Induced over-expression of AtDREB2A CA improves drought tolerance in sugarcane.
Drought is one of the most challenging agricultural issues limiting sustainable sugarcane production and, in some cases, yield losses caused by drought are nearly 50%. DREB proteins play vital regulatory roles in abiotic stress responses in plants. The transcription factor DREB2A interacts with a cis-acting DRE sequence to activate the expression of downstream genes that are involved in drought-, salt- and heat-stress response in Arabidopsis thaliana. In the present study, we evaluated the effects of stress-inducible over-expression of AtDREB2A CA on gene expression, leaf water potential (ΨL), relative water content (RWC), sucrose content and gas exchanges of sugarcane plants submitted to a four-days water deficit treatment in a rhizotron-grown root system. The plants were also phenotyped by scanning the roots and measuring morphological parameters of the shoot. The stress-inducible expression of AtDREB2A CA in transgenic sugarcane led to the up-regulation of genes involved in plant response to drought stress. The transgenic plants maintained higher RWC and ΨL over 4 days after withholding water and had higher photosynthetic rates until the 3rd day of water-deficit. Induced expression of AtDREB2A CA in sugarcane increased sucrose levels and improved bud sprouting of the transgenic plants. Our results indicate that induced expression of AtDREB2A CA in sugarcane enhanced its drought tolerance without biomass penalty.


Factors Associated With Lack of Vision Improvement in Children With Cortical Visual Impairment.
Improvement in vision has been noted in children with cortical visual impairment (CVI), resulting from disparate types of brain injury. The purpose of our study was to determine the risk factors associated with poor recovery of vision in this group of patients. Case records of children who were born before 2010 with at least 4 follow-up visits for CVI were reviewed for underlying etiologies of CVI, visual acuity (VA), and associated neurological and ophthalmological disorders. VA was assessed in 6 qualitative grades. Changes in VA were recorded as the difference between the grades of VA at presentation and the last follow-up visit. The outcome was calculated as a ratio of actual improvement to potential improvement in grades of qualitative VA. Multiple linear regression determined factors associated with lack of vision improvement in all children and based on etiology. Fifty-three children with CVI were identified. The median age at presentation was 13.6 months (range: 2.9-76.4 months) and the median follow-up was 5.8 years (1.1-16.3 years). CVI resulted from central nervous system (CNS) malformation (9.4%), hypoxic/inflammatory injury (15.1%), seizures (24.5%), and combined causes (51.0%). Vision improvement was noted in 83% of children. Lack of VA improvement was associated with older age at presentation in all children with CVI and within each etiological group except CNS malformation. None of the other investigated variables were associated with poor recovery of VA. Most of the children with CVI showed improvement in vision. Older age at presentation, but not etiology of CVI, was associated with poor improvement in VA.


Architecture of the human interactome defines protein communities and disease networks.
The physiology of a cell can be viewed as the product of thousands of proteins acting in concert to shape the cellular response. Coordination is achieved in part through networks of protein-protein interactions that assemble functionally related proteins into complexes, organelles, and signal transduction pathways. Understanding the architecture of the human proteome has the potential to inform cellular, structural, and evolutionary mechanisms and is critical to elucidating how genome variation contributes to disease. Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome, and constitutes, to our knowledge, the largest such network so far. With more than 56,000 candidate interactions, BioPlex 2.0 contains more than 29,000 previously unknown co-associations and provides functional insights into hundreds of poorly characterized proteins while enhancing network-based analyses of domain associations, subcellular localization, and co-complex formation. Unsupervised Markov clustering of interacting proteins identified more than 1,300 protein communities representing diverse cellular activities. Genes essential for cell fitness are enriched within 53 communities representing central cellular functions. Moreover, we identified 442 communities associated with more than 2,000 disease annotations, placing numerous candidate disease genes into a cellular framework. BioPlex 2.0 exceeds previous experimentally derived interaction networks in depth and breadth, and will be a valuable resource for exploring the biology of incompletely characterized proteins and for elucidating larger-scale patterns of proteome organization.


Myocardial motion estimation from medical images using the monogenic signal.
We present a method for the analysis of heart motion from medical images. The algorithm exploits monogenic signal theory, recently introduced as an N-dimensional generalization of the analytic signal. The displacement is computed locally by assuming the conservation of the monogenic phase over time. A local affine displacement model is considered to account for typical heart motions as contraction/expansion and shear. A coarse-to-fine B-spline scheme allows a robust and effective computation of the model's parameters, and a pyramidal refinement scheme helps to handle large motions. Robustness against noise is increased by replacing the standard point-wise computation of the monogenic orientation with a robust least-squares orientation estimate. Given its general formulation, the algorithm is well suited for images from different modalities, in particular for those cases where time variant changes of local intensity invalidate the standard brightness constancy assumption. This paper evaluates the method's feasibility on two emblematic cases: cardiac tagged magnetic resonance and cardiac ultrasound. In order to quantify the performance of the proposed method, we made use of realistic synthetic sequences from both modalities for which the benchmark motion is known. A comparison is presented with state-of-the-art methods for cardiac motion analysis. On the data considered, these conventional approaches are outperformed by the proposed algorithm. A recent global optical-flow estimation algorithm based on the monogenic curvature tensor is also considered in the comparison. With respect to the latter, the proposed framework provides, along with higher accuracy, superior robustness to noise and a considerably shorter computation time.


Experimental and computational studies of strain-conduction velocity relationships in cardiac tissue.
Velocity of electrical conduction in cardiac tissue is a function of mechanical strain. Although strain-modulated velocity is a well established finding in experimental cardiology, its underlying mechanisms are not well understood. In this work, we summarized potential factors contributing to strain-velocity relationships and reviewed related experimental and computational studies. We presented results from our experimental studies on rabbit papillary muscle, which supported a biphasic relationship of strain and velocity under uni-axial straining conditions. In the low strain range, the strain-velocity relationship was positive. Conduction velocity peaked with 0.59 m/s at 100% strain corresponding to maximal force development. In the high strain range, the relationship was negative. Conduction was reversibly blocked at 118+/-1.8% strain. Reversible block occurred also in the presence of streptomycin. Furthermore, our studies revealed a moderate hysteresis of conduction velocity, which was reduced by streptomycin. We reconstructed several features of the strain-velocity relationship in a computational study with a myocyte strand. The modeling included strain-modulation of intracellular conductivity and stretch-activated cation non-selective ion channels. The computational study supported our hypotheses, that the positive strain-velocity relationship at low strain is caused by strain-modulation of intracellular conductivity and the negative relationship at high strain results from activity of stretch-activated channels. Conduction block was not reconstructed in our computational studies. We concluded this work by sketching a hypothesis for strain-modulation of conduction and conduction block in papillary muscle. We suggest that this hypothesis can also explain uni-axially measured strain-conduction velocity relationships in other types of cardiac tissue, but apparently necessitates adjustments to reconstruct pressure or volume related changes of velocity in atria and ventricles.


Systematic isolation of peptide signal molecules regulating development in hydra: LWamide and PW families.
To isolate new peptide signal molecules involved in regulating developmental processes in hydra, a novel screening project was developed. Peptides extracted from the tissue of Hydra magnipapillata were systematically purified to homogeneity using HPLC. A fraction of each purified peptide was examined by differential display-PCR for its ability to affect gene expression in hydra. Another fraction was used to determine the tentative structure using an amino acid sequence analyzer and/or a mass spectrometer. Based on the results, peptides of potential interest were selected for chemical synthesis, followed by confirmation of the identity of the synthetic with the native peptides using HPLC. Using this approach, 286 peptides have been isolated, tentative amino acid sequences have been determined for 95 of them, and 19 synthetic peptides identical to native ones were produced. The 19 synthetic peptides were active in a variety of biological tests. For example, Hym-54 stimulated muscle contraction in adult polyps of hydra and sea anemone, Anthopleura fuscoviridis, and induced metamorphosis of planula, the larval stage, into polyps in a marine hydrozoan species, Hydractinia serrata. Another peptide, Hym-33H, inhibited nerve cell differentiation in hydra and induced tissue contraction in planula of Hydractinia serrata. The evidence obtained so far suggests that hydra contains a large number (>350) of peptide signal molecules involved in regulating developmental or other processes in cnidaria. These peptides can be isolated and their functions examined systematically with the new approach developed in this study.


A review of the acute effects of static and dynamic stretching on performance.
An objective of a warm-up prior to an athletic event is to optimize performance. Warm-ups are typically composed of a submaximal aerobic activity, stretching and a sport-specific activity. The stretching portion traditionally incorporated static stretching. However, there are a myriad of studies demonstrating static stretch-induced performance impairments. More recently, there are a substantial number of articles with no detrimental effects associated with prior static stretching. The lack of impairment may be related to a number of factors. These include static stretching that is of short duration (<90 s total) with a stretch intensity less than the point of discomfort. Other factors include the type of performance test measured and implemented on an elite athletic or trained middle aged population. Static stretching may actually provide benefits in some cases such as slower velocity eccentric contractions, and contractions of a more prolonged duration or stretch-shortening cycle. Dynamic stretching has been shown to either have no effect or may augment subsequent performance, especially if the duration of the dynamic stretching is prolonged. Static stretching used in a separate training session can provide health related range of motion benefits. Generally, a warm-up to minimize impairments and enhance performance should be composed of a submaximal intensity aerobic activity followed by large amplitude dynamic stretching and then completed with sport-specific dynamic activities. Sports that necessitate a high degree of static flexibility should use short duration static stretches with lower intensity stretches in a trained population to minimize the possibilities of impairments.


