Multi-generational pharmacophore modeling for ligands to the cholane steroid-recognition site in the β₁ modulatory subunit of the BKCa channel.
Large conductance, voltage- and Ca(2+)-gated K(+) (BKCa) channels play a critical role in smooth muscle contractility and thus represent an emerging therapeutic target for drug development to treat vascular disease, gastrointestinal, bladder and uterine disorders. Several compounds are known to target the ubiquitously expressed BKCa channel-forming α subunit. In contrast, just a few are known to target the BKCa modulatory β1 subunit, which is highly expressed in smooth muscle and scarce in most other tissues. Lack of available high-resolution structural data makes structure-based pharmacophore modeling of β1 subunit-dependent BKCa channel activators a major challenge. Following recent discoveries of novel BKCa channel activators that act via β1 subunit recognition, we performed ligand-based pharmacophore modeling that led to the successful creation and fine-tuning of a pharmacophore over several generations. Initial models were developed using physiologically active cholane steroids (bile acids) as template. However, as more compounds that act on BKCa β1 have been discovered, our model has been refined to improve accuracy. Database searching with our best-performing model has uncovered several novel compounds as candidate BKCa β1 subunit ligands. Eight of the identified compounds were experimentally screened and two proved to be activators of recombinant BKCa β1 complexes. One of these activators, sobetirome, differs substantially in structure from any previously reported activator.


Magnetic resonance imaging features of discospondylitis in dogs.
The diagnosis of discospondylitis is based mainly on diagnostic imaging and laboratory results. Herein, we describe the magnetic resonance imaging (MRI) findings in 13 dogs with confirmed discospondylitis. In total there were 17 sites of discospondylitis. Eleven (81.1%) of the dogs had spinal pain for >3 weeks and a variable degree of neurologic signs. Two dogs had spinal pain and ataxia for 4 days. Radiographs were available in nine of the dogs. In MR images there was always involvement of two adjacent vertebral endplates and the associated disk. The involved endplates and adjacent marrow were T1-hypointense with hyperintensity in short tau inversion recovery (STIR) images in all dogs, and all dogs also had contrast enhancement of endplates and paravertebral tissues. The intervertebral disks were hyperintense in T2W and STIR images and characterized by contrast enhancement in 15 sites (88.2%). Endplate erosion was present in 15 sites (88.2%) and was associated with T2-hypointense bone marrow adjacent to it. In two sites (11.8%) endplate erosion was not MR images or radiographically. The vertebral bone marrow in these sites was T2-hyperintense. Epidural extension was conspicuous in postcontrast images at 15 sites (88.2%). Spinal cord compression was present at 15 sites (88.2%), and all affected dogs had neurologic signs. Subluxation was present in two sites (11.8%). MRI shows characteristic features of discospondylitis, and it allows the recognition of the exact location and extension (to the epidural space and paravertebral soft tissues) of the infection. Furthermore, MRI increases lesion conspicuity in early discospondylitis that may not be visualized by radiography.


[Daily life of schizofrenia patients after the use of clozapine and group follow up].
This study was carried out with a sample of 11 patients who are part of the atypical medication group at the Hospital das Clínicas of the University of São Paulo at Ribeirão Preto's School of Medicine. For data collection semi-structured interviews guided by a script were held in April 2003. The interviews were first taped and fully transcribed afterwards. Results indicated an improvement in patients' symptoms, demonstrated by decreased social isolation, resumption of home/work activities and studies, as well as by participation in social events. They also point out to the need for a new vision regarding patients who suffer from mental disorders and their family members in the sense of searching for adequate therapeutic attitudes that have an impact on the production of life, aimed at giving a new existential meaning in the different forms of social contact and sociability.


Taste papilla cell differentiation requires the regulation of secretory protein production by ALK3-BMP signaling in the tongue mesenchyme.
Taste papillae are specialized organs, each of which comprises an epithelial wall hosting taste buds and a core of mesenchymal tissue. In the present study, we report that during early taste papilla development in mouse embryos, bone morphogenetic protein (BMP) signaling mediated by type 1 receptor ALK3 in the tongue mesenchyme is required for epithelial Wnt/β-catenin activity and taste papilla differentiation. Mesenchyme-specific knockout (cKO) of Alk3 using Wnt1-Cre and Sox10-Cre resulted in an absence of taste papillae at E12.0. Biochemical and cell differentiation analyses demonstrated that mesenchymal ALK3-BMP signaling governed the production of previously unappreciated secretory proteins, i.e. it suppressed those that inhibit and facilitated those that promote taste papilla differentiation. Bulk RNA-sequencing analysis revealed many more differentially expressed genes (DEGs) in the tongue epithelium than in the mesenchyme in Alk3 cKO versus control. Moreover, we detected downregulated epithelial Wnt/β-catenin signaling and found that taste papilla development in the Alk3 cKO was rescued by the GSK3β inhibitor LiCl, but not by Wnt3a. Our findings demonstrate for the first time the requirement of tongue mesenchyme in taste papilla cell differentiation.


Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.
Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.


Vegan-vegetarian diets in pregnancy: danger or panacea? A systematic narrative review.
Although vegan-vegetarian diets are increasingly popular, no recent systematic reviews on vegan-vegetarian diets in pregnancy exist. To review the literature on vegan-vegetarian diets and pregnancy outcomes. PubMed, Embase, and the Cochrane library were searched from inception to September 2013 for pregnancy and vegan or vegetarian Medical Subject Headings (MeSH) and free-text terms. Vegan or vegetarian diets in healthy pregnant women. We excluded case reports and papers analysing vegan-vegetarian diets in poverty and malnutrition. Searching, paper selection, and data extraction were performed in duplicate. The high heterogeneity of the studies led to a narrative review. We obtained 262 full texts from 2329 references; 22 selected papers reporting maternal-fetal outcomes (13) and dietary deficiencies (nine) met the inclusion criteria. None of the studies reported an increase in severe adverse outcomes or in major malformations, except one report of increased hypospadias in infants of vegetarian mothers. Five studies reported vegetarian mothers had lower birthweight babies, yet two studies reported higher birthweights. The duration of pregnancy was available in six studies and was similar between vegan-vegetarians and omnivores. The nine heterogeneous studies on microelements and vitamins suggest vegan-vegetarian women may be at risk of vitamin B12 and iron deficiencies. The evidence on vegan-vegetarian diets in pregnancy is heterogeneous and scant. The lack of randomised studies prevents us from distinguishing the effects of diet from confounding factors. Within these limits, vegan-vegetarian diets may be considered safe in pregnancy, provided that attention is paid to vitamin and trace element requirements.


The yeast Snt2 protein coordinates the transcriptional response to hydrogen peroxide-mediated oxidative stress.
Regulation of gene expression is a vital part of the cellular stress response, yet the full set of proteins that orchestrate this regulation remains unknown. Snt2 is a Saccharomyces cerevisiae protein whose function has not been well characterized that was recently shown to associate with Ecm5 and the Rpd3 deacetylase. Here, we confirm that Snt2, Ecm5, and Rpd3 physically associate. We then demonstrate that cells lacking Rpd3 or Snt2 are resistant to hydrogen peroxide (H2O2)-mediated oxidative stress and use chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) to show that Snt2 and Ecm5 recruit Rpd3 to a small number of promoters and in response to H2O2, colocalize independently of Rpd3 to the promoters of stress response genes. By integrating ChIP-seq and expression analyses, we identify target genes that require Snt2 for proper expression after H2O2. Finally, we show that cells lacking Snt2 are also resistant to nutrient stress imparted by the TOR (target of rapamycin) pathway inhibitor rapamycin and identify a common set of genes targeted by Snt2 and Ecm5 in response to both H2O2 and rapamycin. Our results establish a function for Snt2 in regulating transcription in response to oxidative stress and suggest Snt2 may also function in multiple stress pathways.


Influence of total reflection on the imaging quality of optical systems.
In the case of total reflection at a boundary surface between two different optical media, the ray reflected at the boundary is spatially shifted with respect to the point where the incident ray intersects the boundary. The light penetrates into the second medium, and the evanescent electromagnetic wave propagates along the boundary. The described effect is called the Goos-Hänchen effect. Our work describes the influence of the Goos-Hänchen effect on the imaging properties of planar optical systems, and a differential equation of a wave-front meridian that corresponds to a reflected bundle of rays is derived. It is shown that the wave front can be described by the d'Alambert differential equation. This equation makes it possible to determine the coordinates of individual points on the wave-front meridian. The influence of total reflection on the value of the Strehl definition of the reflected ray bundle, is also investigated.


