Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study.
Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.


Forgotten Botany: The Politics of Knowledge within the Royal Botanical Garden of New Spain*.
Spanish naturalists established the Viceregal Botanical Garden of New Spain in Mexico City in 1788 to advance agriculture, manufacturing, and medicine. This colonial institution also served the ideological role of cultivating agents of empire. Rather than establish the garden in the already robust tradition of American botany, the Spanish appropriated this space, employing Creole students and servant workers to Europeanize local botanical knowledge through taxonomic colonialism. The different agendas at work in the botanical garden, which straddled the colonial and revolutionary periods in Mexico, destabilized not only this institution, but also the empire itself from the ground up. That the contributions of the agents of the garden have been forgotten is evidence of the fragility and failure of a European institution in the American colonial state.


BMP4 inhibits the proliferation of breast cancer cells and induces an MMP-dependent migratory phenotype in MDA-MB-231 cells in 3D environment.
Bone morphogenetic protein 4 (BMP4) belongs to the transforming growth factor β (TGF-β) family of proteins. BMPs regulate cell proliferation, differentiation and motility, and have also been reported to be involved in cancer pathogenesis. We have previously shown that BMP4 reduces breast cancer cell proliferation through G1 cell cycle arrest and simultaneously induces migration in a subset of these cell lines. Here we examined the effects of BMP4 in a more physiological environment, in a 3D culture system. We used two different 3D culture systems; Matrigel, a basement membrane extract from mouse sarcoma cells, and a synthetic polyethylene glycol (PEG) gel. AlamarBlue reagent was used for cell proliferation measurements and immunofluorescence was used to determine cell polarity. Expression of cell cycle regulators was examined by Western blot and matrix metalloproteinase (MMP) expression by qRT-PCR. The MCF-10A normal breast epithelial cells formed round acini with correct apicobasal localization of α6 integrin in Matrigel whereas irregular structures were seen in PEG gel. The two 3D matrices also supported dissimilar morphology for the breast cancer cells. In PEG gel, BMP4 inhibited the growth of MCF-10A and the three breast cancer cell lines examined, thus closely resembling the 2D culture conditions, but in Matrigel, no growth inhibition was observed in MDA-MB-231 and MDA-MB-361 cells. Furthermore, BMP4 induced the expression of the cell cycle inhibitor p21 both in 2D and 3D culture, thereby partly explaining the growth arrest. Interestingly, MDA-MB-231 cells formed large branching, stellate structures in response to BMP4 treatment in Matrigel, suggestive of increased cell migration or invasion. This effect was reversed by Batimastat, a broad-spectrum MMP inhibitor, and subsequent analyses showed BMP4 to induce the expression of MMP3 and MMP14, that are thus likely to be responsible for the stellate phenotype. Taken together, our results show that Matrigel provides a more physiological environment for breast epithelial cells than PEG gel. Moreover, BMP4 partly recapitulates in 3D culture the growth suppressive abilities previously seen in 2D culture and induces an MMP-dependent migratory phenotype in MDA-MB-231 cells.


Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies.
The nuclear lamina provides structural support to the nucleus and has a central role in nuclear organization and gene regulation. Defects in its constituents, the lamins, lead to a class of genetic diseases collectively referred to as laminopathies. Using live cell imaging, we observed the occurrence of intermittent, non-lethal ruptures of the nuclear envelope in dermal fibroblast cultures of patients with different mutations of lamin A/C. These ruptures, which were absent in normal fibroblasts, could be mimicked by selective knockdown as well as knockout of LMNA and were accompanied by the loss of cellular compartmentalization. This was demonstrated by the influx of cytoplasmic transcription factor RelA and regulatory protein Cyclin B1 into the nucleus, and efflux of nuclear transcription factor OCT1 and nuclear structures containing the promyelocytic leukemia (PML) tumour suppressor protein to the cytoplasm. While recovery of enhanced yellow fluorescent protein-tagged nuclear localization signal in the nucleus demonstrated restoration of nuclear membrane integrity, part of the mobile PML structures became permanently translocated to the cytoplasm. These satellite PML structures were devoid of the typical PML body components, such as DAXX, SP100 or SUMO1. Our data suggest that nuclear rupture and loss of compartmentalization may add to cellular dysfunction and disease development in various laminopathies.


Systemic vasculitis and patient-reported outcomes: how the assessment of patient preferences and perspectives could improve outcomes.
The systemic vasculitides are a group of multisystem diseases, which can be life and organ threatening. High-dose immunosuppressants are required to control inflammation in vital organs, such as the kidneys, lungs, skin, joints, and eyes. Patients report a range of impacts on their health-related quality of life due to symptoms, irreversible damage, and the adverse effects of medications. The measurement of patient perspectives within clinical studies in vasculitis is essential to capture outcomes of greatest importance to patients. Validated generic, disease-specific and symptom-specific patient-reported outcomes available for use in patients with systemic vasculitis are reviewed here.