How children with experiences of intimate partner violence towards the mother understand and relate to their father.
The aim of this study was to describe how, in the aftermath of intimate partner violence against the mother, children understand and relate to their father. Face-to-face interviews with four girls and four boys, aged between eight and twelve, were analysed using an interpretative phenomenological approach. All of the children had been exposed to the father's violence towards the mother. Two super ordinate themes were identified in the analysis: the disjunctive image of the father and being entangled in a conflict. The children's understanding of the father and their relationship with him was built on different versions of the father and his actions; those experienced by the child and those recounted to them. The situational context surrounding the described experience pervaded the image of the father. An ambiguity appeared to exist in the sense of different versions of the father and children described different emotions that could both hinder and elicit other feelings connected to the father. Children also conveyed the sense of being trapped or entangled in a conflict where their own needs and desires could be deemed as unsafe to express, and that they felt responsibility for dealing with the father's influence.


Risk of invasive cervical cancer in relation to clinical investigation and treatment after abnormal cytology: a population-based case-control study.
A substantial proportion of women with cervical cancer that have participated in cervical screening have a history of an abnormal cytology result. Our objective was to assess the impact of histological investigation and treatment of women with abnormal cytology on the subsequent risk of invasive cervical cancer. All invasive cervical cancer cases in Sweden 1999-2001 and five population-based control women per case were investigated. Clinical investigations and treatment were analysed in case women (N = 143) and control women (N = 176) below 67 with abnormal cytology results 0.5-6.5 years before the cases' diagnosis. Cervical cancer risk in relation to investigation [histology or not, punch biopsy, cervical curettage or cone/large loop excision of the transformation zone (LLETZ)], and treatment (treatment or not, excisional or ablative) was estimated as odds ratios (ORs) using logistic regression. Absence of histological assessment was associated with increased cancer risk, both after low-grade [OR 2.37; 95% confidence intervals (CI): 1.27-4.43] and high-grade squamous atypia (8.26; 2.37-28.8). Among women with histology, absence of treatment was associated with increased cancer risk (3.68; 1.53-8.84), also when biopsy showed low-grade atypia or normal findings (3.57; 1.18-10.8). Ablative therapy associated with increased risk compared with excisional (3.82; 1.01-14.4), and laser conisation associated with decreased risk compared with LLETZ (0.06; 0.01-0.36). In conclusion, low-grade as well as high-grade squamous atypical cytology results may warrant histological investigation, treatment reduced cancer risk even when histology was negative or showed low-grade atypia indicating a need for improvements in the diagnosis of high-grade lesions, and laser conisation was the most effective treatment.


The membrane-bound intestinal enzymes of waxwings and thrushes: adaptive and functional implications of patterns of enzyme activity.
Cedar waxwings (Bombycilla cedrorum) feed predominantly on fruits that are rich in simple sugars and low in nitrogen, supplementing this diet with arthropod prey during the summer months as well as flowers and tree sap in springtime. In contrast, thrushes feed extensively on fatty, protein-rich invertebrate prey, supplemented with sugary and lipid-rich fruits. Simple sugars and fats are digested and/or absorbed by distinctly different physiological mechanisms, which suggests the possibility of contrasting digestive strategies in animals specialized to diets containing one of these two energy sources. In this study, we quantified enzymatic activity of three membrane-bound intestinal enzymes of cedar waxwings and five species of thrushes to explore this aspect of their digestive physiology. These enzymes catalyze the final steps in the digestion of carbohydrates (sucrase-isomaltase and maltase-glucoamylase) and protein (aminopeptidase-N). The two carbohydrases are homologous enzymes with overlapping functions; both enzymes catalyze the hydrolysis of maltase and isomaltase. The membrane-bound digestive enzyme systems that we described for cedar waxwings and thrushes can be explained by the particular nutrients contained within their respective natural diets. Consistent with previous work, cedar waxwings displayed intestinal sucrase activity, whereas thrushes did not. Correspondingly, cedar waxwings eat some foods containing sucrose, whereas thrushes do not. Sucrase-isomaltase conferred all maltase and isomaltase activity in cedar waxwings. In contrast, all maltase and isomaltase activity in thrushes was necessarily sucrase independent, which indicated the presence of maltase-glucoamylase. The absence of sucrase-independent maltase activity in cedar waxwings suggests that sucrase-isomaltase obviates the need for maltase-glucoamylase. Indeed, total maltase and isomaltase activities were much higher in cedar waxwings than in thrushes. Neither waxwings nor thrushes eat starchy foods; sucrase-isomaltase in waxwings and maltaseglucoamylase in thrushes probably function in digesting glycogen in animal foods. We suggest that digestive traits associated with specialization to monosaccharide-rich fruits (lack of a grinding gizzard) by frugivorous waxwings and thrushes may prevent utilization of starchy seeds. Total aminopeptidase-N activity in cedar waxwings was indistinguishable from the allometric pattern among thrush species, but the distribution of this enzyme along the intestines of waxwings and thrushes was distinctly different, which demonstrates that total enzyme activity can be insufficient as a descriptor of the functional activity of brush border enzymes. Aminopeptidase-N activity peaked in the anterior part of the intestines of thrushes and in the terminal portion of the intestines of waxwings, which suggests contrasting strategies for protein digestion from fatty versus sugary diets, respectively.


Stressful life events experienced by women in the year before their infants' births--United States, 2000-2010.
Epidemiologic studies suggest that prenatal stress is associated with preterm birth, low birth weight, and peripartum anxiety and depressive symptoms. The most recent population-based study, assessing trends in stress experienced in the year before an infant's birth, used 1990-1995 data from 11 states participating in the Pregnancy Risk Assessment Monitoring System (PRAMS). That study found that 64% of women surveyed reported experiencing at least one stressful life event (SLE), although the prevalence declined slightly over the study period. PRAMS data for 2000-2010 were used to examine more recent trends and to determine if the prevalence of SLEs has continued to decrease in the past decade. Additionally, 2010 data were used to determine the extent that maternal demographics and state of residence are associated with SLEs. This report describes the results of those analyses, which found that most women in the sample reported experiencing ≥1 SLEs in the year before their infant's birth, although the prevalence of experiencing SLEs decreased during 2000-2010. In 2010, based on data from 27 states, 70.2% of women reported ≥1 SLEs. The mean number of SLEs was 1.81, ranging from 1.41 in New York City to 2.26 in Oklahoma. SLEs were most frequently financial. Prevalence of SLEs varied by PRAMS reporting site and maternal demographics. Younger, less educated, unmarried, and Medicaid-covered women had the highest prevalence of SLEs. Public health practitioners and clinicians can use the information on trends and risk factors for SLEs to determine the likelihood that pregnant women might benefit from screening for stressors during pregnancy.


Liposome-supported peritoneal dialysis for detoxification of drugs and endogenous metabolites.
Peritoneal dialysis confers therapeutic advantages in patients with renal insufficiency and has proven beneficial in other indications, such as removal of excess metabolites or overdosed drugs. However, it is used in only about 10% of the dialyzed population worldwide, partly owing to the lower clearance rate compared with hemodialysis. We have developed a dialysis medium based on liposomes with a transmembrane pH gradient (basic or acidic aqueous core) that could improve the efficacy of peritoneal dialysis, specifically for the removal of excess metabolites or overdosed drugs. These scavenging vesicles are able to extract ionizable drugs and toxic metabolites into the peritoneal space and can be easily withdrawn from the body at the end of dialysis. This approach was used to successfully remove ammonia from rats with a greater extraction efficiency than traditional peritoneal dialysis, and may therefore prove useful in the treatment of severe hyperammonemia. Liposomal dialysis was also used to concentrate exogenous compounds in the rat peritoneal cavity, allowing for sequestration of several drugs that are frequently involved in overdose in people. In particular, liposomal dialysis counteracted the hypotensive action of the cardiovascular drug verapamil more efficiently than did control dialysis in a rat model of drug overdose. These findings highlight the versatility and advantage of this liposome-based approach for emergency dialysis.