Psychometric Evaluation of the Young Children's Participation and Environment Measure (YC-PEM) for use in Singapore.
To estimate the psychometric properties of a culturally adapted version of the Young Children's Participation and Environment Measure (YC-PEM) for use among Singaporean families. This is a prospective cohort study. Caregivers of 151 Singaporean children with (n = 83) and without (n = 68) developmental disabilities, between 0 and 7 years, completed the YC-PEM (Singapore) questionnaire with 3 participation scales (frequency, involvement, and change desired) and 1 environment scale for three settings: home, childcare/preschool, and community. Setting-specific estimates of internal consistency, test-retest reliability, and construct validity were obtained. Internal consistency estimates varied from .59 to .92 for the participation scales and .73 to .79 for the environment scale. Test-retest reliability estimates from the YC-PEM conducted on two occasions, 2-3 weeks apart, varied from .39 to .89 for the participation scales and from .65 to .80 for the environment scale. Moderate to large differences were found in participation and perceived environmental support between children with and without a disability. YC-PEM (Singapore) scales have adequate psychometric properties except for low internal consistency for the childcare/preschool participation frequency scale and low test-retest reliability for home participation frequency scale. The YC-PEM (Singapore) may be used for population-level studies involving young children with and without developmental disabilities.


Change in choroidal vascularity in acute central serous chorioretinopathy.
This study aims to compare the effect of laser photocoagulation or observation on choroidal vascularity in acute central serous chorioretinopathy (CSCR). A retrospective analysis of 30 patients with acute CSCR treated either with laser photocoagulation (16 eyes) or sham laser (14 eyes) was performed. Demographic details, visual acuity (VA) assessment, and other relevant clinical data were considered from baseline to the 3rd and 6th month follow-up visits. Participants with chronic CSCR and missing follow-up or inadequate data were excluded. Choroidal analysis including choroidal thickness and choroidal vascularity index (CVI) assessment was done for each visit using Spectral Domain (SD) Optical Coherence Tomography (OCT) images. In laser arm group, there was a statistically significant change in VA, contrast sensitivity and central macular thickness (CMT) and neurosensory detachment (NSD) (P < 0.05) at the 3rd and 6th month visits. However, there was no statistically significant difference in subfoveal choroidal thickens (SFCT) and CVI (P > 0.05) at both the visits. In sham laser group, similarly, there was a significant improvement in VA, contrast sensitivity, CMT, and CVI (P < 0.05) at the 3rd and 6th month visits. There was significant reduction in NSD at the 3rd month; however, it was not statistically significant at the 6th month visit. SFCT did not change significantly at both the visits. There was no significant difference for the changes in parameters between the groups at the 6th month. Regression analysis showed no significant correlation with final VA with any of the baseline parameters. Early laser photocoagulation does lead to change in choroidal morphology, though insignificant, in comparison to observation. The present data, yet again, support no additional benefit of early laser photocoagulation in acute CSCR.


Dopamine prediction error responses integrate subjective value from different reward dimensions.
Prediction error signals enable us to learn through experience. These experiences include economic choices between different rewards that vary along multiple dimensions. Therefore, an ideal way to reinforce economic choice is to encode a prediction error that reflects the subjective value integrated across these reward dimensions. Previous studies demonstrated that dopamine prediction error responses reflect the value of singular reward attributes that include magnitude, probability, and delay. Obviously, preferences between rewards that vary along one dimension are completely determined by the manipulated variable. However, it is unknown whether dopamine prediction error responses reflect the subjective value integrated from different reward dimensions. Here, we measured the preferences between rewards that varied along multiple dimensions, and as such could not be ranked according to objective metrics. Monkeys chose between rewards that differed in amount, risk, and type. Because their choices were complete and transitive, the monkeys chose "as if" they integrated different rewards and attributes into a common scale of value. The prediction error responses of single dopamine neurons reflected the integrated subjective value inferred from the choices, rather than the singular reward attributes. Specifically, amount, risk, and reward type modulated dopamine responses exactly to the extent that they influenced economic choices, even when rewards were vastly different, such as liquid and food. This prediction error response could provide a direct updating signal for economic values.


The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling.
Protein arginine methylation regulates diverse functions of eukaryotic cells, including gene expression, the DNA damage response, and circadian rhythms. We showed that arginine residues within the third intracellular loop of the human D2 dopamine receptor, which are conserved in the DOP-3 receptor in the nematode Caenorhabditis elegans, were methylated by protein arginine methyltransferase 5 (PRMT5). By mutating these arginine residues, we further showed that their methylation enhanced the D2 receptor-mediated inhibition of cyclic adenosine monophosphate (cAMP) signaling in cultured human embryonic kidney (HEK) 293T cells. Analysis of prmt-5-deficient worms indicated that methylation promoted the dopamine-mediated modulation of chemosensory and locomotory behaviors in C. elegans through the DOP-3 receptor. In addition to delineating a previously uncharacterized means of regulating GPCR (heterotrimeric guanine nucleotide-binding protein-coupled receptor) signaling, these findings may lead to the development of a new class of pharmacological therapies that modulate GPCR signaling by changing the methylation status of these key proteins.


Novel electronic refreshers for cardiopulmonary resuscitation: a randomized controlled trial.
Currently the American Red Cross requires that individuals renew their cardiopulmonary resuscitation (CPR) certification annually; this often requires a 4- to 8-hour refresher course. Those trained in CPR often show a decrease in essential knowledge and skills within just a few months after training. New electronic means of communication have expanded the possibilities for delivering CPR refreshers to members of the general public who receive CPR training. The study's purpose was to determine the efficacy of three novel CPR refreshers--online website, e-mail and text messaging--for improving three outcomes of CPR training--skill retention, confidence for using CPR and intention to use CPR. These three refreshers may be considered "novel" in that they are not typically used to refresh CPR knowledge and skills. The study conducted two randomized clinical trials of the novel CPR refreshers. A mailed brochure was a traditional, passive refresher format and served as the control condition. In Trial 1, the refreshers were delivered in a single episode at 6 months after initial CPR training. In Trial 2, the refreshers were delivered twice, at 6 and 9 months after initial CPR training, to test the effect of a repeated delivery. Outcomes for the three novel refreshers vs. the mailed brochure were determined at 12 months after initial CPR training. Assignment to any of three novel refreshers did not improve outcomes of CPR training one year later in comparison with receiving a mailed brochure. Comparing outcomes for subjects who actually reviewed some of the novel refreshers vs. those who did not indicated a significant positive effect for one outcome, confidence for performing CPR. The website refresher was associated with increased behavioral intent to perform CPR. Stated satisfaction with the refreshers was relatively high. The number of episodes of refreshers (one vs. two) did not have a significant effect on any outcomes. There was no consistent evidence for the superiority of novel refreshers as compared with a traditional mailed brochure, but the low degree of actual exposure to the materials does not allow a definitive conclusion. An online web-based approach seems to have the most promise for future research on electronic CPR refreshers.


ACEi/ARB for systolic heart failure: closing the quality gap with a sustainable intervention at an academic medical center.
National guidelines recommend angiotensin converting enzyme inhibitor (ACEi) or angiotensinogen receptor blocker (ARB) therapy for patients with left ventricular systolic dysfunction (LVSD), including those with symptomatic heart failure (HF). However, guideline adherence has not been optimal. The goal of this quality improvement project is to devise and implement a sustainable care-delivery model in a 920-bed academic hospital center that would improve ACEi/ARB adherence before hospital discharge. The Model of intervention is: (1) a computer-based daily screening program; (2) inpatient pharmacist e-flag message; and (3) alerts for inpatient care teams. Its operating algorithm: If eligible adult HF/LVSD inpatients are not on ACEi or ARB nor documentation of contraindications, a flag alert is generated; deficiency is confirmed by a pharmacist and conveyed to the patient-care teams; if alert is acted on and care brought into adherence, the screening program would not re-flag the same patients the succeeding day; if not, the patients would be re-flagged daily until reaching adherence. We compared ACEi/ARB adherence before, during, and after the intervention. Baseline performance (percentage of eligible HF/LVSD patients receiving ACEi/ARB) was 87.5%. After implementation of the Model the ACEi/ARB adherence rate at the time of hospital discharge rose to 96.7% (P < 0.002) and was sustained for 21 months without needing additional personnel. A carefully designed, computer-based care-delivery model is highly efficient and sustainable for enhancing ACEi/ARB adherence.


Synaptotagmins in membrane traffic: which vesicles do the tagmins tag?
The aim of this review is to give a broad picture of what is actually known about the synaptotagmin family. Synaptotagmin I is an abundant synaptic vesicle and secretory granule protein in neurons and endocrine cells which plays a key role in Ca(2+)-induced exocytosis. It belongs to the large family of C2 domain-proteins as it contains two internal repeats that have homology to the C2 domain of protein kinase C. Eleven synaptotagmin genes have been described in rat and mouse. Except for synaptotagmin I, and by analogy synaptotagmin II, the functions of these proteins are unknown. In this review we focus on data obtained on the various isoforms without exhaustively discussing the role of synaptotagmin I in neurotransmission. Numerous in vitro interactions of synaptotagmin I with key components of the exocytosis-endocytosis machinery have been reported. Additional data concerning the other synaptotagmins are now becoming available and are reviewed here. Only interactions which have been described for several synaptotagmins, are mentioned. It is unlikely that a single isoform displays all of these potential interactions in vivo and probably the subcellular distribution of the protein will favor some of them and preclude others. Therefore, to discuss the putative role of the various synaptotagmins we have examined in detail published data concerning their localization.


