seq, we investigated the degree to which alternative splicing patterns are conserved between duplicated genes in Arabidopsis thaliana. Our results revealed that 30% of AS events in α-whole-genome duplicates and 33% of AS events in tandem duplicates are qualitatively conserved within leaf tissue. Loss of ancestral splice forms, as well as asymmetric gain of new splice forms, may account for this divergence. Conserved events had different frequencies, as only 31% of shared AS events in α-whole-genome duplicates and 41% of shared AS events in tandem duplicates had similar frequencies in both paralogs, indicating considerable quantitative divergence. Analysis of published RNA-seq data from nonsense-mediated decay (NMD) mutants indicated that 85% of α-whole-genome duplicates and 89% of tandem duplicates have diverged in their AS-induced NMD. Our results indicate that alternative splicing shows a high degree of divergence between paralogs such that qualitatively conserved alternative splicing events tend to have quantitative divergence. Divergence in AS patterns between duplicates may be a mechanism of regulating expression level divergence.


Metabolic responses to exogenous ghrelin in obesity and early after Roux-en-Y gastric bypass in humans.
Ghrelin is a gastric-derived hormone that stimulates growth hormone (GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en-Y gastric bypass (RYGB). We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg-1 min-1 ) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp. Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post-RYGB individuals in response to ghrelin infusion. These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB.


The antithrombotic and antimicrobial properties of PEG-protected silver nanoparticle coated surfaces.
Cardiovascular implant-associated complications such as infection and thrombosis may be reduced by modification of device surfaces using antimicrobial and antithrombotic agents. Silver nanoparticles (SNPs) are well accepted for its broad-spectrum antimicrobial effect. A recent report suggested its antiplatelet effect also. So the hypothesis of this study is that polyethylene glycol (PEG) protected SNPs can be incorporated with biomaterials to attain dual properties; and by adjusting an optimum concentration, its cytotoxicity to tissues and cells can be prevented. To prove this, detailed study of PEG-SNP was done at three levels: (i) direct inhibitory effect on platelet activation, aggregation and biochemical pathways when PEG-SNP is added into platelet suspension; (ii) inhibition of platelet adhesion to PEG-SNP incorporated biological matrix and polymer scaffold and (iii) non-cytotoxic behavior of immobilized PEG-SNP in fibrin matrix. Inhibitory effects demonstrated are on: platelet function by aggregometry, exposure of activation and apoptosis markers by flow cytometry, biochemical pathway by malondealdehyde (MDA) estimation and protein phosphorylation by Western blot. Reduced platelet adhesion onto PEG-SNP incorporated scaffold is shown using scanning electron microscopy (SEM). Non-toxic behavior of endothelial cells (EC) and smooth muscle cells (SMC) grown on PEG-SNP-fibrin disc is shown by fluorescence microscopy and cell phenotype stability by real-time polymerase chain reaction (PCR).


A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia.
Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m(2)/h, 32 mg/m(2)/h or 24 mg/m(2)/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.


Functional interactions between anthrax toxin receptors and the WNT signalling protein LRP6.
To exert its activity, anthrax toxin must be endocytosed and its enzymatic toxic subunits delivered to the cytoplasm. It has been proposed that, in addition to the anthrax toxin receptors (ATRs), lipoprotein-receptor-related protein 6 (LRP6), known for its role in Wnt signalling, is also required for toxin endocytosis. These findings have however been challenged. We show that LRP6 can indeed form a complex with ATRs, and that this interaction plays a role both in Wnt signalling and in anthrax toxin endocytosis. We found that ATRs control the levels of LRP6 in cells, and thus the Wnt signalling capacity. RNAi against ATRs indeed led to a drastic decrease in LRP6 levels and a subsequent drop in Wnt signalling. Conversely, LRP6 plays a role in anthrax toxin endocytosis, but is not essential. We indeed found that toxin binding triggered tyrosine phosphorylation of LRP6, induced its redistribution into detergent-resistant domains, and its subsequent endocytosis. RNAis against LRP6 strongly delayed toxin endocytosis. As the physiological role of ATRs is probably to interact with the extracellular matrix, our findings raise the interesting possibility that, through the ATR-LRP6 interaction, adhesion to the extracellular matrix could locally control Wnt signalling.