Stability boundaries and lateral postural control in parkinson's disease.
Postural instability is a major problem in patients with Parkinson's disease (PD). We examined balance control in PD by using center of pressure (CP) variability and time-to-contact to investigate boundary relevant postural control behavior under quiet stance leaning conditions. Postural orientation was manipulated by having patients (n = 10) and healthy older controls (n = 7) lean forward and backward with varying degrees of lean on a force platform. The subjects were instructed to lean forward or backward (either halfway or as far as possible) without bending their hips or lifting their heels or toes off the ground. Time-to-contact of the CP with the geometric stability boundary defined by the feet as well as CP position and variability were analyzed. Medio-lateral CP variability was increased in the patients with PD. Medio-lateral average time-to-contact was decreased in the patients but not so in the anterior-posterior direction. In contrast to the CP variability, the medio-lateral variability of time-to-contact was lower in the patients. Patients as well as healthy older controls responded to lean manipulations with an increase in CP variability. Boundary relevant CP measures thus show clear changes in control strategies and confirm the role of lateral instability in PD.


Arabic Version of the Personality Inventory for the DSM-5 (PID-5) in a Community Sample of United Arab Emirates Nationals.
Section III of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) proposes a model for conceptualizing personality disorders in which they are characterized by impairments in personality functioning and maladaptive personality traits. The Personality Inventory for DSM-5 (PID-5) is a self-report measure that assesses the presence and severity of these maladaptive personality traits. The current study examined the reliability and validity of the Arabic version of the Personality Inventory for DSM-5 (PID-5) to measure maladaptive personality traits in the Emirati population of the United Arab Emirates. The Arabic version of the PID-5 was administered to a community sample of 1,090 United Arab Emirates nationals (89.5% female and 10.5% male, mean age = 22.44 years old). The descriptive measures, internal consistency, test-retest reliability, convergent validity with NEO - Five Factor Inventory, as well as PID-5's factor structure, were all addressed. The PID-5facets and domains mean scores were higher in the Emirati sample compared to the original US sample. Internal consistency of the PID-5 scales was acceptable to high and test-retest coefficients ranged from 0.84 (facets) to 0.87 (domains). As expected, the five domains of the Arabic version of the PID-5 correlated significantly with all Five-Factor Model domains of personality. Additionally, the Arabic version of the PID-5 confirmed a five-factor structure that resembles the PID-5 domains. The findings of this study provided initial support for the use of the Arabic version of the PID-5 to assess maladaptive personality traits in the Emirati population of the United Arab Emirates.


Cross-modal interactions in time and space: auditory influence on visual attention in hemispatial neglect.
Recent studies indicate that auditory tone presentation and auditory alerting can temporarily ameliorate visuospatial attention deficits in patients with unilateral neglect [Frassinetti, F., Pavani, F., & Ladavas, E. Acoustical vision of neglected stimuli: Interaction among spatially converging audiovisual inputs in neglect patients. Journal of Cognitive Neuroscience, 14, 62-69, 2002; Robertson, I. H., Mattingley, J. B., Rorden, C., & Driver, J. Phasic alerting of neglect patients overcomes their spatial deficit in visual awareness. Nature, 395, 169-172, 1998]. The current study investigated proposed mechanisms of cross-modal interaction to determine conditions in which auditory stimulation affects spatial and nonspatially lateralized attention deficits in a patient with hemispatial neglect. In Experiment 1, a target was presented among related distracters (conjunction search) while a tone was presented either bilaterally or in a congruent or incongruent spatial location with respect to the visual target. Whereas the results suggest a benefit of both general alerting and cross-modal spatial integration on visual search efficiency, the most significant improvement occurred when the target and tone were both presented in contralesional space. In Experiment 2, the effect of auditory alerting on selective attention was examined in a rapid serial visual search procedure with visual targets embedded in a stream of distracters presented at central fixation. When two targets were presented without an alerting tone, the patient missed the second target for up to 1000 msec after the first target appeared (a finding known as the "attentional blink" [AB] and, on average, about 400-500 msec in normals). An alerting tone presented at a fixed temporal location significantly reduced the AB in a tone-duration-dependent manner. Experiment 3 examined the effect of cross-modal space on selective attention in an AB paradigm in which T2 occurred randomly to the left or right of T1 with a spatially congruent or incongruent tone. Discrimination of T2 in contralesional space significantly improved when the tone was presented in the same location, and was impaired when the tone was presented on the ipsilesional side. The findings are discussed as they relate to cross-modal interactions and their influence on spatial and nonspatially lateralized attention deficits in neglect.


Violent offending and IQ level as predictors of suicide in schizophrenia: national cohort study.
Currently there is a lack of strong epidemiological evidence for violent offending and intelligence quotient (IQ) level as predictors of suicide risk among people with schizophrenia. We interlinked several Swedish routinely collected national registers, including the Hospital Discharge, Crime, Conscript, Migration and Cause of Death Registers, to identify 13,804 patients admitted at least twice with a schizophrenia diagnosis during 1973-2004. All deaths by specific cause were ascertained and suicides identified, and rate ratios were estimated using Poisson regression models with adjustment for age and period effects. There were 871 suicides: 6.3% of the cohort. Almost 80% of these cases were aged 20-39 years, and 80% occurred within 10 years of second discharge, with almost a quarter taking place within a year. The following risk factors were identified: younger age, 15-19 versus 40 years and older (rate ratio 3.18, 95% confidence interval 1.82-5.56), male sex (rate ratio 1.37, 1.18-1.59) and history of violent offending (rate ratio 1.45, 1.21-1.73). Intelligence quotient data were unavailable for women, but in men, lower IQ appeared protective compared to those of average or higher levels of intelligence (rate ratio 0.71, 0.58-0.86). Further stratified analyses to identify effect modification indicated that the elevated risk associated with past violent offending was restricted to males, and specifically to those with a lower IQ. Further research is needed to identify additional risk and protective factors for suicide that may be unique to people diagnosed with schizophrenia, and also other modifiers of the increased risk linked with violent offending.


Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics.
Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.


Age-related changes in the sulphation of the chondroitin sulphate linkage region from human articular cartilage aggrecan.
The chondroitin sulphate (CS) linkage regions have been isolated from human articular cartilage aggrecan (from 10- to 72-year-olds) by chondroitin ABC endolyase digestion and size-exclusion chromatography. Linkage region hexasaccharides have been characterized and their abundance estimated by high-pH anion-exchange chromatography. The basic structure for the CS linkage region oligosaccharides identified from human aggrecan is as follows: DeltaUA(beta1-3)GalNAc[0S/4S/6S](beta1-4)GlcA(beta1-3)Gal[0S/6S](beta1-3)Gal(beta1-4)Xyl, where DeltaUA represents 4,5-unsaturated hexuronic acid, 4S and 6S represent an O-ester sulphate group on C-4 and C-6 respectively, and 0S represents zero sulphation. There are significant age-related changes in the abundance of the various N-acetylgalactosamine (GalNAc) sulphation forms identified, occurring up to approx. 20 years old. During the period from 10 to 20 years old the level of GalNAc 6-sulphation at the linkage region increases from approx. 43% to approx. 75%, while there is a corresponding reduction in unsulphated (approx. 30% to approx. 20%) and 4-sulphated (approx. 25% to approx. 6%) GalNAc residues. There is also an increase in the incidence of linkage region galactose 6-sulphation (approx. 2% to approx. 10%) which was only observed in linkage regions with GalNAc 6-sulphation. Beyond 20 years old there are few changes in the relative abundance of these GalNAc sulphation variants; however, there is a slight increase in the abundance of 6-sulphation between approx. 20 years old and approx. 40 years old and a slight decrease in its abundance beyond approx. 40 years old. Our data show that in the majority of chains from tissues of all ages the GalNAc residue closest to the linkage region is 6-sulphated, but the level of GalNAc 6-sulphation within the linkage region is lower than the average level observed within the repeat region.


Characterization of human iodothyronine sulfotransferases.
Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is known about which human sulfotransferase isoenzymes are involved. We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively. In all cases, the substrate preference was 3,3'-T2 >> rT3 > T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L 3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2) was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol, 0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation of 3,3'-T2 was inhibited by the other iodothyronines in a concentration-dependent manner. The inhibition profiles of the 3,3'-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 micromol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3. These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney.


Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part 1: determinants operating at individual and household level.
A high burden of malaria, tuberculosis, and HIV infection contributes to national and individual poverty. We have reviewed a broad range of evidence detailing factors at individual, household, and community levels that influence vulnerability to malaria, tuberculosis, and HIV infection and used this evidence to identify strategies that could improve resilience to these diseases. This first part of the review explores the concept of vulnerability to infectious diseases and examines how age, sex, and genetics can influence the biological response to malaria, tuberculosis, and HIV infection. We highlight factors that influence processes such as poverty, livelihoods, gender discrepancies, and knowledge acquisition and provide examples of how approaches to altering these processes may have a simultaneous effect on all three diseases.


Basal cell carcinoma chemoprevention with nonsteroidal anti-inflammatory drugs in genetically predisposed PTCH1+/- humans and mice.
In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1(+/-) mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1(+/-)) patients with the basal cell nevus syndrome. In Ptch1(+/-) mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (P(difference) = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1(+/-) mice and had a significant anti-BCC effect in humans with less severe disease.