Cullin 3SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6.
The histone deacetylase 6 (HDAC6) plays critical roles in human tumorigenesis and metastasis. As such, HDAC6-selective inhibitors have entered clinical trials for cancer therapy. However, the upstream regulator(s), especially ubiquitin E3 ligase(s), responsible for controlling the protein stability of HDAC6 remains largely undefined. Here, we report that Cullin 3SPOP earmarks HDAC6 for poly-ubiquitination and degradation. We found that the proteasome inhibitor MG132, or the Cullin-based E3 ligases inhibitor MLN4924, but not the autophagosome-lysosome inhibitor bafilomycin A1, stabilized endogenous HDAC6 protein in multiple cancer cell lines. Furthermore, we demonstrated that Cullin 3-based ubiquitin E3 ligase(s) primarily reduced the stability of HDAC6. Importantly, we identified SPOP, an adaptor protein of Cullin 3 family E3 ligases, specifically interacted with HDAC6, and promoted its poly-ubiquitination and subsequent degradation in cells. Notably, cancer-derived SPOP mutants disrupted their binding with HDAC6 and thereby failed to promote HDAC6 degradation. More importantly, increased cellular proliferation and migration in SPOP-depleted HCT116 colon cancer cells could be partly reversed by additional depletion of HDAC6, suggesting that HDAC6 is a key downstream effector for SPOP tumor suppressor function. Together, our data identify the tumor suppressor SPOP as an upstream negative regulator for HDAC6 stability, and SPOP loss-of-function mutations might lead to elevated levels of the HDAC6 oncoprotein to facilitate tumorigenesis and metastasis in various human cancers.


Analyzing age-specific genetic effects on human extreme age survival in cohort-based longitudinal studies.
The analysis of age-specific genetic effects on human survival over extreme ages is confronted with a deceleration pattern in mortality that deviates from traditional survival models and sparse genetic data available. As human late life is a distinct phase of life history, exploring the genetic effects on extreme age survival can be of special interest to evolutionary biology and health science. We introduce a non-parametric survival analysis approach that combines population survival information with individual genotype data in assessing the genetic effects in cohort-based longitudinal studies. Our approach is characterized by non-parametric analysis of late age survival to capture the observed pattern of mortality deceleration and frailty modeling to account for individual heterogeneity in unobserved frailty. The method is applied to ApoE genotype data in the Danish 1905 birth cohort to estimate effect of the e4 allele. Our results revealed an age-specific relative risk of the allele that increases nonlinearly with age and non-proportional patterns in hazard of death for carriers and non-carriers of the allele, suggesting that the e4 mutation preserves its deleterious effect that progressively affect human survival even at extreme ages.


Cdk2 catalytic activity is essential for meiotic cell division in vivo.
Cyclin-dependent kinases (Cdks) control the eukaryotic cell cycle by phosphorylating serine and threonine residues in key regulatory proteins, but some Cdk family members may exert kinase-independent functions that cannot easily be assessed using gene knockout approaches. While Cdk2-deficient mice display near-normal mitotic cell proliferation due to the compensatory activities of Cdk1 and Cdk4, they are unable to undergo meiotic generation of gametes and are consequently sterile. To investigate whether Cdk2 regulates meiosis via protein phosphorylation or by alternative kinase-independent mechanisms, we generated two different knockin mouse strains in which Cdk2 point mutations ablated enzyme activity without altering protein expression levels. Mice homozygous for the mutations Cdk2(D145N/D145N) or Cdk2(T160A/T160A) expressed only 'kinase-dead' variants of Cdk2 under the control of the endogenous promoter, and despite exhibiting normal expression of cell cycle regulatory proteins and complexes, both mutations rendered mice sterile. Mouse cells that expressed only 'kinase-dead' variants of Cdk2 displayed normal mitotic cell cycle progression and proliferation both in vitro and in vivo, indicating that loss of Cdk2 kinase activity exerted little effect on this mode of cell division. In contrast, the reproductive organs of Cdk2 mutant mice exhibited abnormal morphology and impaired function associated with defective meiotic cell division and inability to produce gametes. Cdk2 mutant animals were therefore comparable to gene knockout mice, which completely lack the Cdk2 protein. Together, our data indicate that the essential meiotic functions of Cdk2 depend on its kinase activity, without which the generation of haploid cells is disrupted, resulting in sterility of otherwise healthy animals.


Sleep stage characteristics of long and short sleepers.
The possibility of different sleep stage characteristics being associated with different sleep lengths was explored by comparing two groups of high school seniors, who characteristically slept 6(1/2) hours or less or who slept 8(1/2) hours or more, with an age-matched control group not selected on the basis of sleep length. All-night electroencephalography was used to examine the sleep stage characteristics of these groups. Compared with the unselected age-matched group, the short sleepers showed no significant diminution in their stage 4 (deep) or rapid eye movement (dream) sleep. The long sleepers were observed to obtain significantly more rapid eye movement sleep than did the other groups.


Exercise training improves liver steatosis in mice.
Non-alcoholic fatty liver disease (NAFLD) is rapidly turning into the most common liver disorder worldwide. One of the strategies that has been shown to effectively improve NAFLD is regular exercise, which seems to lower steatosis partly independent of weight loss. However, limited data are available about the mechanisms involved. The aim of the present study was to identify the mechanisms underlying the effect of regular exercise on liver steatosis. Non-obese male mice were rendered steatotic by feeding a sucrose-enriched choline-deficient diet. They were then subjected to daily treadmill running for three weeks, whereas the control mice remained sedentary. Compared to the untrained mice, trained mice showed similar adipose tissue mass but had significantly reduced size of lipid droplets in the liver coupled with a reduction in liver triglyceride content (~30 %, P < 0.05). Levels of various plasma lipid parameters and plasma glucose were similar between the trained and untrained mice, whereas levels of hepatic glycogen were significantly higher in the trained mice. Hepatic triglyceride secretion rate and de novo lipogenesis were unchanged between the two sets of mice, as were indicators of lipolysis and autophagy. Finally, whole genome expression profiling indicated a mild stimulatory effect of exercise training on PPARα-mediated regulation of oxidative metabolism, including fatty acid oxidation. Taken together, our study suggests that the lowering of hepatic steatosis by repeated exercise is likely due to activation of fuel oxidation pathways in liver.


An evaluation of the global network of field epidemiology and laboratory training programmes: a resource for improving public health capacity and increasing the number of public health professionals worldwide.
Given that many infectious diseases spread rapidly, across borders and species, there is a growing worldwide need to increase the number of public health professionals skilled in controlling infectious epidemics. Needed also are more public health professionals skilled in non-communicable disease surveillance and interventions. As a result, we surveyed all 57 field epidemiology training programmes (FETPs) that are members of the Training Program in Epidemiology and Public Health Interventions Network (TEPHINET), to evaluate the progress of the FETPs, the only global applied epidemiology network, toward increasing public health capacity globally. Data on the FETP programmes and the training they provide were abstracted from TEPHINET membership surveys and verified with FETP directors for all FETPs that were members of TEPHINET in 2012. Data on abstracts submitted to the recent TEPHINET Global Scientific Conference, on recent accomplishments by each FETP, and on quality improvement were also compiled to provide a worldwide view of the public health human resource capacity produced by these programmes. A total of 6980 public health professionals worldwide have graduated from an FETP or from the Center for Disease Control and Prevention's Epidemiology Intelligence Service (EIS). FETP residents and graduates participate in key public health prevention, control, and response activities. Each FETP has adapted its curriculum and objectives over time to align with its country's public health priorities. FETPs are well integrated into their national public health infrastructures, and they have many partners at the national, regional and global levels. FETPs are a competent and diverse source of highly skilled public health professionals who contribute significantly to public health's global human resource needs. This finding is evidenced by 1) the training curricula that were adapted over time to meet public health's human resource needs, 2) the FETPs' continued support from internal and external partners, 3) the increasing number of FETP residents and graduates and their increasing contribution to effective public health work, and 4) the increased quality improvement initiatives facilitated through the FETPs membership in one global network, TEPHINET.


Effects of pH and substrate on the competition between glycogen and phosphorus accumulating organisms.
This article evaluates effects of pH and substrate on the competition between glycogen (GAOs) and phosphorus accumulating organisms (PAOs). A sequencing batch reactor system was operated for enhanced biological phosphorus removal (EBPR) with acetate as the sole carbon source and acetate added domestic wastewater at different influent acetate/phosphate ratios. Some batch tests were performed using acetate added domestic wastewater at different influent acetate, phosphate ratios, with different initial pH values of acetate and domestic wastewater mixture. The resulting experimental data supported the presence of GAOs for all tested HAC P ratios, especially under P limiting conditions for acetate as sole carbon source. Strong evidence is observed that acetate added domestic wastewater system had higher PAOs fraction than acetate system as sole source carbon, with using model components, namely substrate uptake, glycogen utilization and P release.