Statistical learning of multiple speech streams: A challenge for monolingual infants.
Language acquisition depends on the ability to detect and track the distributional properties of speech. Successful acquisition also necessitates detecting changes in those properties, which can occur when the learner encounters different speakers, topics, dialects, or languages. When encountering multiple speech streams with different underlying statistics but overlapping features, how do infants keep track of the properties of each speech stream separately? In four experiments, we tested whether 8-month-old monolingual infants (N = 144) can track the underlying statistics of two artificial speech streams that share a portion of their syllables. We first presented each stream individually. We then presented the two speech streams in sequence, without contextual cues signaling the different speech streams, and subsequently added pitch and accent cues to help learners track each stream separately. The results reveal that monolingual infants experience difficulty tracking the statistical regularities in two speech streams presented sequentially, even when provided with contextual cues intended to facilitate separation of the speech streams. We discuss the implications of our findings for understanding how infants learn and separate the input when confronted with multiple statistical structures.


Plasmid composition in Aeromonas salmonicida subsp. salmonicida 01-B526 unravels unsuspected type three secretion system loss patterns.
Aeromonas salmonicida subsp. salmonicida is a ubiquitous psychrophilic waterborne bacterium and a fish pathogen. The numerous mobile elements, especially insertion sequences (IS), in its genome promote rearrangements that impact its phenotype. One of the main virulence factors of this bacterium, its type three secretion system (TTSS), is affected by these rearrangements. In Aeromonas salmonicida subsp. salmonicida most of the TTSS genes are encoded in a single locus on a large plasmid called pAsa5, and may be lost when the bacterium is cultivated at a higher temperature (25 °C), producing non-virulent mutants. In a previous study, pAsa5-rearranged strains that lacked the TTSS locus on pAsa5 were produced using parental strains, including 01-B526. Some of the generated deletions were explained by homologous recombination between ISs found on pAsa5, whereas the others remained unresolved. To investigate those rearrangements, short- and long-read high-throughput sequencing technologies were used on the A. salmonicida subsp. salmonicida 01-B526 whole genome. Whole genome sequencing of the 01-B526 strain revealed that its pAsa5 has an additional IS copy, an ISAS5, compared to the reference strain (A449) sequence, which allowed for a previously unknown rearrangement to occur. It also appeared that 01-B526 bears a second large plasmid, named pAsa9, which shares 40 kbp of highly similar sequences with pAsa5. Following these discoveries, previously unexplained deletions were elucidated by genotyping. Furthermore, in one of the derived strains a fusion of pAsa5 and pAsa9, involving the newly discovered ISAS5 copy, was observed. The loss of TTSS and hence virulence is explained by one consistent mechanism: IS-driven homologous recombination. The similarities between pAsa9 and pAsa5 also provide another example of genetic diversity driven by ISs.


Distinct online and offline effects of alpha and beta transcranial alternating current stimulation (tACS) on continuous bimanual performance and task-set switching.
In the present study we examined the effect of bihemispheric in-phase synchronization of motor cortical rhythms on complex bimanual coordination. Twenty young healthy volunteers received 10 Hz or 20 Hz tACS in a double-blind crossover design while performing a bimanual task-set switching paradigm. We used a bilateral high-density montage centred over the hand knob representation within the primary motor cortices to apply tACS time-locked to the switching events. Online tACS in either frequency led to faster but more erroneous switching transitions compared to trials without active stimulation. When comparing stimulation frequencies, 10 Hz stimulation resulted in higher error rates and slower switching transitions than 20 Hz stimulation. Furthermore, the stimulation frequencies showed distinct carry-over effects in trials following stimulation trains. Non-stimulated switching transitions were generally faster but continuous performance became more erroneous over time in the 20 Hz condition. We suggest that the behavioural effects of bifocal in-phase tACS are explained by online synchronization of long-range interhemispheric sensorimotor oscillations, which impacts on interhemispheric information flow and the top-down control required for flexible control of complex bimanual actions. Different stimulation frequencies may lead to distinct offline effects, which potentially accumulate over time and therefore need to be taken into account when evaluating subsequent performance.