Characteristics of Crimean-Congo hemorrhagic fever virus (Xinjiang strain) in China.
Virus strains isolated from blood of patients during a hemorrhagic fever outbreak in 1968 in southern Xinjiang, China, from Hyalomma asiaticum and from sheep, were found to be identical or closely related to Crimean-Congo hemorrhagic fever (C-CHF) virus by complement fixation and indirect immunofluorescence tests with convalescent sera of patients and with C-CHF reference antibody. The virus was inactivated by ether and acid. Viral synthesis was not suppressed by 5-iododeoxyuridine suggesting an RNA-containing genome. The buoyant density in sucrose was 1.16-1.18 g/cm3. The particle weight was estimated at 3.26 +/- 0.46 X 10(8). The diameter of the virus particles was 85-105 nm.


Co-Producing Interprofessional Round Work: Designing Spaces for Patient Partnership.
Within wide-ranging quality improvement agendas, patient involvement in health care is widely accepted as crucial. Ward rounds that include patients' active participation are growing as an approach to involve patients, ensure safety, and improve quality. An emerging approach to studying quality improvement is to focus on "clinical microsystems," where patients, professionals, and information systems interact. This provides an opportunity to study ward rounds more deeply. A new model of conducting ward rounds implemented through quality improvement work was studied, using the theory of practice architectures as an analytical tool. Practice architecture focuses on the cultural-discursive, social-political, and material-economic conditions that shape what people do in their work. Practice architecture is a sociomaterial theoretical perspective that has the potential to change how we understand relationships between practice, learning, and change. In this study, we examine how changes in practices are accomplished. The results show that practice architecture formed co-productive learning rounds, a possible model integrating quality improvement in daily work. This emerged in the interplay between patients through their "double participation" (as people and as information on screens), and groups of professionals in a ward round room. However, social interplay had to be renegotiated in order to accomplish the goals of all ward rounds.


Historical, observed, and modeled wildfire severity in montane forests of the Colorado Front Range.
Large recent fires in the western U.S. have contributed to a perception that fire exclusion has caused an unprecedented occurrence of uncharacteristically severe fires, particularly in lower elevation dry pine forests. In the absence of long-term fire severity records, it is unknown how short-term trends compare to fire severity prior to 20th century fire exclusion. This study compares historical (i.e. pre-1920) fire severity with observed modern fire severity and modeled potential fire behavior across 564,413 ha of montane forests of the Colorado Front Range. We used forest structure and tree-ring fire history to characterize fire severity at 232 sites and then modeled historical fire-severity across the entire study area using biophysical variables. Eighteen (7.8%) sites were characterized by low-severity fires and 214 (92.2%) by mixed-severity fires (i.e. including moderate- or high-severity fires). Difference in area of historical versus observed low-severity fire within nine recent (post-1999) large fire perimeters was greatest in lower montane forests. Only 16% of the study area recorded a shift from historical low severity to a higher potential for crown fire today. An historical fire regime of more frequent and low-severity fires at low elevations (<2260 m) supports a convergence of management goals of ecological restoration and fire hazard mitigation in those habitats. In contrast, at higher elevations mixed-severity fires were predominant historically and continue to be so today. Thinning treatments at higher elevations of the montane zone will not return the fire regime to an historic low-severity regime, and are of questionable effectiveness in preventing severe wildfires. Based on present-day fuels, predicted fire behavior under extreme fire weather continues to indicate a mixed-severity fire regime throughout most of the montane forest zone. Recent large wildfires in the Front Range are not fundamentally different from similar events that occurred historically under extreme weather conditions.


Visual cues to female physical attractiveness.
Evolutionary psychology suggests that a woman's sexual attractiveness is based on cues of health and reproductive potential. In recent years, research has focused on the ratio of the width of the waist to the width of the hips (the waist-to-hip ratio (WHR). A low WHR (i.e. a curvaceous body) is believed to correspond to the optimal fat distribution for high fertility, and so this shape should be highly attractive. In this paper we present evidence that weight scaled for height (the body mass index (BMI)) is the primary determinant of sexual attractiveness rather than WHR. BMI is also strongly linked to health and reproductive potential. Furthermore, we show how covariation of apparent BMI and WHR in previous studies led to the overestimation of the importance of WHR in the perception of female attractiveness. Finally, we show how visual cues, such as the perimeter-area ratio (PAR), can provide an accurate and reliable index of an individual's BMI and could be used by an observer to differentiate between potential partners.


Improving Body Mechanics Using Experiential Learning and Ergonomic Tools in Massage Therapy Education.
Current industry data suggest that the rise in occupational injuries for massage therapists is contributing to a significant number leaving the profession after a few short years. While many massage therapists are taught methods for proper body mechanics and self-care within their career educational programs, there are few consistencies in the theoretical approaches to these concepts, even though it is a required component in massage therapy career training. This study demonstrates a measurable and effective teaching method using a combination of experiential and transformative learning theory models and authentic ergonomics measurement tools to teach effective body mechanics in entry level career training that may be sustainable for new massage therapists entering the field. Four cohorts of students (N = 17) enrolled in a kinesiology course for massage therapists were studied using a mixed-methods time series experimental design. A pre- and post-test was conducted by utilizing two industry standard ergonomics risk factor assessment tools as measurable data for score comparison, to denote improvements in each student's risk factor tendencies and provide evidentiary support of learning transfer. Between the pre- and post-test, students participated in a series of experiential learning exercises within class sessions during the semester and completed two reflection journals discussing their experiences. The results showed that there was a statistically significant reduction in ergonomics risk factor scores for all students studied. The success of this study demonstrates that the instructional design using experiential and transformative educational theory and general ergonomics concepts is an effective approach to teaching proper body mechanics to massage therapy students which can be adopted into universally accepted curriculum on many levels and could eventually contribute to reduction of occupational injury in the future.


Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD.
The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.


Hominoid seminal protein evolution and ancestral mating behavior.
Hominoid mating systems show extensive variation among species. The degree of sexual dimorphism in body size and canine size varies among primates in accordance with their mating system, as does the testes size and the consistency of ejaculated semen, in response to differing levels of sperm competition. To investigate patterns of evolution at hominoid seminal proteins and to make inferences regarding the mating systems of extinct taxa, we sequenced the entire coding region of the prostate-specific transglutaminase (TGM4) gene in human, chimpanzee, bonobo, western lowland gorilla, eastern lowland gorilla, orangutan, and siamang, including multiple humans, chimps, and gorillas. Partial DNA sequence of the coding regions was also obtained for one eastern lowland gorilla at the semenogelin genes (SEMG1 and SEMG2), which code for the predominant proteins in semen. Patterns of nucleotide variation and inferred protein sequence change were evaluated within and between species. Combining the present data with previous studies demonstrates a high rate of amino acid substitutions, and low intraspecific variation, at seminal proteins in Pan, presumably driven by strong sperm competition. Both gorilla species apparently possess nonfunctional TGM4, SEMG1, and SEMG2 genes, suggesting that gorillas have had low sperm competition, and therefore their current polygynous mating system, for a long time before their divergence. Similarly, orangutans show longstanding stasis at TGM4, which may be interpreted as evidence for an unchanging mating system for most of their evolution after their divergence from African apes. In contrast to the great apes, the data from humans could be interpreted as evidence of fluctuations between different mating systems or alternatively as a relaxed functional constraint in these proteins. It is our hope that this study is a first step toward developing a model to predict ancestral mating systems from extant molecular data to complement interpretations from the fossil record.


FoxP2 expression in avian vocal learners and non-learners.
Most vertebrates communicate acoustically, but few, among them humans, dolphins and whales, bats, and three orders of birds, learn this trait. FOXP2 is the first gene linked to human speech and has been the target of positive selection during recent primate evolution. To test whether the expression pattern of FOXP2 is consistent with a role in learned vocal communication, we cloned zebra finch FoxP2 and its close relative FoxP1 and compared mRNA and protein distribution in developing and adult brains of a variety of avian vocal learners and non-learners, and a crocodile. We found that the protein sequence of zebra finch FoxP2 is 98% identical with mouse and human FOXP2. In the avian and crocodilian forebrain, FoxP2 was expressed predominantly in the striatum, a basal ganglia brain region affected in patients with FOXP2 mutations. Strikingly, in zebra finches, the striatal nucleus Area X, necessary for vocal learning, expressed more FoxP2 than the surrounding tissue at post-hatch days 35 and 50, when vocal learning occurs. In adult canaries, FoxP2 expression in Area X differed seasonally; more FoxP2 expression was associated with times when song becomes unstable. In adult chickadees, strawberry finches, song sparrows, and Bengalese finches, Area X expressed FoxP2 to different degrees. Non-telencephalic regions in both vocal learning and non-learning birds, and in crocodiles, were less variable in expression and comparable with regions that express FOXP2 in human and rodent brains. We conclude that differential expression of FoxP2 in avian vocal learners might be associated with vocal plasticity.