Access to essential medicines for sexual and reproductive health care: the role of the pharmaceutical industry and international regulation.
The range of medicines and technologies that are essential for sexual and reproductive health care is well established, but access to them is far from universally assured, particularly in less developed countries. This paper shows how the pharmaceutical industry plays a major role in the lack of access to essential medicines for sexual and reproductive health care, by a) investing in products for profit-making reasons despite their negative health impact (e.g. hormone replacement therapy), b) marketing new essential medicines at prices beyond the reach of countries that most need them (e.g. HPV vaccines), and c) failing to invest in the development of new products (e.g. microbicides and medical abortion pills). Small companies, some of them non-profit-making, struggle to fill some of that demand (e.g. for female condoms). International patent protection contributes to high prices of medicines, and while international agreements such as compulsory licensing under TRIPS and the Medicines Patent Pool allow for mechanisms to enable poorer countries to get access to essential medicines, the obstacles created by "big pharma" are daunting. All these barriers have fostered a market in sub-standard medicines (e.g. fake medical abortion pills sold over the internet). An agenda driven by sexual and reproductive health needs, based on the right to health, must focus on universal access to essential medicines at prices developing countries can afford. We call for greater public investment in essential medicines, expanded production of affordable generic drugs, and the development of broad strategic plans, that include affordable medicines and technologies, for addressing identified public health problems, such as cervical cancer.


Determination of interferometer phase distributions by use of wavelets.
A new technique for directly extracting phase gradients from two-dimensional (2-D) interferometer fringe data is presented. One finds the gradients by tracking the maximum modulus of the continuous wavelet transform of the fringe data and the phase distribution that is obtained, with a small error, by integration. Problems associated with phase unwrapping are thereby avoided. The technique is compared with standard methods, and excellent agreement is found. In common with Fourier-transform methods, the technique is capable of extracting the full 2-D phase distribution from a single image.


PE/PPE proteins mediate nutrient transport across the outer membrane of Mycobacterium tuberculosis.
Mycobacterium tuberculosis has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to the periplasm. We discovered that 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) inhibits the growth of M. tuberculosis, and resistance to this compound is conferred by mutation within a member of the proline-proline-glutamate (PPE) family, PPE51. Deletion of PPE51 rendered M. tuberculosis cells unable to replicate on propionamide, glucose, or glycerol. Growth was restored upon loss of the mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation of the corresponding substrate. Phthiocerol dimycocerosate determined the low permeability of the mycobacterial outer membrane, and the PE/PPE proteins apparently act as solute-specific channels.


EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.
Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.


Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic IBD center.
Despite dietary factors being implicated in the pathogenesis of inflammatory bowel disease (IBD), nutritional therapy, outside of exclusive enteral nutrition (EEN), has not had a defined role within the treatment paradigm of pediatric IBD within IBD centers. Based on emerging data, Seattle Children's Hospital IBD Center has developed an integrated dietary program incorporating the specific carbohydrate diet (SCD) into its treatment paradigm. This treatment paradigm uses the SCD as primary therapy as well as adjunctive therapy for the treatment of IBD. The aim of this study was to evaluate the potential effects of the SCD on clinical outcomes and laboratory studies of pediatric patients with Crohn's disease (CD) and ulcerative colitis (UC). In this retrospective study, we reviewed the medical records of patients with IBD on SCD. We analyzed 26 children on the SCD: 20 with CD and 6 with UC. Duration of the dietary therapy ranged from 3 to 48 mo. In patients with active CD (Pediatric Crohn's Disease activity index [PCDAI] >10), PCDAI dropped from 32.8 ± 13.2 at baseline to 20.8 ± 16.6 by 4 ± 2 wk, and to 8.8 ± 8.5 by 6 mo. The mean Pediatric Ulcerative Colitis Activity Index for patients with active UC decreased from a baseline of 28.3 ± 10.3 to 20.0 ± 17.3 at 4 ± 2 wk, to 18.3 ± 31.7 at 6 mo. This retrospective review provides evidence that the SCD can be integrated into a tertiary care center and may improve clinical and laboratory parameters for pediatric patients with nonstructuring, nonpenetrating CD as well as UC. Further prospective studies are needed to fully assess the safety and efficacy of the SCD in pediatric patients with IBD.


Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling.
The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20.


A cis-phase interaction study of genetic variants within the MAOA gene in major depressive disorder.
The genetic basis of major depressive disorder (MDD) has been explored extensively, but the mode of transmission of the disease has yet to be established. To better understand the mechanism by which the monoamine oxidase A (MAOA) gene may play a role in developing MDD, the present work examined the cis-phase interaction between genetic variants within the MAOA gene for the pathogenesis of MDD. A variable number tandem repeat (VNTR) and 19 single nucleotide polymorphisms (SNPs) within the gene were genotyped in 512 unrelated patients with MDD and 567 unrelated control subjects among a Chinese population. Quantitative real-time polymerase chain reaction analysis was applied to test the effect of genetic variants on expression of the MAOA gene in MDD. Neither the VNTR polymorphism nor seven informative SNPs showed allelic association with MDD, but the cis-acting interactions between the VNTR polymorphism and four individual SNPs were strongly associated with MDD risk, of which the VNTR-rs1465107 combination showed the strongest association (p = .000011). Quantitative real-time polymerase chain reaction analysis showed that overall relative quantity of MAOA messenger RNA was significantly higher in patients with MDD than in control subjects (fold change = 5.28, p = 1.7 × 10⁻⁷) and that in the male subjects carrying the VNTR-L, rs1465107-A, rs6323-G, rs2072743-A, or rs1137070-T alleles, expression of MAOA messenger RNA was significantly higher in the patient group than in the control group. The cis-phase interaction between the VNTR polymorphism and functional SNPs may contribute to the etiology of MDD.


Distal-Less Homeobox 5 Is a Therapeutic Target for Attenuating Hypertrophy and Apoptosis of Mesenchymal Progenitor Cells.
Chondrocyte hypertrophy is a hallmark of osteoarthritis (OA) pathology. In the present study, we elucidated the mechanism underlying the relationship between the hypertrophy/apoptotic phenotype and OA pathogenesis in bone marrow-derived mesenchymal stem cells (BM-MSCs) via gene targeting of distal-less homeobox 5 (DLX5). Our primary objectives were (1) to determine whether DLX5 is a predictive biomarker of cellular hypertrophy in human osteoarthritic tissues; (2) To determine whether modulating DLX5 activity can regulate cell hypertrophy in mesenchymal stem/progenitor cells from marrow and cartilage. Whole transcriptome sequencing was performed to identify differences in the RNA expression profile between human-cartilage-derived mesenchymal progenitors (C-PCs) and bone-marrow-derived mesenchymal progenitors (BM-MSCs). Ingenuity Pathway Analysis (IPA) software was used to compare molecular pathways known to regulate hypertrophic terminal cell differentiation. RT-qPCR was used to measure DLX5 and hypertrophy marker COL10 in healthy human chondrocytes and OA chondrocytes. DLX5 was knocked down or overexpressed in BM-MSCs and C-PCs and RT-qPCR were used to measure the expression of hypertrophy/terminal differentiation markers following DLX5 modulation. Apoptotic cell activity was characterized by immunostaining for cleaved caspase 3/7. We demonstrate that DLX5 and downstream hypertrophy markers were significantly upregulated in BM-MSCs, relative to C-PCs. DLX5 and COL10 were also significantly upregulated in cells from OA knee joint tissues, relative to normal non-arthritic joint tissues. Knocking down DLX5 in BM-MSCs inhibited cell hypertrophy and apoptotic activity without attenuating their chondrogenic potential. Overexpression of DLX5 in C-PCs stimulated hypertrophy markers and increased apoptotic cell activity. Modulating DLX5 activity regulates cell hypertrophy and apoptosis in BM-MSCs and C-PCs. These findings suggest that DLX5 is a biomarker of OA changes in human knee joint tissues and confirms the DLX5 mechanism contributes to hypertrophy and apoptosis in BM-MSCs.


Introduction of periodic boundary conditions into UNRES force field.
In this article, implementation of periodic boundary conditions (PBC) into physics-based coarse-grained UNited RESidue (UNRES) force field is presented, which replaces droplet-like restraints previously used. Droplet-like restraints are necessary to keep multichain systems together and prevent them from dissolving to infinitely low concentration. As an alternative for droplet-like restrains cuboid PBCs with imaging of the molecules were introduced. Owing to this modification, artificial forces which arose from restraints keeping a droplet together were eliminated what leads to more realistic trajectories. Due to computational reasons cutoff and smoothing functions were introduced on the long range interactions. The UNRES force field with PBC was tested by performing microcanonical simulations. Moreover, to asses the behavior of the thermostat in PBCs Langevin and Berendsen thermostats were studied. The influence of PBCs on association pattern was compared with droplet-like restraints on the ββα hetero tetramer 1 protein system.