Early and late abdominal bleeding after Roux-en-Y gastric bypass: sources and tailored therapeutic strategies.
Bleeding is a potentially serious complication after Roux-en-Y gastric bypass (RYGB). Preventive measures and therapeutic strategies have not been adequately defined. We reviewed data on 742 consecutive patients treated at the University of California San Francisco to identify cases of early and late bleeding (less or greater than 30 days after surgery) after RYGB. Bleeding was defined as symptoms or signs of bleeding, associated with blood transfusion. We recorded patient characteristics, details of the operative technique, diagnostic approach, therapeutic strategies, and outcomes. Twenty-six patients (3.5%) had postoperative bleeding, which mostly occurred in the first 30 days postoperatively (N=19). Hematocrit decreased significantly from preoperative values (-5.2 ± 3.1 without bleeding vs. -14.8 ± 4.7 with, p<0.01). Type 2 diabetes was more prevalent in patients who had bleeding (58% vs. 32%, p=0.03). No other patient characteristics or details of the operative technique were associated with different rates of bleeding. Therapeutic intervention other than transfusion was needed for seven patients with early bleeding (36.8%) and for all patients with late bleeding. Four patients with early bleeding required reoperation. Early bleeding source was intraluminal in four patients, intraperitoneal in five, and self-limited and of unknown location in ten. Late bleeding occurred on average at 62.6 months (range, 5 to 300 months) after index surgery, five patients required reoperation, and the source was always intraluminal. Bleeding after RYGB may be from various anatomic sites; details of the operative technique were not associated with different rates of bleeding, and therapy should be tailored to suspected location of bleeding.


Outcomes of pregnant patients with low back pain undergoing chiropractic treatment: a prospective cohort study with short term, medium term and 1 year follow-up.
Low back pain in pregnancy is common and research evidence on the response to chiropractic treatment is limited. The purposes of this study are 1) to report outcomes in pregnant patients receiving chiropractic treatment; 2) to compare outcomes from subgroups; 3) to assess predictors of outcome. Pregnant patients with low back or pelvic pain, no contraindications to manipulative therapy and no manual therapy in the prior 3 months were recruited.Baseline numerical rating scale (NRS) and Oswestry questionnaire data were collected. Duration of complaint, number of previous LBP episodes, LBP during a previous pregnancy, and category of pain location were recorded.The patient's global impression of change (PGIC) (primary outcome), NRS, and Oswestry data (secondary outcomes) were collected at 1 week, 1 and 3 months after the first treatment. At 6 months and 1 year the PGIC and NRS scores were collected. PGIC responses of 'better' or 'much better' were categorized as 'improved'.The proportion of patients 'improved' at each time point was calculated. Chi-squared test compared subgroups with 'improvement'. Baseline and follow-up NRS and Oswestry scores were compared using the paired t-test. The unpaired t-test compared NRS and Oswestry scores in patients with and without a history of LBP and with and without LBP during a previous pregnancy. Anova compared baseline and follow-up NRS and Oswestry scores by pain location category and category of number of previous LBP episodes. Logistic regression analysis also was also performed. 52% of 115 recruited patients 'improved' at 1 week, 70% at 1 month, 85% at 3 months, 90% at 6 months and 88% at 1 year. There were significant reductions in NRS and Oswestry scores (p < 0.0005). Category of previous LBP episodes number at one year (p = 0.02) was related to ,improvement' when analyzed alone, but was not strongly predictive in logistic regression. Patients with more prior LBP episodes had higher 1 year NRS scores (p = 0.013). Most pregnant patients undergoing chiropractic treatment reported clinically relevant improvement at all time points. No single variable was strongly predictive of, improvement' in the logistic regression model.