Effect of L-arginine supplementation on insulin resistance and adipocitokines levels in head and neck cancer non diabetic patients after surgery.
Previous studies have found that L-arginine induced beneficial effects over insulin resistance both in type 2 diabetes mellitus patients and healthy individuals. The aim of our study was to investigate whether an L-arginine enteral supplementation (20 g per day) in head and neck cancer patients could modify insulin resistance, leptin and adiponectin levels after surgery. At surgery 82 patients were randomly allocated to two groups: group I received an enteral diet supplements with a high dose of arginine (20g per day) and group II received an enteral formula without arginine. At basal time and on postoperative day 10, the following parameters were recorded: glucose, c-reactive protein, insulin, HOMA (homeostasis model assessment), leptin and adiponectin. Values of weight, body mass index, fat mass and fat free mass remained unchaged during the acute nutritional intervention in both groups. Insulin levels UI/L (-0.21+/-0.18) and HOMA units (-0.07+/-0.13) decreased in the arginine group. Adiponectin levels (+1.8+/-2.3ng/ml) increased in the arginine group. Short-term enteral L-arginine therapy addeded to usual enteral nutrition of patients affected by head and neck cancer and surgery without diabetes mellitus type 2 is able to improve insulin resistance and adiponectin levels.


Trends in Alcohol Consumption Among Older Americans: National Health Interview Surveys, 1997 to 2014.
The majority of U.S. older adults consume alcoholic beverages. The older population is projected to almost double by 2050. Substantially more drinkers are likely. To describe gender-specific trends (1997 to 2014) in prevalence of drinking status (lifetime abstention, former drinking, current drinking [including average volume], and binge drinking) among U.S. adults ages 60+ by age group and birth cohort. In the 1997 to 2014 National Health Interview Surveys, 65,303 respondents ages 60+ (31,803 men, 33,500 women) were current drinkers; 6,570 men and 1,737 women were binge drinkers. Prevalence estimates and standard errors were computed by age group (60+, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80+) and birth cohort (<1925, 1925 to 1935, 1936 to 1945, 1946 to 1954). Trends were examined using joinpoint regression and described as average annual percent change (AAPC; overall change 1997 to 2014) and annual percent change (APC; in-between infection points). Primary analyses were unadjusted. All analyses (unadjusted and adjusted for demographics/lifestyle) were weighted to produce nationally representative estimates. Statistical procedures accounted for the complex survey design. Among men ages 60+, unadjusted prevalence of current drinking trended upward, on average, 0.7% per year (AAPC, p = 0.02); average volume and prevalence of binge drinking remained stable. Adjusted results were similar. Among women age 60+, unadjusted prevalence of current drinking trended upward, on average, 1.6% per year (AAPC, p < 0.0001), but average volume remained stable; prevalence of binge drinking increased, on average, 3.7% per year (AAPC, p < 0.0001). Adjusted results were similar. Trends varied by age group and birth cohort. Among men born 1946 to 1954, unadjusted prevalence of current drinking trended upward, on average, 2.4% per year (AAPC, p = 0.02); adjusted results were nonsignificant. Our finding of upward trends in drinking among adults ages 60+, particularly women, suggests the importance of public health planning to meet future needs for alcohol-related programs.


Glucocorticoid modulation of casein gene transcription in mouse mammary gland.
The influence of cortisol and prolactin on casein gene expression in the mammary gland of lactating BALB/c mice was measured by using a specific cDNA probe to 15S casein mRNA (cDNAcsn). Casein mRNA (mRNAcsn) level in the mammary gland was decreased by 85% 5 days after adrenal ablation, but then was increased 4.4-fold 12 hr after a single injection of hydrocortisone-21-acetate. An 80% decrease in serum prolactin level, induced by the prolactin inhibitor 2-bromo-alpha-ergocryptin (CB-154), did not alter the level of mRNAcsn in the gland. Specific transcription of the casein gene in nuclei isolated from lactating mammary glands was measured by cDNAcsn hybridization to the in vitro synthesized Hg-CTP-containing RNA (Hg-RNA), which was purified by SH-agarose chromatography. The level of the mRNAcsn in Hg-RNA synthesized in the isolated nuclei was 0.09% and this was decreased 85% by alpha-amanitin, indicating that the mRNAcsn sequences in the Hg-RNA were the products of RNA polymerase II-directed DNA-dependent RNA synthesis. Transcription of the mRNAcsn in isolated nuclei was decreased by 70% 5 days after adrenalectomy and a single injection of the glucocorticoid then increased the transcription level 2-fold at 6 hr. Essentially no alteration of the level of transcription was detectable in mammary nuclei isolated from lactating mice with 80% decreased serum prolactin level, induced by CB-154 treatment. The results thus demonstrate a glucocorticoid involvement on the modulation of casein gene expression at the transcriptional level of control.


Thalamocortical dynamics of the McCollough effect: boundary-surface alignment through perceptual learning.
This article further develops the FACADE neural model of 3-D vision and figure-ground perception to quantitatively explain properties of the McCollough effect (ME). The model proposes that many ME data result from visual system mechanisms whose primary function is to adaptively align, through learning, boundary and surface representations that are positionally shifted due to the process of binocular fusion. For example, binocular boundary representations are shifted by binocular fusion relative to monocular surface representations, yet the boundaries must become positionally aligned with the surfaces to control binocular surface capture and filling-in. The model also includes perceptual reset mechanisms that use habituative transmitters in opponent processing circuits. Thus the model shows how ME data may arise from a combination of mechanisms that have a clear functional role in biological vision. Simulation results with a single set of parameters quantitatively fit data from 13 experiments that probe the nature of achromatic/chromatic and monocular/binocular interactions during induction of the ME. The model proposes how perceptual learning, opponent processing, and habituation at both monocular and binocular surface representations are involved, including early thalamocortical sites. In particular, it explains the anomalous ME utilizing these multiple processing sites. Alternative models of the ME are also summarized and compared with the present model.


Orbitofrontal contributions to human working memory.
Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in human memory, the necessity of the orbitofrontal cortex for key competencies of working memory remains largely unexplored. We therefore studied human brain lesion patients to determine whether the orbitofrontal cortex is necessary for working memory function, administering subtests of the Wechsler memory scale, the Wechsler adult intelligence scale, and the n-back task to 3 participant groups: orbitofrontal lesions (n = 24), prefrontal lesions not involving orbitofrontal cortex (n = 40), and no brain lesions (n = 54). Orbitofrontal damage was reliably associated with deficits on neuropsychological tests involving the coordination of working memory maintenance, manipulation, and monitoring processes (n-back task) but not on pure tests of working memory maintenance (digit/spatial span forward) or manipulation (digit/spatial span backward and letter-number sequencing). Our findings elucidate a central component of the neural architecture of working memory, providing key neuropsychological evidence for the necessity of the orbitofrontal cortex in executive control functions underlying the joint maintenance, manipulation, and monitoring of information in working memory.


Cyclooxygenase-2 inhibition and coagulation.
Selective inhibitors of cyclooxygenase-2 (COX-2) have come under scrutiny because of a possibly increased thrombotic risk observed in retrospective studies and comparatively small cancer trials. Indeed, inhibition of COX-2 may favor a prothrombotic environment by suppressing endothelial prostacyclin synthesis while leaving COX-1-dependent platelet thromboxane (TX) A2 synthesis unopposed. However, in vitro studies have shown that the effect of coxibs on coagulation is dependent on several variables; for example, the coxib celecoxib reduces endothelial tissue factor expression, a key initiator of the coagulation cascade. Furthermore, animal studies are inconclusive as some studies investigating the effect of COX-2 inhibition in atherosclerosis imply a detrimental effect of coxibs, whereas others suggest a beneficial effect on plaque progression and stability. In healthy human subjects and in patients with atherosclerotic vascular diseases, the effect of COX-2 inhibition on coagulation is equally unclear as no prospective, randomized, double-blinded studies sufficiently powered to investigate cardiovascular endpoints have been performed to directly investigate a potentially cardiotoxic effect of coxibs. Here, we review the effect of COX-2 inhibition on the coagulation system; we discuss the molecular mechanisms involved and summarize important clinical trials in which an increased frequency of thrombotic complications coxibs was observed.


Meat and haem iron intake in relation to glioma in the European Prospective Investigation into Cancer and Nutrition study.
Diets high in red or processed meat have been associated positively with some cancers, and several possible underlying mechanisms have been proposed, including iron-related pathways. However, the role of meat intake in adult glioma risk has yielded conflicting findings because of small sample sizes and heterogeneous tumour classifications. The aim of this study was to examine red meat, processed meat and iron intake in relation to glioma risk in the European Prospective Investigation into Cancer and Nutrition study. In this prospective cohort study, 408 751 individuals from nine European countries completed demographic and dietary questionnaires at recruitment. Multivariable Cox proportional hazards models were used to examine intake of red meat, processed meat, total dietary iron and haem iron in relation to incident glioma. During an average follow-up of 14.1 years, 688 incident glioma cases were diagnosed. There was no evidence that any of the meat variables (red, processed meat or subtypes of meat) or iron (total or haem) were associated with glioma; results were unchanged when the first 2 years of follow-up were excluded. This study suggests that there is no association between meat or iron intake and adult glioma. This is the largest prospective analysis of meat and iron in relation to glioma and as such provides a substantial contribution to a limited and inconsistent literature.