Laser-induced damage in deuterated potassium dihydrogen phosphate.
Laser-induced pinpoint bulk damage of deuterated potassium dihydrogen phosphate at 351 nm is shown to depend on the propagation direction relative to the crystallographic axes and on growth temperature in addition to the previously reported dependence on continuous filtration. Pulse-length scaling is also consistent with earlier reports. The leading hypothesis for the cause of pinpoint damage is absorbing nanoparticle impurities, and our results are consistent with but not conclusive for that model. Advances in technology have led to greatly improved damage resistance.


Comparative analysis of three- and two-antibody cocktails to AMACR and basal cell markers for the immunohistochemical diagnosis of prostate carcinoma.
Immunohistochemistry using antibody cocktails against basal cell specific and cancer-associated markers is important in the diagnosis of prostate carcinoma in needle biopsies. We compared the usefulness for detecting prostate carcinoma of a three-marker cocktail of antibodies to α-methylacyl-CoA racemase (AMACR), p63 and cytokeratin (CK) 5 with a traditional two-marker cocktail of AMACR and p63. Sixty-six prostate needle biopsies were analysed prospectively. Serial sections were immunostained with the two- and three- antibody cocktails. Blinded slides were assessed individually by two pathologists and sensitivity, specificity and kappa statistics were calculated. Both antibody cocktails contributed to the detection of prostate carcinoma in needle biopsies. There was an acceptable level of agreement between the pathologists for both the cocktails. Sensitivity was similar for one pathologist comparing both the cocktails (76.4% and 75.7%), but was slightly lower comparing the three-antibody with the two-antibody cocktail for the other pathologist (66.6% vs. 77.4%, respectively). Higher specificity values of 90.3% were achieved by both pathologists using three-antibody as compared with two-antibody cocktails (68.7% and 71.8%). Antibody cocktails are important in diagnosing prostate carcinoma in needle biopsies. Adding an extra basal cell marker to the traditional two-antibody cocktail improves the specificity of detecting prostate carcinoma in limited needle biopsy material, and should be considered for routine diagnostic use. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2492231327330327.


Blinding in Surgical Randomized Clinical Trials in 2015.
: Lack of blinding in randomized clinical trials can bias the effect estimates of the observed intervention. In trials assessing nonpharmacological interventions (eg, surgical randomized clinical trials) blinding is usually more difficult. In this mini-review the blinding and reporting of blinding was assessed from surgical randomized clinical trials that were published in leading medical and surgical journals in 2015. Conducting a systematic search on PubMed, a total of 99 studies were deemed as relevant and blinding status assessed. Blinding was explicitly stated for practitioners, patients, and outcome observers in 3%, 37%, and 52%, respectively. The blinding status was not clearly stated in a large proportion of studies or had sometimes a misleading classification. Hence, authors and journals publishing randomized controlled trials should pay attention that status of blinding is unambiguously reported.


The Gambling Related Cognitions Scale (GRCS): development, confirmatory factor validation and psychometric properties.
The aims of this study are to develop and validate a measure to screen for a range of gambling-related cognitions (GRC) in gamblers. A total of 968 volunteers were recruited from a community-based population. They were divided randomly into two groups. Principal axis factoring with varimax rotation was performed on group one and confirmatory factor analysis (CFA) was used on group two to confirm the best-fitted solution. The Gambling Related Cognition Scale (GRCS) was developed for this study and the South Oaks Gambling Screen (SOGS), the Motivation Towards Gambling Scale (MTGS) and the Depression Anxiety Stress Scale (DASS-21) were used for validation. Exploratory factor analysis performed using half the sample indicated five factors, which included interpretative control/bias (GRCS-IB), illusion of control (GRCS-IC), predictive control (GRCS-PC), gambling-related expectancies (GRCS-GE) and a perceived inability to stop gambling (GRCS-IS). These accounted for 70% of the total variance. Using the other half of the sample, CFA confirmed that the five-factor solution fitted the data most effectively. Cronbach's alpha coefficients for the factors ranged from 0.77 to 0.91, and 0.93 for the overall scale. This paper demonstrated that the 23-item GRCS has good psychometric properties and thus is a useful instrument for identifying GRC among non-clinical gamblers. It provides the first step towards devising/adapting similar tools for problem gamblers as well as developing more specialized instruments to assess particular domains of GRC.


Plasma adiponectin and insulin resistance in Korean type 2 diabetes mellitus.
Insulin resistance, which implies impairment of insulin signaling in the target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor-alpha, plasminogen activator inhibitor-1, leptin, resistin, angiotensinogen, and adiponectin. Adiponectin was estimated to be a protective adipocytokine against atherosclerosis, and also to have an anti-inflammatory effect. In this study, the relationship between fasting plasma adiponectin concentration and adiposity, body composition, insulin sensitivity (ITT, HOMAIR, QUICK), lipid profile, fasting insulin concentration were examined in Korean type 2 diabetes. The difference in the adiponectin concentrations was also examined in diabetic and non-diabetic subjects, with adjustment for gender, age and body mass index. 102 type 2 diabetics and 50 controls were examined. After a 12-h overnight fast, all subjects underwent a 75 gram oral glucose tolerance test. Baseline blood samples were drawn for the determinations of fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol. The body composition was estimated using a bioelectric impedance analyzer (Inbody 2.0). The insulin sensitivity was estimated using the insulin tolerance test (ITT), HOMAIR and QUICK methods. In the diabetic group, the fasting adiponectin concentrations were significantly lower in men than in women. They were negatively correlated with BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMAIR (r= -0.233). In addition, they were positively correlated with systolic blood pressure (r=0.321) and HDL-cholesterol (r= 0.291). The systolic blood pressure and HDL-cholesterol were found to be independent variables, from a multiple logistic regression analysis, which influenced the adiponectin concentration. Compared with the non-diabetic group, the adiponectin concentrations were significantly lower in the diabetic group, with the exception of obese males. In conclusion, the plasma adiponectin concentrations were closely related to the insulin resistance parameters in Korean type 2 diabetic patients.


Examining Cognitive Biases Uniquely Associated with Schizotypy.
Individuals with schizotypy can experience a number of cognitive biases that may increase their risk in developing schizophrenia-spectrum psychopathology. However, cognitive biases are also present in mood and anxiety disorders, and it is currently unclear which biases are specific to schizotypy and which may be a result of comorbid depression and/or anxiety. 462 participants completed measures of depression, anxiety, cognitive biases, cognitive schemas, and schizotypy. Correlation analyses were conducted to examine the relationship between these constructs. Three hierarchical regression analyses were conducted to examine if schizotypy, depression, and anxiety explained a statistically significant amount of variance in cognitive biases after controlling for depression and anxiety, schizotypy and anxiety, and schizotypy and depression, respectively. Moderated regression analyses were also conducted to investigate the moderating role of biological sex and ethnicity in the association between cognitive biases and schizotypy. Self-referential processing, belief inflexibility, and attention for threat were associated with schizotypy. The belief inflexibility bias and social cognition problems were specifically associated with schizotypy after controlling for depression and anxiety and were not directly associated with either depression or anxiety. These associations were not moderated by biological sex or ethnicity. The belief inflexibility bias may be an important cognitive bias underlying schizotypal personality, and further research will be important to determine whether this bias is also associated with an increased likelihood of transitioning to psychosis.


Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals.
To express the antioxidant capacity of plant foods in a more familiar and easily understood manner (equivalent to vitamin C mg/100 g), two stable radical species, ABTS(*)(-) and DPPH(*), commonly used for antioxidant activity measurements, were employed independently to evaluate their efficacies using apple polyphenolic extracts and seven polyphenolic standards including synthetic Trolox. Their antioxidant activities were expressed as vitamin C equivalent antioxidant capacity (VCEAC) in mg/100 g apple or mg/100 mL of the reference chemical compounds in 10 and 30 min using the ABTS(*)(-) and DPPH(*) scavenging assays, respectively. The antioxidant capacity of Gala apples and seven phenolic standards, determined by both ABTS(*)(-) and DPPH(*) scavenging assays, showed a dose-response of the first-order. Fresh Gala apples had a VCEAC of 205.4 +/- 5.6 mg/100 g using the ABTS assay, and the relative VCEACs of phenolic standards were as follows: gallic acid > quercetin > epicatechin > catechin > vitamin C > rutin > chlorogenic acid > Trolox. With the DPPH radical assay, the VCEAC of fresh Gala apples was 136.0 +/- 6.6 mg/100 g, and the relative VCEACs of seven phenolic standards were, in decreasing order, as follows: gallic acid > quercetin > epicatechin > catechin > or = vitamin C > Trolox > rutin > chlorogenic acid. Because the ABTS assay can be used in both organic and aqueous solvent systems, employs a specific absorbance at a wavelength remote from the visible region, and requires a short reaction time, it is a more desirable method than the DPPH assay. Therefore, it is recommended that antioxidant capacity be expressed as vitamin C mg/100 g equivalent (VCEAC) using the ABTS assay.