Application of a handheld Pressure Application Measurement device for the characterisation of mechanical nociceptive thresholds in intact pig tails.
The assessment of nociceptive thresholds is employed in animals and humans to evaluate changes in sensitivity potentially arising from tissue damage. Its application on the intact pig tail might represent a suitable method to assess changes in nociceptive thresholds arising from tail injury, such as tail docking or tail biting. The Pressure Application Measurement (PAM) device is used here for the first time on the tail of pigs to determine the reliability of the methods and to provide novel data on mechanical nociceptive thresholds (MNT) associated with four different age groups (9, 17, 24 and 32weeks) and with proximity of the target region to the body of the animal. We recorded an overall acceptable level of intra-individual reliability, with mean values of CV ranging between 30.1 and 32.6%. Across all age groups, the first single measurement of MNT recorded at region 1 (proximal) was significantly higher (P<0.05) than the following two. This was not observed at tail regions 2 and 3 (more distal). Age had a significant effect (P<0.05) on the mean thresholds of nociception with increasing age corresponding to higher thresholds. Furthermore, a significant effect of proximity of tail region to the body was observed (P<0.05), with MNT being higher in the proximal tail region in pigs of 9, 17 and 24weeks of age. There was also a significant positive correlation (P<0.05) between mechanical nociceptive thresholds and age/body size of the animals. To the best of our knowledge, no other investigation of tail nociceptive thresholds has been performed with the PAM device or alternative methods to obtain mechanical nociceptive thresholds in intact tails of pigs of different age/body size. The reliability of the data obtained with the PAM device support its use in the measurement of mechanical nociceptive threshold in pig tails. This methodological approach is possibly suitable for assessing changes in tail stump MNTs after tail injury caused by tail docking and biting.


Expanding the capabilities of microfluidic gradient elution moving boundary electrophoresis for complex samples.
Gradient elution moving boundary electrophoresis (GEMBE) is a robust, continuous injection separation technique that uses electrophoresis to drive electrically charged analytes into a capillary or microfluidic channel for detection, while opposing electroosmosis and controlled variable pressure-driven flow prevent other sample components-for example, cells, proteins, or particulates in complex samples that can interfere with analysis-from entering the channel. This work expands the sample-in/answer-out analytical capabilities of GEMBE for complex samples by demonstrating the quantitative analysis of anions, implementing aqueous background electrolyte (BGE) solutions at neutral pH, and introducing the use of additives to the sample solution to optimize performance. Dirt was analyzed quantitatively, with the sole preparatory step of suspension in an aqueous BGE solution at neutral pH, for dissolved chloride, nitrite, nitrate, sulfate, and oxalate using GEMBE with capacitively-coupled contactless conductivity detection. In addition to altering the pH of the BGE solution, optimization of the analysis of dirt and whole blood was achieved using various commercially available additives. These results, taken together with previous demonstrations of GEMBE for the analysis of complex samples, underscore the uncomplicated versatility of GEMBE, facilitate effective analysis of biological complex samples using BGE solutions at physiological pH, and offer a sufficient set of techniques and tools to build a foundation for the analysis of a broad range of complex samples.


Trends in surgical management of urachal anomalies.
We have noted an increasing frequency of diagnosed urachal anomalies. The purpose of this study is to evaluate this increase, as well as the outcomes of management at our institution over 10 years. A retrospective analysis of urachal anomalies at our institution was performed. Inclusion criteria were Anomalies of Urachus (ICD 753.7) or Urinary Anomaly NOS (ICD 753.9) between January 2000 and December 2010. Exclusion criteria were having an asymptomatic urachal remnant incidentally excised. Eighty-five patients (49 male, 36 female) presented between 0 and 17 years of age (mean 1.5 years). Diagnoses increased from 0 in 2000 to 21 in 2010. Zero was surgically managed in 2000 while 21 were managed in 2010 (p=0.0145). Fifteen patients (17.6%) were observed with 13 (13/15, or 15.3%) resolving without complication while 2 were operated on. Average time to resolution (clinical or radiologic) was 4.9 months (Range: 0.4-12.6). A total of seventy-two patients (84.7%) underwent excision. Thirty-nine (54%) surgical cases were outpatient while 33 (46%) were admitted. Thirteen (18%) had post-operative complications. Ten (77%) of the complications were wound infections. Patients under 6 months of age accounted for 60% (6 of 10) of all wound infections and 52% (17 of 33) of hospitalizations. Our experience and review of the literature suggest a high complication rate with surgical management in young patients, mostly from infections and support non-operative management of all non-infected urachal remnants in children.


Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing.
To measure the interdose milk to plasma ratio (M/P) of R- and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure. Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of >or=40 mg day-1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0-4, 4-8, 8-12, 12-16, 16-20, and 20-24 h after dose. R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/P(AUC) was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg(-1). For immature milk (n = 8) the M/P(AUC) for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/P(AUCs) for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). Breastfeeding during medium to high dose methadone appears to be 'safe' according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk-benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome.


Responsiveness to thyroid hormone and to ambient temperature underlies differences between brown adipose tissue and skeletal muscle thermogenesis in a mouse model of diet-induced obesity.
Thyroid hormone accelerates energy expenditure (EE) and is critical for cold-induced thermogenesis. To define the metabolic role played by thyroid hormone in the dissipation of calories from diet, hypothyroid mice were studied for 60 d in a comprehensive lab animal monitoring system. Hypothyroidism decreased caloric intake and body fat while down-regulating genes in the skeletal muscle but not brown adipose tissue thermogenic programs, without affecting daily EE. Only at thermoneutrality (30 C) did hypothyroid mice exhibit slower rate of EE, indicating a metabolic response to hypothyroidism that depends on ambient temperature. A byproduct of this mechanism is that at room temperature (22 C), hypothyroid mice are protected against diet-induced obesity, i.e. only at thermoneutrality did hypothyroid mice become obese when placed on a high-fat diet (HFD). This is in contrast to euthyroid controls, which on a HFD gained more body weight and fat at any temperature while activating the brown adipose tissue and accelerating daily EE but not the skeletal muscle thermogenic program. In the liver of euthyroid controls, HFD caused an approximately 5-fold increase in triglyceride content and expression of key metabolic genes, whereas acclimatization to 30 C cut triglyceride content by half and normalized gene expression. However, in hypothyroid mice, HFD-induced changes in liver persisted at 30 C, resulting in marked liver steatosis. Acclimatization to thermoneutrality dramatically improves glucose homeostasis, but this was not affected by hypothyroidism. In conclusion, hypothyroid mice are metabolically sensitive to environmental temperature, constituting a mechanism that defines resistance to diet-induced obesity and hepatic lipid metabolism.


Biochemical Identification of Nonmethylated DNA by BioCAP-Seq.
CpG islands are regions of vertebrate genomes that often function as gene regulatory elements and are associated with most gene promoters. CpG island elements usually contain nonmethylated CpG dinucleotides, while the remainder of the genome is pervasively methylated. We developed a biochemical approach called biotinylated CxxC affinity purification (BioCAP) to unbiasedly isolate regions of the genome that contain nonmethylated CpG dinucleotides. The resulting highly pure nonmethylated DNA is easily analyzed by quantitative PCR to interrogate specific loci or via massively parallel sequencing to yield genome-wide profiles.


Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter.
The catecholamine uptake inhibitor tetrabenazine (TBZ) binds to a high affinity site on the chromaffin granule membrane, presumably on the monoamine transporter. The hydrophobicity of the TBZ-binding site was investigated by comparing the potency of drugs to displace [3H]dihydrotetrabenazine (TBZOH), a ligand of the TBZ-binding site, with the lipophilicity of these drugs reflected by their octanol/buffer apparent partition coefficient (P o/b). Drugs tested were five substrates of the transporter, seven TBZ derivatives, and the inhibitors reserpine, haloperidol, and chlorpromazine. The validity of apparent P o/b as an index of lipophilicity was shown by measuring drug partitioning between buffer and chromaffin granule membranes. For most of the inhibitors tested, octanol/buffer and membrane/buffer apparent partition coefficients were correlated. For substrates of uptake and TBZ derivatives, the potency of a compound to displace [3H]TBZOH from its binding site was correlated to its apparent P o/b. This relationship was valid over a range of 5 orders of magnitude. These data are interpreted as indicating that the TBZ-binding site is hydrophobic and is in equilibrium with the ligand present in the membrane phase, and that substrates and TBZ derivatives are characterized by an equal intrinsic affinity for this site of about 1 microM. The 3-fold difference in affinity observed between alpha- and beta-diastereoisomers of TBZOH was accounted for by a similar difference in apparent P o/b. Reserpine, haloperidol, and chlorpromazine have much lower intrinsic affinity for the TBZ-binding site.