Effects of Coffee Components on Muscle Glycogen Recovery: A Systematic Review.
Coffee is one of the most consumed beverages in the world, and it can improve insulin sensitivity, stimulating glucose uptake in skeletal muscle when adequate carbohydrate intake is observed. The aim of this review is to analyze the effects of coffee and coffee components on muscle glycogen metabolism. A literature search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis, and seven studies were included, that explored the effects of coffee components on various substances and signaling proteins. In one of the studies with humans, caffeine was shown to increase glucose levels, Ca2+/calmodulin-dependent protein kinase phosphorylation, glycogen resynthesis rates, and glycogen accumulation after exercise. After intravenous injection of caffeine in rats, caffeine increased adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, and glucose transport. In in vitro studies, caffeine raised AMPK and ACC phosphorylation, increasing glucose transport activity and reducing energy status in rat muscle cells. Cafestol and caffeic acid increased insulin secretion in rat beta cells and glucose uptake into human muscle cells. Caffeic acid also increased AMPK and ACC phosphorylation, reducing the energy status and increasing glucose uptake in rat muscle cells. Chlorogenic acid did not show any positive or negative effect. The findings from this review must be taken with caution due to the limited number of studies on the subject. In conclusion, various coffee components had a neutral or positive role in the metabolism of glucose and muscle glycogen, whereas no detrimental effect was described. Coffee beverages should be tested as an option for athletes' glycogen recovery.


Fatal acute interstitial pneumonitis complicating polymyositis in a 41-year-old man.
We report a case of a previously healthy 41-year-old man who was admitted for progressive dyspnea and cough, which culminated in respiratory failure, shock, and death. Lung and muscle biopsy results were consistent with interstitial lung disease secondary to polymyositis. Polymyositis and dermatomyositis are rare autoimmune diseases that primarily affect the muscles and skin, with frequent extramuscular and specifically pulmonary manifestations. Respiratory complications are in 2 categories: primary (the interstitial lung diseases, which can be acute or chronic) and secondary (aspiration pneumonia/pneumonitis, muscle weakness, infection, drug-induced disease, pulmonary congestion secondary to heart failure, pulmonary hypertension, and pneumomediastinum). Diagnosis of a specific interstitial lung disease relies mainly on high-resolution computed tomography of the chest and on tissue diagnosis. Prognosis depends on the histopathology findings and the specific form of interstitial lung disease and its response to therapy, which consists of high-dose steroids and immunomodulating agents. Unfortunately, patients with polymyositis/dermatomyositis associated with pulmonary complications have a worse prognosis than patients with isolated forms.


Predicting neurodevelopmental outcomes at preschool age for children with very low birth weight.
The purpose of this study was to examine predictors of neurodevelopmental outcome in very low birth weight children without major impairment at 5 years of age, as well as to identify the contribution of early neurodevelopmental assessment to preterm children's later developmental outcomes. The participants in this study included 126 children who were prematurely born with very low birth weight. Outcomes of the childrens' later development were measured in tests that factored cognitive function, motor performance, and adaptive behavior. The results indicated that more than 50% of full-scale intelligence and 30% of both motor performance and adaptive behavior at the age of 5 can be explained by four predictors. The four predictors include preterm children's medical complications at birth, maternal education, early motor assessments, and cognitive assessments. Adding each test score obtained in early ages provides additional information to predict children's cognitive, motor, and adaptive behavior at 5 years of age. Manifold assessments conducted in multiple time periods strengthen the predictive values of later developmental outcomes. In addition, the findings of this study indicate that very low birth weight children tend to have lower adaptive behavior at 5 years old. With regard to our findings, we believe that having adaptive function is a reflection of a child's overall integrated abilities. Further study is warranted to increase understanding of this topic, as well as to be able to predict adaptive strengths and weakness and pinpoint limiting factors that may be useful for targeting behaviors in intervention.


OptEase and TrapEase vena cava filters: a single-center experience in 258 patients.
We aimed to evaluate the efficacy and safety of the OptEase and TrapEase (both from Cordis, Roden, Netherlands) vena cava filters in the prevention of pulmonary embolism (PE). Between May 2004 and December 2008, OptEase (permanent/retrievable; n = 228) or TrapEase (permanent; n = 30) vena cava filters were placed in 258 patients (160 female and 98 male; mean age 62 years [range 22 to 97]). Indications were as follows: prophylaxis for PE (n = 239), contraindication for anticoagulation in the presence of PE or DVT (n = 10), and development of PE or DVT despite anticoagulation (n = 9). Medical records were retrospectively reviewed for indications, clinical results, and procedure-related complications during placement and retrieval. Clinical PE did not develop in any of the patients. However, radiologic signs of segmental PE were seen in 6 of 66 patients with follow-up imaging data. Migration or fracture of the filter or cava perforation was not seen in any of the patients. Except for a single case of asymptomatic total cava thrombosis, no thrombotic occlusion was observed. One hundred forty-one patients were scheduled to undergo filter removal; however, 17 of them were not suitable for such based on venography evaluation. Removal was attempted in 124 patients and was successful in 115 of these (mean duration of retention 11 days [range 4 to 23]). Nine filters could not be removed. Permanent/retrievable vena cava filters are safe and effective devices for PE prophylaxis and for the management of venous thromboembolism by providing the option to be left in place.


Understanding Attachment Transitions Through the Lived Experiences of Young Black Gay and Bisexual Men.
We conducted a mixed-methods study to identify factors that influence transitions in attachment style between childhood and adulthood among 28 young Black gay and bisexual men (YBGBM) in the United States. We used a phenomenological approach to data integration, with the major component to the results being garnered from the qualitative interviews. We organized our results by four attachment transition groups: stable secure (secure attachment in childhood and young adulthood), stable insecure (insecure attachment in childhood and young adulthood), secure to insecure (secure in childhood and insecure in adulthood) and insecure to secure (insecure in childhood and secure in adulthood). Within each of the typologies, two major themes emerged: social support and religion. Generally, transitions from secure to insecure attachment were related to experiences of perceived rejection by a parental figure during adolescence that corresponded with sexual orientation disclosure. Transitions from insecure to secure attachment appeared to be related to the absence of an attachment figure early in life, but with the acquisition of an attachment figure during early to late adolescence. The findings from our study suggest a need for attachment-based approaches to social support interventions, as well as for an increased understanding of social and cultural factors that impact attachment changes among practitioners who use attachment-based therapy models for YBGBM.


Water induces the same crown shapes as Li+ or Na+ in 15-crown-5 ether: a broadband rotational study.
15-Crown-5 ether (15C5) and its complexes with water have been studied using broadband Fourier transform microwave spectroscopy in a supersonic jet. A new conformer of 15C5 has been observed and established as the new global minimum out of a total of nine isolated structures. In addition, two 15C5-H2O and two 15C5-(H2O)2 clusters have been observed. The cluster structures have been unambiguously identified through the observation of water 18O isotopologue spectra. In all the clusters, at least one water molecule, located close to the axis of the 15C5 ring, interacts through two simultaneous hydrogen bonds to the endocyclic oxygen atoms. This interaction reshapes the 15C5 ring to reduce its rich conformational landscape to only two open structures, related to those found in complexes with Li+ or Na+ ions. In the most abundant 15C5-(H2O)2 form, the two water molecules repeat the same interaction scheme while binding to opposite sides of the ring. In the second most abundant dihydrated form the two water molecules lie on the same side of the ring. This finding is exceptionally rare because water-water interactions typically prevail over the formation of additional solute-water contacts, and it showcases the particular binding features of crown ethers.


Speech perception with the ACE and the SPEAK speech coding strategies for children implanted with the Nucleus cochlear implant.
The aim of this study is to determine whether implanted children using the ACE speech coding strategy demonstrate superior performances compared to implanted children using the SPEAK speech coding strategy over time. Cochlear implanted children with prelinguistic sensorineural bilateral deafness of profound degree, using either the ACE or SPEAK coding strategy, were evaluated and compared. Both groups of children used one of the speech coding strategies continuously from the initial programming session and for a period of 2 years post-switch-on. One group comprised children who were retrospectively implanted and had received the SPEAK speech coding strategy (n=32) and the second group consisted of prospectively implanted children who received the ACE speech coding strategy (n=26). Both populations were homogenous as far as age of implantation, degree of hearing loss, anatomy of the cochlea, depth of electrode insertion, and educational and rehabilitative support provided. Children were assessed at 6, 12 and 24 months post switch-on via pure-tone audiometry and for speech perception tests. Children using the ACE speech coding strategy were additionally evaluated using the MAIS and MUSS language scales. Satisfactory benefits in speech perception were demonstrated by both groups of implanted children. No significant difference between the mean pure tone thresholds was observed postoperatively between the groups. Two years post switch-on the group using the ACE speech coding strategy demonstrated superior results for vowel discrimination in comparison to children using the SPEAK coding strategy. No significant difference was observed between the groups for performance on discrimination of syllable patterns (ESP) or for disyllablic word recognition tests. Additionally, the group of ACE users demonstrated maximum performance on MAIS and MUSS scales, 2 years post switch-on. The results clearly demonstrate significant benefit of cochlear implantation in prelinguistically deafened children for speech perception ability when using either the SPEAK or ACE speech coding strategies. Children using the ACE speech coding strategy demonstrate more rapid progress in improved speech perception ability initially, however 2 years post switch-on, no significant difference in performance on open-set speech recognition tests can be noted irrespective of the strategy in use.