The corpus cavernosum after treatment with dutasteride or finasteride: A histomorphometric study in a benign prostatic hyperplasia rodent model.
Erectile dysfunction is a common side effect of finasteride and dutasteride treatments. The objective of this study was to investigate the structural changes in the penis using a benign prostatic hyperplasia (BPH) rodent model treated with dutasteride or finasteride. Sixty male rats were divided into the following groups: C, untreated control rats; C + D, control rats receiving dutasteride; C + F, control rats receiving finasteride; H, untreated spontaneously hypertensive rats (SHRs); H + D, SHRs treated with dutasteride; and H + F, SHRs treated with finasteride. Treatments were performed for 40 days, and penises were collected immediately thereafter. The organs were analyzed using histomorphometric methods to determine the cross-sectional penile area, as well as the surface density (Sv) of smooth muscle fibers, connective tissue, elastic system fibers, and sinusoidal spaces of the corpus cavernosum. The results were compared using a one-way ANOVA with Bonferroni's posttest. Groups C + D and C + F had a significantly smaller penile cross-sectional area, but more elastic system fiber Sv compared to Group C. Group C + D showed less smooth muscle Sv, and Group H showed more connective tissue but a smaller sinusoidal space Sv in the corpus cavernosum compared to Group C. Groups H + D and H + F had less smooth muscle Sv than Group H. Group H + D also had more connective tissue and elastic system fiber Sv than Group H. Both dutasteride and finasteride promoted penile modifications in the control rat penis, although this affect was greater in Group H animals. In this rodent model, dutasteride was the drug that most affected the corpus cavernosum.


The Anatomical Basis of Paradoxical Masseteric Bulging after Botulinum Neurotoxin Type A Injection.
The aim of this study was to determine the detailed anatomical structures of the superficial part of the masseter and to elucidate the boundaries and locations of the deep tendon structure within the superficial part of the masseter. Forty-four hemifaces from Korean and Thai embalmed cadavers were used in this study. The deep tendon structure was located deep in the lower third of the superficial part of the masseter. It was observed in all specimens and was designated as a deep inferior tendon (DIT). The relationship between the masseter and DIT could be classified into three types according to the coverage pattern: Type A, in which areas IV and V were covered by the DIT (27%, 12/44); Type B, in which areas V and VI were covered by the DIT (23%, 10/44); and Type C, in which areas IV, V, and VI were covered by the DIT (50%, 22/44). The superficial part of the masseter consists of not only the muscle belly but also the deep tendon structure. Based on the results obtained in this morphological study, we recommend performing layer-by-layer retrograde injections into the superficial and deep muscle bellies of the masseter.


Adenine nucleotide translocase 1 deficiency results in dilated cardiomyopathy with defects in myocardial mechanics, histopathological alterations, and activation of apoptosis.
the aim of this study was to test the hypothesis that chronic mitochondrial energy deficiency causes dilated cardiomyopathy, we characterized the hearts of age-matched young and old adenine nucleotide translocator (ANT)1 mutant and control mice. ANTs export mitochondrial adenosine triphosphate into the cytosol and have a role in the regulation of the intrinsic apoptosis pathway. Mitochondrial energy deficiency has been hypothesized, on the basis of indirect evidence, to be a factor in the pathophysiology of dilated cardiomyopathies. Ant1 inactivation should limit adenosine triphosphate for contraction and calcium transport, thereby resulting in early cardiac dysfunction with later dilation and heart failure. we conducted a multiyear study of 73 mutant (Ant1-/-) and 57 control (Ant1+/+) mice, between the ages of 2 and 21 months. Hearts were characterized by cardiac anatomy, echocardiographic imaging with velocity vector analysis, histopathology, and apoptosis assays. the Ant1-/- mice developed a distinctive concentric dilated cardiomyopathy, characterized by substantial myocardial hypertrophy and ventricular dilation, with cardiac function declining earlier in age as compared to control mice. Left ventricular circumferential, radial, and rotational mechanics were reduced even in the younger mutants with preserved systolic function. Histopathologic analysis demonstrated increased myocyte hypertrophy, fibrosis, and calcification in the mutant mice as compared with control mice. Furthermore, increased cytoplasmic cytochrome c levels and caspase 3 activation were observed in the mutant mice. our results demonstrate that mitochondrial energy deficiency is sufficient to cause dilated cardiomyopathy, confirming that energy defects are a factor in this disease. Energy deficiency initially leads to early mechanical dysfunction before a decline in left ventricular systolic function. Chronic energy deficiency with age then leads to heart failure. Our results now allow us to use the Ant1-/- mouse model for testing new therapies for ANT1 mutant patients.