Contribution of aggregation to the growth mechanism of seeded calcium carbonate precipitation in the presence of polyacrylic acid.
Our work investigates the precipitation mechanism of a seeded calcium carbonate reaction, by using cryogenic TEM to observe the early stages of the reaction. The early precipitation of a hydrated phase is proposed as an intermediate phase before transformation into calcite. Thermodynamic modeling in conjunction with pH, surface potential measurements, and colloidal stability modeling demonstrate that calcite growth is dominated by agglomeration. This is in agreement with the cryogenic TEM observations, which suggest oriented attachment dominates early aggregation. The final stage of the reaction is described by a ripening mechanism that is significantly inhibited when high concentrations of polyacrylic acid (PAA) are used. The different concentrations of PAA lead to significant differences in the final particle substructure observed using cross section TEM. At low PAA concentrations, single crystal particles result, coherent with the proposed early oriented attachment mechanism and interfacial energy calculations. A core shell model is proposed for high PAA concentrations, whereas internal ripening of nanosized pores has been observed for low PAA concentrations, suggesting trapped solvent during the rapid initial particle formation at the relatively high supersaturations (S = 30) investigated.


Turning cold tumors into hot tumors: harnessing the potential of tumor immunity using nanoparticles.
Immune checkpoint inhibitors have considerably changed the landscape of oncology. However apart from world-acclaimed success stories limited to melanoma and lung cancer, many solid tumors failed to respond to immune checkpoint inhibitors due to limited immunogenicity, unfavorable tumor micro-environments (TME), lack of infiltrating T lymphocytes or increases in Tregs. Areas covered: Combinatorial strategies are foreseen as the future of immunotherapy and using cytotoxics or modulating agents is expected to boost the efficacy of immune checkpoint inhibitors. In this respect, nanoparticles displaying unique pharmacokinetic features such as tumor targeting properties, optimal payload delivery and long-lasting interferences with TME, are promising candidates for such combinations. This review covers the basis, expectancies, limits and pitfalls of future combination between nanoparticles and immune check point inhibitors. Expert opinion: Nanoparticles allow optimal delivery of variety of payloads in tumors while sparing healthy tissue, thus triggering immunogenic cell death. Depleting tumor stroma could further help immune cells and monoclonal antibodies to better circulate in the TME, plus immune-modulating properties of the charged cytotoxics. Finally, nanoparticles themselves present immunogenicity and antigenicity likely to boost immune response at the tumor level.


Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery.
After coronary artery bypass surgery, patients have a high cumulative rate of graft closure and recurrent ischemic events. We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin, the accepted standard, in these patients. The event rates for all-cause mortality, vascular death, myocardial infarction, stroke, and rehospitalization were determined for the 1480 patients with a history of cardiac surgery randomized to either clopidogrel or aspirin in a trial of 19 185 patients. The event rate per year of vascular death, myocardial infarction, stroke, or rehospitalization was 22.3% in the 705 patients randomized to aspirin and 15.9% in the 775 patients randomized to clopidogrel (P:=0.001). A risk reduction was also seen in each of the individual end points examined, including a 42.8% relative risk reduction in vascular death in patients on clopidogrel versus aspirin (P:=0.030). In a multivariate model incorporating baseline clinical characteristics, clopidogrel therapy was independently associated with a decrease in vascular death, myocardial infarction, stroke, or rehospitalization in patients with a history of cardiac surgery, with a 31.2% relative risk reduction (95% CI, 15.8 to 43.8; P:=0.0003). Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) population, multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit (P:=0.015). Compared with aspirin, clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery, along with a decreased risk of bleeding.