Parental alienation, DSM-5, and ICD-11: response to critics.
There has been considerable interest among forensic practitioners in the proposals that parental alienation be included in the next editions of the Diagnostic and Statistical Manual of Mental Diseases (DSM) and The International Classification of Diseases (ICD). However, there has also been a great deal of misunderstanding about the proposals, and misinformation has been expressed in professional meetings, on websites, and in journal articles. In this article we address four common misunderstandings regarding parental alienation: that there is a lack of research to support it as a diagnosis; that adopting parental alienation as a diagnosis will lead to serious adverse consequences; that the advocates of parental alienation are driven by self-serving or malevolent motives; and that Richard Gardner should be criticized for self-publishing his description of parental alienation syndrome.


Effects of long-term nocturnal oxygen treatment in patients with severe heart failure.
Sleep-disordered breathing (SDB) is common in patients with heart failure (HF) and leads to disturbed sleep. The objective of this study was to determine the persistent effects of long-term nocturnal oxygen treatment in patients with severe HF regarding (1) objective outcomes, such as sleep, SDB, cardiac function, and functional capacity; (2) subjective outcomes, such as self-assessed sleep difficulties, daytime sleepiness, and health-related quality of life (HRQOL); and (3) the relationship between objective and subjective outcomes. In this open nonrandomized experimental study, 22 patients, median age 71 years, with severe HF were studied before and after 3 months of receiving nocturnal oxygen. The measures used were overnight polysomnography, echocardiography, 6-minute walk test, self-assessed sleep difficulties (Uppsala Sleep Inventory-HF), daytime sleepiness (Epworth Sleepiness Scale), and HRQOL (36-Item Short Form Health Survey and Minnesota Living with Heart Failure Questionnaire). SDB, with a 90% dominance of central sleep apnea, occurred in 41% of the patients with severe HF before intervention. After intervention, functional capacity improved for both the whole group of patients with HF (P < .01) and HF patients with SDB (P < .05). No improvements regarding cardiac function, objective sleep, subjective sleep, or SDB were seen, except for a decrease of > or = 4% desaturations (P < .05). HRQOL did not differ significantly between HF patients with and without SDB before or after intervention with nocturnal oxygen. Long-term nocturnal oxygen treatment improved functional capacity in patients with severe HF, with or without SDB. No improvements were seen regarding sleep, daytime sleepiness, SDB, cardiac function, or HRQOL.


MICRAT: a novel algorithm for inferring gene regulatory networks using time series gene expression data.
Reconstruction of gene regulatory networks (GRNs), also known as reverse engineering of GRNs, aims to infer the potential regulation relationships between genes. With the development of biotechnology, such as gene chip microarray and RNA-sequencing, the high-throughput data generated provide us with more opportunities to infer the gene-gene interaction relationships using gene expression data and hence understand the underlying mechanism of biological processes. Gene regulatory networks are known to exhibit a multiplicity of interaction mechanisms which include functional and non-functional, and linear and non-linear relationships. Meanwhile, the regulatory interactions between genes and gene products are not spontaneous since various processes involved in producing fully functional and measurable concentrations of transcriptional factors/proteins lead to a delay in gene regulation. Many different approaches for reconstructing GRNs have been proposed, but the existing GRN inference approaches such as probabilistic Boolean networks and dynamic Bayesian networks have various limitations and relatively low accuracy. Inferring GRNs from time series microarray data or RNA-sequencing data remains a very challenging inverse problem due to its nonlinearity, high dimensionality, sparse and noisy data, and significant computational cost, which motivates us to develop more effective inference methods. We developed a novel algorithm, MICRAT (Maximal Information coefficient with Conditional Relative Average entropy and Time-series mutual information), for inferring GRNs from time series gene expression data. Maximal information coefficient (MIC) is an effective measure of dependence for two-variable relationships. It captures a wide range of associations, both functional and non-functional, and thus has good performance on measuring the dependence between two genes. Our approach mainly includes two procedures. Firstly, it employs maximal information coefficient for constructing an undirected graph to represent the underlying relationships between genes. Secondly, it directs the edges in the undirected graph for inferring regulators and their targets. In this procedure, the conditional relative average entropies of each pair of nodes (or genes) are employed to indicate the directions of edges. Since the time delay might exist in the expression of regulators and target genes, time series mutual information is combined to cooperatively direct the edges for inferring the potential regulators and their targets. We evaluated the performance of MICRAT by applying it to synthetic datasets as well as real gene expression data and compare with other GRN inference methods. We inferred five 10-gene and five 100-gene networks from the DREAM4 challenge that were generated using the gene expression simulator GeneNetWeaver (GNW). MICRAT was also used to reconstruct GRNs on real gene expression data including part of the DNA-damaged response pathway (SOS DNA repair network) and experimental dataset in E. Coli. The results showed that MICRAT significantly improved the inference accuracy, compared to other inference methods, such as TDBN, etc. CONCLUSION: In this work, a novel algorithm, MICRAT, for inferring GRNs from time series gene expression data was proposed by taking into account dependence and time delay of expressions of a regulator and its target genes. This approach employed maximal information coefficients for reconstructing an undirected graph to represent the underlying relationships between genes. The edges were directed by combining conditional relative average entropy with time course mutual information of pairs of genes. The proposed algorithm was evaluated on the benchmark GRNs provided by the DREAM4 challenge and part of the real SOS DNA repair network in E. Coli. The experimental study showed that our approach was comparable to other methods on 10-gene datasets and outperformed other methods on 100-gene datasets in GRN inference from time series datasets.


Women's empowerment in Pakistan-definitions and enabling and disenabling factors: a secondary data analysis.
The purpose of the study was to explore Pakistani women's definition of women's empowerment, including its enabling and disenabling factors. Through understanding empowerment, interventions may be developed for women to be empowered. Transcriptions of 35 interviews from a previous study were reanalyzed through secondary data analysis. The themes of economic stability, social acceptability, educational achievement, and family harmony emerged for the concept of definition of empowerment. Themes for enabling factors were strength of personality and openness of mind. Disenabling factors had sociocultural influences, religious misinterpretations, and dominant ideology as themes. Pakistani women hold on to their customs, traditions, and religion tenaciously. The views of empowerment leading to the themes were expressed as true for their lives.


Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.
Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease. Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects. Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans. Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.


Mitochondrial DNA diversity in 17th-18th century remains from Tenerife (Canary Islands).
Mitochondrial DNA sequences and restriction fragment length polymorphisms were retrieved (with >80% efficiency) from a 17th-18th century sample of 213 teeth from Tenerife. The genetic composition of this population reveals an important ethnic heterogeneity. Although the majority of detected haplotypes are of European origin, the high frequency of sub-Saharan African haplotypes (15.63%), compared to that of the present-day population (6.6%), confirms the importance of the Canary Islands in the black slave trade of that epoch. The aboriginal substrate, inferred from the U6b1 haplotypes (8.59%), has also decreased due to European input. Finally, the presence of Amerindian lineages (1.5%) reveals that the Canary Islands have also received genetic flow from America.


Synthesis and solid-state structural characterization of a series of aqueous heterometallic tridecameric group 13 clusters.
The synthesis and solid-state characterization of a complete series of new heterometallic aqueous nanoscale Ga/In tridecameric clusters is presented. These hydroxo-aquo species significantly expand the library of discrete, aqueous group 13 clusters. This report details the synthetic and structural characterization of these compounds, which are of interest as precursors (inks) for thin-film oxides with materials applications. Single-crystal X-ray diffraction (XRD) data show that the hexagonal unit cell lengths of these clusters fall within the range a, b = 20.134-20.694 Å and c = 18.266-18.490 Å. The unit cell volumes become larger (V = 6494-6774 A(3)) with increasing indium occupancy. The compositions of several Ga/In clusters determined by electron probe microanalysis and elemental analysis are in agreement with single-crystal XRD results. The transformation of the Ga/In clusters to metal oxides at high temperature was studied using variable-temperature powder XRD. With heating, the Ga/In clusters with lower indium occupancies convert to the β-Ga2O3 structure. For clusters with higher indium occupancies, phase separation occurs, and an In2O3 bixbyite-type structure forms. The stoichiometric control at the molecular level demonstrated herein is important in designing functional thin films of metal oxides due to the tunable nature of these heterometallic solution precursors. In addition, information about the solid-state structure of these compounds leads to a fundamental understanding of the materials properties of these clusters for future thin-film and precursor development.