Mobile DNA in Old World monkeys: a glimpse through the rhesus macaque genome.
The completion of the draft sequence of the rhesus macaque genome allowed us to study the genomic composition and evolution of transposable elements in this representative of the Old World monkey lineage, a group of diverse primates closely related to humans. The L1 family of long interspersed elements appears to have evolved as a single lineage, and Alu elements have evolved into four currently active lineages. We also found evidence of elevated horizontal transmissions of retroviruses and the absence of DNA transposon activity in the Old World monkey lineage. In addition, approximately 100 precursors of composite SVA (short interspersed element, variable number of tandem repeat, and Alu) elements were identified, with the majority being shared by the common ancestor of humans and rhesus macaques. Mobile elements compose roughly 50% of primate genomes, and our findings illustrate their diversity and strong influence on genome evolution between closely related species.


Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets.
Inflammatory intestinal diseases are characterized by abnormal immune responses and affect distinct locations of the gastrointestinal tract. Although the role of several immune subsets in driving intestinal pathology has been studied, a system-wide approach that simultaneously interrogates all major lineages on a single-cell basis is lacking. We used high-dimensional mass cytometry to generate a system-wide view of the human mucosal immune system in health and disease. We distinguished 142 immune subsets and through computational applications found distinct immune subsets in peripheral blood mononuclear cells and intestinal biopsies that distinguished patients from controls. In addition, mucosal lymphoid malignancies were readily detected as well as precursors from which these likely derived. These findings indicate that an integrated high-dimensional analysis of the entire immune system can identify immune subsets associated with the pathogenesis of complex intestinal disorders. This might have implications for diagnostic procedures, immune-monitoring, and treatment of intestinal diseases and mucosal malignancies.


Developing detailed records of relative sea-level change using a foraminiferal transfer function: an example from North Norfolk, UK.
This paper provides a brief overview of the transfer function approach to sea-level reconstruction. Using the example of two overlapping sediment cores from the North Norfolk coast, UK, the advantages and limitations of the transfer function methodology are examined. While the selected cores are taken from different sites, and display contrasting patterns of sedimentation, the foraminiferal transfer function distils comparable records of relative sea-level change from both sequences. These reconstructions are consistent with existing sea-level index points from the region but produce a more detailed record of relative sea-level change. Transfer functions can extract sea-level information from a wider range of sedimentary sub-environments. This increases the amount of data that can be collected from coastal deposits and improves record resolution. The replicability of the transfer function methodology, coupled with the sequential nature of the data it produces, assists in the compilation and analysis of sea-level records from different sites. This technique has the potential to bridge the gap between short-term (instrumental) and long-term (geological or geophysical) records of sea-level change.


The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.
The inherent glycosidase inhibitory activity and potentially therapeutic value of the polyhydroxylated pyrrolizidine alkaloids containing a hydroxymethyl substituent at the C-3 position have been well documented. Belonging to this class, the naturally occurring hyacinthacine C-type alkaloids are of general interest among iminosugar researchers. Their selective micromolar α -glycosidase inhibitory ranges (10 - 100 μM) suggest that these azasugars are potential leads for treating type II diabetes. However, the structures of hyacinthacine C1, C3 and C4 are insecure with hyacinthacine C5 being recently corrected. This review presents the hyacinthacine C-type alkaloids: their first discovery to the most recent advancements on the structures, biological activities and total synthesis. The hyacinthacine C-type alkaloids are of exponentially increasing interest and will undoubtedly continue to be reported as synthetic targets. They represent a challenging but rewarding synthetic feat for the community of those interested in accessing biologically active iminosugars. Since 2009, ten total syntheses have been employed towards accessing similarly related products but only three have assessed the glycosidase inhibitory activity of the final products. This suggests the need for an accessible and universal glycosidase inhibitory assay so to accurately determine the structure-activity relationship of how the hyacinthacine C-type alkaloids inhibit specific glycosidases. Confirming the correct structures of the hyacinthacine C-type alkaloids as well as accessing various analogues continues to strengthen the foundation towards a marketable treatment for type II diabetes and other glycosidase related illnesses.


Identification and characterization of a novel siglec, siglec-7, expressed by human natural killer cells and monocytes.
We describe the characterization of sialic acid-binding Ig-like lectin-7 (siglec-7), a novel member of the siglec subgroup of the immunoglobulin superfamily. A full-length cDNA encoding siglec-7 was isolated from a human primary dendritic cell cDNA library. Siglec-7 is predicted to contain three extracellular immunoglobulin-like domains that comprise an N-terminal V-set domain and two C2-set domains, a transmembrane region and a cytoplasmic tail containing two tyrosine residues embodied in immunoreceptor tyrosine-based inhibition motif-like motifs. Overall, siglec-7 exhibited a high degree of sequence similarity to genes encoding CD33 (siglec-3), siglec-5, OBBP1/siglec-6, and OBBP-like protein and mapped to the same region on chromosome 19q13.3. When siglec-7 was expressed on COS or Chinese hamster ovary cells, it was able to mediate high levels of sialic acid-dependent binding to human erythrocytes and soluble sialoglycoconjugates, suggesting that it may be involved in cell-cell interactions. Among human peripheral blood leukocytes, siglec-7 was found to be present at low levels on granulocytes, intermediate levels on monocytes, and relatively high levels on a major subset of natural killer cells and a minor subset of CD8(+) T cells. Immunoprecipitation experiments indicated that siglec-7 is expressed as a monomer of approximately 65 kDa.


Exposure to ambient concentrations of particulate air pollution does not influence vascular function or inflammatory pathways in young healthy individuals.
Particulate air pollution is associated with increased risk of cardiovascular events although the involved mechanisms are poorly understood. The objective of the present study was to investigate the effects of controlled exposure to ambient air fine and ultrafine particles on microvascular function and biomarkers related to inflammation, haemostasis and lipid and protein oxidation. Twenty-nine subjects participated in a randomized, two-factor crossover study with or without biking exercise for 180 minutes and with 24 hour exposure to particle rich (number concentrations, NC: 11600 +/- 5600 per cm3, mass concentrations: 13.8 +/- 7.4 mug/m3 and 10.5 +/- 4.8 mug/m3 for PM10-2.5 and PM2.5, respectively) or particle filtered (NC: 555 +/- 1053 per cm3) air collected above a busy street. Microvascular function was assessed non-invasively by measuring digital peripheral artery tone following arm ischemia. Biomarkers included haemoglobin, red blood cells, platelet count, coagulation factors, C-reactive protein, fibrinogen, interleukin-6, tumour necrosis factor alpha, lag time to copper-induced oxidation of plasma lipids and protein oxidation measured as 2-aminoadipic semialdehyde in plasma. No statistically significant differences were observed on microvascular function or the biomarkers after exposure to particle rich or particle filtered air. This study indicates that exposure to air pollution particles at outdoor concentrations is not associated with detectable systemic inflammation, lipid or protein oxidation, altered haemostasis or microvascular function in young healthy participants.


Control of an electrical prosthesis with an SSVEP-based BCI.
Brain-computer interfaces (BCIs) are systems that establish a direct connection between the human brain and a computer, thus providing an additional communication channel. They are used in a broad field of applications nowadays. One important issue is the control of neuroprosthetic devices for the restoration of the grasp function in spinal-cord-injured people. In this communication, an asynchronous (self-paced) four-class BCI based on steady-state visual evoked potentials (SSVEPs) was used to control a two-axes electrical hand prosthesis. During training, four healthy participants reached an online classification accuracy between 44% and 88%. Controlling the prosthetic hand asynchronously, the participants reached a performance of 75.5 to 217.5 s to copy a series of movements, whereas the fastest possible duration determined by the setup was 64 s. The number of false negative (FN) decisions varied from 0 to 10 (the maximal possible decisions were 34). It can be stated that the SSVEP-based BCI, operating in an asynchronous mode, is feasible for the control of neuroprosthetic devices with the flickering lights mounted on its surface.


Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer.
Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of this study is to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action. qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival. Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC.