Proceedings from the First Global Artificial Intelligence in Gastroenterology and Endoscopy Summit.
Artificial intelligence (AI), specifically deep learning, offers the potential to enhance the field of GI endoscopy in areas ranging from lesion detection and classification to quality metrics and documentation. Progress in this field will be measured by whether AI implementation can lead to improved patient outcomes and more efficient clinical workflow for GI endoscopists. The aims of this article are to report the findings of a multidisciplinary group of experts focusing on issues in AI research and applications related to gastroenterology and endoscopy, to review the current status of the field, and to produce recommendations for investigators developing and studying new AI technologies for gastroenterology. A multidisciplinary meeting was held on September 28, 2019, bringing together academic, industry, and regulatory experts in diverse fields including gastroenterology, computer and imaging sciences, machine learning, computer vision, U.S. Food and Drug Administration, and the National Institutes of Health. Recent and ongoing studies in gastroenterology and current technology in AI were presented and discussed, key gaps in knowledge were identified, and recommendations were made for research that would have the highest impact in making advances and implementation in the field of AI to gastroenterology. There was a consensus that AI will transform the field of gastroenterology, particularly endoscopy and image interpretation. Powered by advanced machine learning algorithms, the use of computer vision in endoscopy has the potential to result in better prediction and treatment outcomes for patients with gastroenterology disorders and cancer. Large libraries of endoscopic images, "EndoNet," will be important to facilitate development and application of AI systems. The regulatory environment for implementation of AI systems is evolving, but common outcomes such as colon polyp detection have been highlighted as potential clinical trial endpoints. Other threshold outcomes will be important, as well as clarity on iterative improvement of clinical systems. Gastroenterology is a prime candidate for early adoption of AI. AI is rapidly moving from an experimental phase to a clinical implementation phase in gastroenterology. It is anticipated that the implementation of AI in gastroenterology over the next decade will have a significant and positive impact on patient care and clinical workflows. Ongoing collaboration among gastroenterologists, industry experts, and regulatory agencies will be important to ensure that progress is rapid and clinically meaningful. However, several constraints and areas will benefit from further exploration, including potential clinical applications, implementation, structure and governance, role of gastroenterologists, and potential impact of AI in gastroenterology.


An adenovirus mutant that replicates selectively in p53-deficient human tumor cells.
The human adenovirus E1B gene encodes a 55-kilodalton protein that inactivates the cellular tumor suppressor protein p53. Here it is shown that a mutant adenovirus that does not express this viral protein can replicate in and lyse p53-deficient human tumor cells but not cells with functional p53. Ectopic expression of the 55-kilodalton EIB protein in the latter cells rendered them sensitive to infection with the mutant virus. Injection of the mutant virus into p53-deficient human cervical carcinomas grown in nude mice caused a significant reduction in tumor size and caused complete regression of 60 percent of the tumors. These data raise the possibility that mutant adenoviruses can be used to treat certain human tumors.


Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes.
Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans. In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg. EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients. Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.


Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging.
Physical exercise, particularly aerobic exercise, is documented as providing a low cost regimen to counter well-documented cognitive declines including memory, executive function, visuospatial skills, and processing speed in normally aging adults. Prior aging studies focused largely on the effects of medium to long term (>6 months) exercise training; however, the shorter term effects have not been studied. In the present study, we examined changes in brain blood flow, cognition, and fitness in 37 cognitively healthy sedentary adults (57-75 years of age) who were randomized into physical training or a wait-list control group. The physical training group received supervised aerobic exercise for 3 sessions per week 1 h each for 12 weeks. Participants' cognitive, cardiovascular fitness and resting cerebral blood flow (CBF) were assessed at baseline (T1), mid (T2), and post-training (T3). We found higher resting CBF in the anterior cingulate region in the physical training group as compared to the control group from T1 to T3. Cognitive gains were manifested in the exercise group's improved immediate and delayed memory performance from T1 to T3 which also showed a significant positive association with increases in both left and right hippocampal CBF identified earlier in the time course at T2. Additionally, the two cardiovascular parameters, VO2 max and rating of perceived exertion (RPE) showed gains, compared to the control group. These data suggest that even shorter term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.


Surface-Based Structure Analysis and Visualization for Multifield Time-Varying Datasets.
This paper introduces a new feature analysis and visualization method for multifield datasets. Our approach applies a surface-centric model to characterize salient features and form an effective, schematic representation of the data. We propose a simple, geometrically motivated, multifield feature definition. This definition relies on an iterative algorithm that applies existing theory of skeleton derivation to fuse the structures from the constitutive fields into a coherent data description, while addressing noise and spurious details. This paper also presents a new method for non-rigid surface registration between the surfaces of consecutive time steps. This matching is used in conjunction with clustering to discover the interaction patterns between the different fields and their evolution over time. We document the unified visual analysis achieved by our method in the context of several multifield problems from large-scale time-varying simulations.