Suicide and homicide bereavement among African Americans: implications for survivor research and practice.
Suicide and homicide are among the leading causes of death for young African-American men; however, little is known about how family members cope with these types of deaths. This exploratory phenomenological study examines the traumatic loss and coping experiences of a purposive convenience sample of 12 immediate African-American surviving family members with a combined experience of 13 deaths, 8 suicides and 5 homicides. Novel aspects of suicide and homicide survivor phenomenon were identified, including Survivor Responses and Reactions, Coping Strategies, and Survivor Service Needs. The implications for research and for those providing services to surviving African-American families are discussed.


Couples referred to a sexual dysfunction clinic. Psychological and physical morbidity.
Two hundred couples referred to a sexual problems clinic were assessed in a standardised way for their suitability for sex therapy. The assessment focused on the nature of the sexual dysfunction, motivation for treatment, marital and relationship problems, psychiatric status, and physical problems. Approximately one-third of the couples were found to have significant marital and relationship problems, and more than 30% were suffering from psychiatric disorders, although these were usually of mild to moderate intensity. A third of males and 18% of females were suffering from physical disorders likely to contribute to the sexual dysfunction. Patients who were offered sex therapy and who completed their course of treatment were more likely to show high levels of motivation and an absence of physical disorders, marital relationship problems and psychiatric disorder. There should be careful assessment of couples suffering from sexual dysfunction before specific treatment is offered.


Insight, self-stigma and psychosocial outcomes in Schizophrenia: a structural equation modelling approach.
Poor insight is prevalent in patients with schizophrenia and has been associated with acute illness severity, medication non-adherence and poor treatment outcomes. Paradoxically, high insight has been associated with various undesirable outcomes, including low self-esteem, depression and low subjective quality of life (QoL) in patients with schizophrenia. Despite the growing body of studies conducted in Western countries supporting the pernicious effects of improved insight in psychosis, which bases on the level of self-stigma, the effects are unclear in non-Western societies. The current study examined the role of self-stigma in the relationship between insight and psychosocial outcomes in a Chinese population. A total of 170 outpatients with schizophrenia spectrum disorders were recruited from two general university hospitals. Sociodemographic data and clinical variables were recorded and self-report scales were employed to measure self-stigma, depression, insight, self-esteem and subjective QoL. Structural equation modelling (SEM) was used to analyse the cross-sectional data. High levels of self-stigma were reported by 39% of the participants (n = 67). The influences of insight, self-stigma, self-esteem and depression on subjective QoL were confirmed by the SEM results. Our model with the closest fit to the data (χ 2 = 33.28; df = 20; p = 0.03; χ 2/df = 1.66; CFI = 0.98; TLI = 0.97; RMSEA = 0.06) demonstrated that self-stigma might fully mediate the association of insight with low self-esteem, depression and poor subjective QoL. High insight into illness contributed to self-stigma, which caused low self-esteem and depression and, consequently, low QoL. Notably, insight did not directly affect self-esteem, depression or QoL. Furthermore, the association of insight with poor psychosocial outcomes was not moderated by self-stigma. Our findings support the mediating model of insight relevant to the poor psychosocial outcomes of individuals diagnosed with schizophrenia in non-Western societies, in which self-stigma plays a pivotal role. These findings elucidate the direct and indirect effects of insight on psychosocial outcomes and imply that identifying and correcting self-stigma in people with schizophrenia could be beneficial. Additional studies are required to identify whether several other neurocognitive or psychosocial variables mediate or moderate the association of insight with self-esteem, depression and QoL in patients with schizophrenia. Studies with detailed longitudinal assessments are necessary to confirm our findings.


Hypomethylating agents after allogeneic blood stem cell transplantation.
Allogeneic blood stem cell transplantation (allo-SCT) is a potentially curative treatment for patients with myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but relapse remains the major cause of treatment failure. So far, therapeutic options for patients with AML or MDS who relapse after allo-SCT generally consisted of palliative care, low-dose or intensive chemotherapy as well as cellular therapies such as donor lymphocyte infusions (DLI) and second transplantation in selected cases. Nevertheless, the prognosis of patients with myeloid malignancies relapsing after allo-SCT remains dismal therefore asking for novel treatment strategies. Considering their well-balanced profile of good efficacy and moderate toxicity in the non-transplant setting, the hypomethylating agents (HMA) azacitidine (Aza) and decitabine (DAC) have also been tested either alone or in combination with DLI in the post-transplant period. This review summarizes the current knowledge about the use of these two HMA as pre-emptive, salvage or consolidation therapy mostly retrieved from retrospective studies but also from a few prospective trials. Within this review, we also comment on some practical issues such as optimal dose and schedule, the choice of HMA candidates and the role of additional cellular interventions. Finally, we also give an overview on the assumed mode of actions, ongoing research, clinical studies and potential combination partners aiming to improve this treatment approach.


Adult Treatment Panel III: do we really need another set of cholesterol guidelines?
Reducing high levels of plasma low-density lipoprotein cholesterol (LDL-C) is still the primary focus of the Adult Treatment Panel III (ATP III) guidelines developed by the National Cholesterol Education Program. The LDL-C goal of less than 100 mg/dL for those with coronary heart disease (CHD) is now extended to patients with diabetes and those with a Framingham risk score of greater than 20% in 10 years, both of which are now considered "CHD risk equivalents." Consequently, many more people will be considered candidates for aggressive lipid-lowering therapy under the new ATP III guidelines. Other prominent features in the new guidelines include determining an individual's absolute risk category by using a nine-step process, instituting therapeutic lifestyle changes to reduce LDL-C levels, and strategies for treating patients with other forms of dyslipidemia such as metabolic syndrome.


N-formylation and N-methylation of amines using metal-free N-heterocyclic carbene catalysts and CO2 as carbon source.
N-formylation and N-methylation of amines are important reactions that are used to produce a wide range of key intermediates and compounds. This protocol describes the environmentally benign N-formylation and N-methylation of primary and secondary amines using carbon dioxide (CO2) as the carbon source, hydrosilanes as reductants and N-heterocyclic carbenes (NHCs) as catalysts. Using CO2 as a reagent has the advantage of low cost and negligible toxicity. However, the catalyst is air-sensitive and must be generated fresh before use; consequently, the techniques used to prepare and manipulate the catalyst are described. The synthetic approach described in this protocol does not use any toxic reagents; using the appropriate catalyst, N-formylated or N-methylated products can be obtained with high selectivity. The overall time for catalyst preparation and for conducting several catalytic reactions in parallel is 15-48 h, depending on the nature of the substrates.


Optimizing colour for camouflage and visibility using deep learning: the effects of the environment and the observer's visual system.
Avoiding detection can provide significant survival advantages for prey, predators, or the military; conversely, maximizing visibility would be useful for signalling. One simple determinant of detectability is an animal's colour relative to its environment. But identifying the optimal colour to minimize (or maximize) detectability in a given natural environment is complex, partly because of the nature of the perceptual space. Here for the first time, using image processing techniques to embed targets into realistic environments together with psychophysics to estimate detectability and deep neural networks to interpolate between sampled colours, we propose a method to identify the optimal colour that either minimizes or maximizes visibility. We apply our approach in two natural environments (temperate forest and semi-arid desert) and show how a comparatively small number of samples can be used to predict robustly the most and least effective colours for camouflage. To illustrate how our approach can be generalized to other non-human visual systems, we also identify the optimum colours for concealment and visibility when viewed by simulated red-green colour-blind dichromats, typical for non-human mammals. Contrasting the results from these visual systems sheds light on why some predators seem, at least to humans, to have colouring that would appear detrimental to ambush hunting. We found that for simulated dichromatic observers, colour strongly affected detection time for both environments. In contrast, trichromatic observers were more effective at breaking camouflage.


Fibromyalgia family and relationship impact exploratory survey.
Fibromyalgia is frequently associated with impairments in activities of daily living and work disability. Limited data have investigated the impact of fibromyalgia on relationships with family and friends. This exploratory study was designed to survey a large community sample of adults with fibromyalgia about the impact on the spouse/partner, children and close friends. A 40-question, multiple-choice survey was made available online for a two-month period, with potential participants recruited through fibromyalgia and migraine community websites. Items included questions about demographics, fibromyalgia symptoms, comorbid mood disturbance and relationship impact, including the Relationship Assessment Scale. The survey was completed by 6,126 adults who had been diagnosed with fibromyalgia. Using updated diagnostic criteria from the American College of Rheumatology, 91% satisfied the criteria for fibromyalgia (Fibromyalgia Severity score ≥13 and pain ≥3 months). Half of participants endorsed that fibromyalgia had mildly to moderately damaged relationship(s) with their spouse(s)/partner(s) or contributed to a break-up with a spouse or partner. Half of participants scored as not being satisfied with their current spouse/partner relationship, with satisfaction negatively affected by the presence of mood disturbance symptoms and higher fibromyalgia severity. Relationships with children and close friends were also negatively impacted for a substantial minority of participants. In addition to physical impairments that are well documented among individuals with fibromyalgia, fibromyalgia can result in a substantial negative impact on important relationships with family and close friends.