Unaccompanied refugee minors' early life narratives of physical abuse from caregivers and teachers in their home countries.
The early life narratives of 34 unaccompanied refugee minors, especially their reports of interpersonal violence, were analyzed using Interpretative Phenomenological Analysis (IPA). The youth originated from eight countries, with Afghanistan, Eritrea, and Sri Lanka being the most frequent origins, and they arrived to Norway before the age of 15. Four of these youth were girls. The physical violence took place at home and/or at school and could be extremely harsh. Approximately half of the youth expressed some type of ambivalence toward the perpetrator. In analyzing how the youth understood the reasons for violence two categories of internal and three categories of external attributions were found. Several of the youth blamed their own behavior for the abuse, although such internal attributions were frequently combined with external attributions. Some different patterns of attributions emerged between home and school violence. Most of the youth placed the blame for school violence on their own behavior or that violence was part of normal school discipline. For violence at home there was a tendency to place more blame on the perpetrator (mostly fathers). Possible long-term consequences of the experiences and the different attributional styles as well as implications of the findings are discussed. Professionals should assess refugee children for interpersonal violence experiences as well as for other experiences in their home country.


A Model of Consultation in Prostate Cancer Care: Evidence From a Systematic Review.
There has been an evolution of various consultation models in the literature. Men affected by prostate cancer can experience a range of unmet supportive care needs. Thus, effective consultations are paramount in the delivery of supportive care to optimize tailored self-management plans at the individual level of need. The aim of this study is to critically appraise existing models of consultation and make recommendations for a model of consultation within the scope of clinical practice for prostate cancer care. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement Guidelines. Electronic databases were searched using a wide range of keywords and free text items to increase the sensitivity and inclusiveness of the searches. Findings were integrated in a narrative synthesis. A total of 1829 articles were retrieved and 17 papers were included. Beneficial features ranged across a number of models that included a person-centered consultation, shared management plans, and safety netting. None of the reviewed models of consultation are suitable for use in prostate cancer care because of a range of limitations and the clinical context in which models were developed. A Cancer Care Consultation Model was informed from critical appraisal of the evidence and expert clinical and service user comment. Further research is needed to empirically test consultation models in routine clinical practice, specifically for advanced cancer specialist nurses. The Prostate Cancer Model of Consultation can be used to structure clinical consultations to target self-management care plans at the individual level of need over the cancer care continuum.


Data Linkage Strategies to Advance Youth Suicide Prevention: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop.
Linking national, state, and community data systems to data from prevention programs could allow for longer-term assessment of outcomes and evaluation of interventions to prevent suicide. To identify and describe data systems that can be linked to data from prevention studies to advance youth suicide prevention research. A systematic review, an environmental scan, and a targeted search were conducted to identify prevention studies and potentially linkable external data systems with suicide outcomes from January 1990 through December 2015. Studies and data systems had to be U.S.-based and include persons aged 25 years or younger. Data systems also had to include data on suicide, suicide attempt, or suicidal ideation. Information about participants, intervention type, suicide outcomes, primary analytic method used for linkage, statistical approach, analyses performed, and characteristics of data systems was abstracted by 2 reviewers. Of 47 studies (described in 59 articles) identified in the systematic review, only 6 were already linked to data systems. A total of 153 unique and potentially linkable data systems were identified, but only 66 were classified as "fairly accessible" and had data dictionaries available. Of the data systems identified, 19% were established primarily for research, 11% for clinical care or operations, 29% for administrative services (such as billing), and 52% for surveillance. About one third (37%) provided national data, 12% provided regional data, 63% provided state data, and 41% provided data below the state level (some provided coverage for >1 geographic unit). Only U.S.-based studies published in English were included. There is untapped potential to evaluate and enhance suicide prevention efforts by linking suicide prevention data with existing data systems. However, sparse availability of data dictionaries and lack of adherence to standard data elements limit this potential. Agency for Healthcare Research and Quality.


If it ain't broke don't fix it? Ethics of splinting deformed newborn ears.
Neonatal ear splinting is a proven and safe method to mold deformed ears into a more common shape. Based on our earlier studies, splinting is recommended only before the age of six weeks and preferably within the first week after birth. This can be done by initiating a system in which this intervention is actively proposed to parents. In this paper, we ethically evaluate such a system. By molding perfectly healthy newborn ears, we reach the boundary between treatment and enhancement. A key question is, therefore, whether we could classify neonatal ear splinting as a therapy. On the level of the individual, the advantages outweigh the drawbacks, but on the level of society, it is more complicated. Making ear deformities a part of official national screening programs fails to meet WHO criteria. Moreover, by systematically offering ear molding, professionals may be promoting guilt or fear of missing the opportunity. Additionally, it could affect societal attitudes toward cosmetic deformities. However, if we argue that on the individual level infants may benefit from ear splinting, then active detection of ear deformities allows parents to choose in a timely way from the full range of options, including splinting and a wait-and-see approach. We are inclined to optimally inform parents without setting up a full-blown public health program. The extent to which it is possible to timely offer splints to parents of newborns depends on the infrastructure of health care systems. The key will be for everyone involved, public or commercial, to responsibly educate and facilitate.


Review of quantitative phase-digital holographic microscopy: promising novel imaging technique to resolve neuronal network activity and identify cellular biomarkers of psychiatric disorders.
Quantitative phase microscopy (QPM) has recently emerged as a new powerful quantitative imaging technique well suited to noninvasively explore a transparent specimen with a nanometric axial sensitivity. In this review, we expose the recent developments of quantitative phase-digital holographic microscopy (QP-DHM). Quantitative phase-digital holographic microscopy (QP-DHM) represents an important and efficient quantitative phase method to explore cell structure and dynamics. In a second part, the most relevant QPM applications in the field of cell biology are summarized. A particular emphasis is placed on the original biological information, which can be derived from the quantitative phase signal. In a third part, recent applications obtained, with QP-DHM in the field of cellular neuroscience, namely the possibility to optically resolve neuronal network activity and spine dynamics, are presented. Furthermore, potential applications of QPM related to psychiatry through the identification of new and original cell biomarkers that, when combined with a range of other biomarkers, could significantly contribute to the determination of high risk developmental trajectories for psychiatric disorders, are discussed.


Interaction design of community-driven environmental projects (CDEPs): A case study from the Anacostia Watershed.
Water is becoming an increasingly precious resource across the world, but citizens can help ensure good-quality water by helping to manage their local watersheds. Local, place-based advocacy projects that are strongly grounded within their geographical area have the potential to inspire environmental change as citizens come together to collectively address environmental challenges in their own neighborhoods. However, less attention has been given to these small, intensely place-based local projects. Our research focuses on the interaction design of technology to support small, local, place-based "community-driven environmental projects" (CDEPs) for water management in the Anacostia River Watershed. Analysis of case study data collected over a 3-y period to identify the needs of CDEP members provides the basis for the interaction design of technology known as NatureNet to support CDEPs. From this research, six design insights for supporting CDEPs are suggested: (i) a shared common endeavor connected to the identity of the members, (ii) ways for newcomers and experienced participants to share a common space and function together effectively, (iii) support for different sources of knowledge, (iv) different modes of participation and ways for participants to express themselves, (v) different ways to express status through diverse opportunities, and (vi) support for porous and changing leadership roles. Taken together, the findings from our study suggest a preference for technology-lite, highly flexible software that supports the diverse needs of CDEP members.


Active pharmaceutical ingredient (API) production involving continuous processes--a process system engineering (PSE)-assisted design framework.
A systematic framework is proposed for the design of continuous pharmaceutical manufacturing processes. Specifically, the design framework focuses on organic chemistry based, active pharmaceutical ingredient (API) synthetic processes, but could potentially be extended to biocatalytic and fermentation-based products. The method exploits the synergic combination of continuous flow technologies (e.g., microfluidic techniques) and process systems engineering (PSE) methods and tools for faster process design and increased process understanding throughout the whole drug product and process development cycle. The design framework structures the many different and challenging design problems (e.g., solvent selection, reactor design, and design of separation and purification operations), driving the user from the initial drug discovery steps--where process knowledge is very limited--toward the detailed design and analysis. Examples from the literature of PSE methods and tools applied to pharmaceutical process design and novel pharmaceutical production technologies are provided along the text, assisting in the accumulation and interpretation of process knowledge. Different criteria are suggested for the selection of batch and continuous processes so that the whole design results in low capital and operational costs as well as low environmental footprint. The design framework has been applied to the retrofit of an existing batch-wise process used by H. Lundbeck A/S to produce an API: zuclopenthixol. Some of its batch operations were successfully converted into continuous mode, obtaining higher yields that allowed a significant simplification of the whole process. The material and environmental footprint of the process--evaluated through the process mass intensity index, that is, kg of material used per kg of product--was reduced to half of its initial value, with potential for further reduction. The case-study includes reaction steps typically used by the pharmaceutical industry featuring different characteristic reaction times, as well as L-L separation and distillation-based solvent exchange steps, and thus constitutes a good example of how the design framework can be useful to efficiently design novel or already existing API manufacturing processes taking advantage of continuous processes.