Asymmetric Total Synthesis of Distaminolyne A and Revision of Its Absolute Configuration.
The first total synthesis of a marine derived polyacetylene, distaminolyne A, and its enantiomer were achieved from the commercially available undec-10-en-1-ol. A key proline-catalyzed asymmetric α-aminooxylation of an aldehyde intermediate was used to introduce the chiral center en route to the enantiomerically pure 1,2-amino alcohols. The absolute configuration of both synthesized enantiomers of distaminolyne A was confirmed by using chiral derivatizing agents, leading to revision of the natural product absolute configuration from 2S to 2R. Antibacterial, pancreatic lipase (PL) inhibitory, and protein-tyrosine phosphatase 1B (PTP1B) inhibitory activities were evaluated.


Does clinician's knowledge of B-type natriuretic peptide levels translate to improvement of quality of life and less hospitalization days in patients with heart failure?
This pilot study was conducted to determine whether clinicians' knowledge of b-type natriuretic peptide (BNP) levels in individuals with heart failure (HF) correlates with better outcomes including quality of life (QOL) and hospital length of stay (LOS) over a 90-day period. HF clinic patients were randomized into 2 groups: clinician aware (BNP group; n=50) or blinded to BNP levels (control group; n=42). BNP levels were measured at baseline using the BNP Immunoassay Kit. QOL was measured by the Minnesota Living with Heart Failure (MLWHF) questionnaire, and hospital LOS were measured at baseline and 90 days. There was no significant difference in BNP levels between groups. Compared with baseline scores (46.87+/-29.63), mean QOL scores at 90 days (37.46+/-28.67) were not significantly different for both groups. Hospital LOS was also similar for both groups (mean=3 days). BNP levels were significantly correlated with New York Heart Association classification (P=.05), ejection fraction (P=0.0001), creatinine levels (P=0.05), and overall Minnesota Living with Heart Failure Questionnaire scores (P=.01). Clinician's knowledge of BNP levels is not associated with better outcomes of QOL or hospital LOS in HF patients. However, BNP levels are correlated with functional status and physiological parameters. Further research is needed to determine whether other factors influence QOL and hospital LOS of HF patients.


Treatment of infected knee arthroplasty.
Forty-eight patients with 51 infected knee arthroplasties were treated at the authors' institution between 1973 and 1986 and followed for 5.5 (range, 0-14) years. Six methods to treat the infections were employed: antibiotics only, soft-tissue surgery, removal of the prosthesis, revision arthroplasty, arthrodesis, and amputation. Failure of the initial surgical treatment led to second revision surgery in 20 patients. At the follow-up examination, three patients (five knees) had died from septic complications and two patients had had above-knee amputation. Two of 32 patients had been successfully treated with antibiotics with no additional surgery. Four patients had successful soft-tissue surgery. Following removal of the prosthesis, the infection healed in four patients. In 12 of 19 patients (13 knees) with revision arthroplasty the infection healed, but only seven of these had functioning prostheses. The infection healed in all but one of the 21 patients with arthrodeses, and all but two were fused. Infected compartmental prostheses with good bone stock can be treated with an exchange arthroplasty using a two-stage procedure with tricompartmental revision prostheses. Otherwise, an arthrodesis using a two-stage procedure is recommended for the treatment of infected knee arthroplasty.


Explosive deep water basalt in the sumisu backarc rift.
Eruption of 1-million-year-old tholeiitic basalt >1800 meters below sea level (>18 megapascals) in a backarc rift behind the Bonin arc produced a scoriaceous breccia similar in some respects to that formed during subaerial eruptions. Explosion of the magma is thought to have produced frothy agglutinate which welded either on the sea floor or in a submarine eruption column. The resulting 135-meter-thick pyroclastic deposit has paleomagnetic inclinations that are random at a scale of <2.5 meters. High magmatic water content, which is about 1.3 percent by weight after vesiculation, contributed to the explosivity.