Comparative study of different cytotoxicity of bonding systems with different dentin thickness on L929 cell line: An experimental study.
Dentin-bonding agents should have good biocompatibility as they come into close and prolonged contact with vital dentin. The present study aimed to evaluate and compare the cytotoxicity of total etch and self-etch dentin bonding systems with two different dentin thickness on L929 cell line. In this in vitro study 80 Class I cavities were prepared on the occlusal surfaces. The teeth were randomly divided to two groups of 40 each based on two RDT 0.5 mm and 1.5 mm. Samples were further subdivided into four subgroups of 10. Group 1: Adper Scotch bond Multi-Purpose (SBMP), Group 2: Adper Single Bond Plus (SBP), Group 3: Adper Scotch bond SE (SSE) and Group 4: Adper Easy One (EO). Group 1 and 2 were total-etch and Group 3 and 4 were self-etch. The cavities were sealed after applying of dentin bonding. Then crowns were immersed in culture medium for 24 hours and the cytotoxicity of resultant toxic extraction was measured with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in 4 serial dilutions (neat,1/2 ,1/10 ,1/100). Data were analyzed by Two-way ANOVA and t-test. For all the dilutions, cytotoxicity was significantly higher with 0.5 mm remaining dentin thickness (RDT) relative to 1.5 mm RDT (P ≤ 0.05). In neat dilution for both RDTs, cytotoxicity was different among all the four dentin bondings. Expression in decreasing order of cytotoxicity was SBP > SBMP > SSE > EO for both RDTs in neat dilution (P < 0.05). For all the dilutions, cytotoxicity was significantly lower for self-etch bonding systems in comparison with total-etch bonding systems (P < 0.05). In the present study, lower cytotoxicity was found with an increase in the dilution of toxic extract and also cytotoxicity decreased with an increased dentin thickness. The adhesive systems had degrees of cytotoxic effects on cultured L929 compared to the control, except for the EO group.


Behavioural relevance of spontaneous, transient brain network interactions in fMRI.
How spontaneously fluctuating functional magnetic resonance imaging (fMRI) signals in different brain regions relate to behaviour has been an open question for decades. Correlations in these signals, known as functional connectivity, can be averaged over several minutes of data to provide a stable representation of the functional network architecture for an individual. However, associations between these stable features and behavioural traits have been shown to be dominated by individual differences in anatomy. Here, using kernel learning tools, we propose methods to assess and compare the relation between time-varying functional connectivity, time-averaged functional connectivity, structural brain data, and non-imaging subject behavioural traits. We applied these methods to Human Connectome Project resting-state fMRI data to show that time-varying fMRI functional connectivity, detected at time-scales of a few seconds, has associations with some behavioural traits that are not dominated by anatomy. Despite time-averaged functional connectivity accounting for the largest proportion of variability in the fMRI signal between individuals, we found that some aspects of intelligence could only be explained by time-varying functional connectivity. The finding that time-varying fMRI functional connectivity has a unique relationship to population behavioural variability suggests that it might reflect transient neuronal communication fluctuating around a stable neural architecture.


Cardiovascular magnetic resonance tagging imaging correlates with myocardial dysfunction and T2 mapping in idiopathic dilated cardiomyopathy.
To evaluate the details of myocardial dysfunction in dilated cardiomyopathy (DCM) patients using tagging images and the correlation of tagging imaging with tissue characteristics. Circumferential strain (Ecc) derived from tagging images was measured in 15 normal (NML) subjects (15 males; mean age 28.5 years) and 12 DCM patients (7 males; mean age 48.9 years). The following parameters were compared: (1) the magnitude of peak Ecc (Ecc*); (2) the coefficient of variation of the time of Ecc* (CVtime*), which indexes dyssynchrony; and (3) descriptive findings of time-Ecc curves. We also evaluated the correlations of Ecc* in DCM patients with ejection fraction (EF), myocardial T2 values, and late gadolinium enhancement (LGE). Mean Ecc*s in DCM patients and NML subjects were -12.7 and -23.5%, respectively (P < 0.0001). Mean CVtime*s were 15.2 and 4.5%, respectively (P = 0.0002). The findings of pre-systolic extension and systolic stretch in the septum were observed in 6 (50%) and 10 (83.3%) DCM patients and in none of the NML participants. Ecc* was correlated with EF (P < 0.0001, R2 = 0.90) and T2 values (P = 0.018, R2 = 0.44) but not with LGE (P = 0.072, R2 = 0.28). Tagging images revealed the reduction of myocardial function as well as dyssynchrony in DCM patients. Myocardial dysfunction occurred coincidently with myocardial inflammation.


TMPRSS2-ERG Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in PTEN and TP53-Mutated Prostate Cancer.
Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance.Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray.Results: Transgenic ERG expression in mice blocked Pten/Trp53 alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth.Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer. Clin Cancer Res; 24(18); 4551-65. ©2018 AACR.


Single dose oral paracetamol (acetaminophen) for postoperative pain in adults.
This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on 'Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain'. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way. To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain. We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008. Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults. Two review authors independently assessed trial quality and extracted data. Area under the "pain relief versus time" curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected. Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome.About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms. A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events.


[Chronic complications, hypertension and obesity in diabetic patients living in Cartagena, Colombia].
Identifying the presence of chronic complications and evaluating obesity and hypertension control in diabetic patients taking part in a control and monitoring programme in Cartagena, Colombia. This was a descriptive cross-sectional study which reviewed 499 medical records from a basic health care unit in Cartagena during 2006. Sociodemographic data (age and sex) and other information concerning disease stage, hypertension, obesity, chronic complications and attending control appointments were collected using a structured form. 161 (32%) of the patients had chronic complications, the most frequently occurring being neuropathy (41%) and nephropathy (29%). More complications were found in older patients. Neuropathy predominated in women (48.1%) and nephropathy in men (45.6%); 80% of the patients were suffering from hypertension. There was no significant difference between those who had complications and those who did not (83.2 % and 77.2%, respectively). Only 29% of the patients had normal weight, the rest were obese (31%) or overweight (40%). Patients with complications attended control appointments less frequently. Body weight control strategies must be strengthened, as must hypertension and foot care strategies. An active search for retinopathy must be made to postpone or prevent the onset of chronic complications.


Autolytic activation and localization in Schneider cells (S2) of calpain B from Drosophila.
Calpain B is one of the two calpain homologues in Drosophila melanogaster that are proteolytically active. We studied its activation by Ca2+ both in vitro and in vivo, in Schneider (S2) cells. Activation involves the autolytic cleavage, at two major sites, of the N-terminal segment, the length of which was earlier underestimated. Site-directed mutagenesis at the autolytic sites did not prevent autolysis, but only shifted its sites. Calpain B mRNA was detectable in all developmental stages of the fly. In situ hybridization and immunostaining showed expression in ovaries, embryo and larvae, with high abundance in larval salivary glands. In S2 cells, calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.


Renal cell carcinoma marker reliably discriminates central nervous system haemangioblastoma from brain metastases of renal cell carcinoma.
The distinction between central nervous system (CNS) metastases of clear cell renal cell carcinoma (RCC) and CNS haemangioblastoma still poses a challenge to the pathologist. Since both entities occur in von Hippel-Lindau disease, this aggravates the issue. The antibody renal cell carcinoma marker (RCC-ma) has been suggested to identify primary RCCs specifically, but its value for diagnosing metastases of RCC is controversial. The aim was to assess two distinct clones of the RCC-ma for their potential to: (i) identify primary RCCs and (ii) differentiate between CNS metastases of clear cell RCC and CNS haemangioblastomas. Using tissue microarrays, 77% (n = 363; PN-15) and 66% (n = 355; 66.4C2) of clear cell RCCs, and 93% (PN-15) and 74% (66.4C2) of papillary RCCs (n = 46) were immunopositive for RCC-ma, whereas none of the investigated chromophobe RCCs (n = 22) or any of the oncocytomas (n = 15) showed immunoreactivity. Importantly, 50.9% of CNS metastases of clear cell RCCs (n = 55) exhibited RCC-ma expression, whereas all CNS haemangioblastomas (71) were negative. Both RCC-ma clones, despite some variation in their sensitivity to detect clear cell and papillary RCCs, are of value in differentiating subtypes of primary RCC and are excellent markers for discriminating clear cell lesions in the brain.


The internal heavy-atom effect on 3-phenylselanyl and 3-phenyltellanyl BODIPY derivatives studied by transient absorption spectroscopy.
Three monosubstituted 3-phenylselanyl and 3-phenyltellanyl BODIPY derivatives were synthesized and their spectroscopic properties were characterized and compared to those of iodine and chlorine-atoms containing analogues as well as an unsubstituted BODIPY derivative. The fluorescence quantum yields were found to decrease, whereas the intersystem crossing quantum yields (ΦISC), determined by transient spectroscopy, increased in the order of the H → Cl → Se/I → Te substitution. The maximum ΦISC, found for the 3-phenyltellanyl derivative, was 59%. The results are interpreted in terms of the internal heavy-atom effect of the substituents.