Egg retention and dispersal activity in the parasitoid wasp, Trichogramma principium.
Abstract Effects of egg retention on movement and dispersal activity of Trichogramma principium (Hymenoptera, Trichogrammatidae) females were investigated under laboratory conditions. Individual females were observed during one minute in the absence of hosts. Movement activity and dispersal rate were estimated by the length of the track and by the distance from the start point, respectively. Before the test, all wasps during 2 - 4 days were presented with a possibility to parasitize a factitious laboratory host, Sitotroga cerealella Oliv. (Lepidoptera, Gelechiidae). Wasps that had parasitized before the test show significant reduction of spontaneous walking activity and dispersal rate when compared with females that refused to parasitize the non-preferred host (i.e. manifested egg retention). This effect cannot be considered as a direct arrestment reaction to the host because during the test period, no hosts were provided. Thus, egg retention results not only in temporal spread, but also in more intensive spatial dispersal of a group of simultaneously emerged females.


Confirmation bias: why psychiatrists stick to wrong preliminary diagnoses.
Diagnostic errors can have tremendous consequences because they can result in a fatal chain of wrong decisions. Experts assume that physicians' desire to confirm a preliminary diagnosis while failing to seek contradictory evidence is an important reason for wrong diagnoses. This tendency is called 'confirmation bias'. To study whether psychiatrists and medical students are prone to confirmation bias and whether confirmation bias leads to poor diagnostic accuracy in psychiatry, we presented an experimental decision task to 75 psychiatrists and 75 medical students. A total of 13% of psychiatrists and 25% of students showed confirmation bias when searching for new information after having made a preliminary diagnosis. Participants conducting a confirmatory information search were significantly less likely to make the correct diagnosis compared to participants searching in a disconfirmatory or balanced way [multiple logistic regression: odds ratio (OR) 7.3, 95% confidence interval (CI) 2.53-21.22, p<0.001; OR 3.2, 95% CI 1.23-8.56, p=0.02]. Psychiatrists conducting a confirmatory search made a wrong diagnosis in 70% of the cases compared to 27% or 47% for a disconfirmatory or balanced information search (students: 63, 26 and 27%). Participants choosing the wrong diagnosis also prescribed different treatment options compared with participants choosing the correct diagnosis. Confirmatory information search harbors the risk of wrong diagnostic decisions. Psychiatrists should be aware of confirmation bias and instructed in techniques to reduce bias.


Metabolomic changes in fatty liver can be modified by dietary protein and calcium during energy restriction.
To characterise the effect of energy restriction (ER) on liver lipid and primary metabolite profile by using metabolomic approach. We also investigated whether the effect of energy restriction can be further enhanced by modification of dietary protein source and calcium. Liver metabolomic profile of lean and obese C57Bl/6J mice (n = 10/group) were compared with two groups of weight-reduced mice. ER was performed on control diet and whey protein-based high-calcium diet (whey + Ca). The metabolomic analyses were performed using the UPLC/MS based lipidomic platform and the HPLC/MS/MS based primary metabolite platform. ER on both diets significantly reduced hepatic lipid accumulation and lipid droplet size, while only whey + Ca diet significantly decreased blood glucose (P < 0.001) and serum insulin (P < 0.01). In hepatic lipid species the biggest reduction was in the level of triacylglycerols and ceramides while the level of cholesterol esters was significantly increased during ER. Interestingly, diacylglycerol to phospholipid ratio, an indicator of relative amount of diabetogenic diglyceride species, was increased in the control ER group, but decreased in the whey + Ca ER group (P < 0.001, vs obese). ER on whey + Ca diet also totally reversed the obesity induced increase in the relative level of lipotoxic ceramides (P < 0.001, vs obese; P > 0.05, vs lean). These changes were accompanied with up-regulated TCA cycle and pentose phosphate pathway metabolites. ER-induced changes on hepatic metabolomic profile can be significantly affected by dietary protein source. The therapeutic potential of whey protein and calcium should be further studied.


Spinal lesion level in spina bifida: a source of neural and cognitive heterogeneity.
The aim of this study was to evaluate whether the level of a spinal lesion is associated with variations in anomalous brain development and neurobehavioral outcomes in children suffering from the meningomyelocele form of spina bifida and hydrocephalus (SBM-H). Two hundred sixty-eight children with SBM-H were divided into upper (T-12 and above; 82 patients) and lower (L-1 and below; 186 patients) lesion-level groups. Magnetic resonance images were qualitatively coded by radiologists and quantitatively segmented for cerebrum and cerebellum volumes. Psychometric assessments of handedness, intelligence, academic skills, and adaptive behavior were compared between lesion-level groups and also used to determine the number of children who met research-based criteria for mental retardation, attention deficit hyperactivity disorder, and learning disabilities. The magnetic resonance images obtained in children with upper-level spinal lesions demonstrated more qualitative abnormalities in the midbrain and tectum, pons, and splenium, although not in the cerebellum, compared with images obtained in children with lower-level spinal lesions. Upper-level lesions were also associated with reductions in cerebrum and cerebellum volumes, lower scores on measures of intelligence, academic skills, and adaptive behavior, and with a higher frequency of individuals meeting the criteria for mental retardation. Hispanic children (who were also more economically disadvantaged) were more likely to have upper-level lesions and poorer neurobehavioral outcomes, but lesion-level effects were generally independent of ethnicity. A higher level of spinal lesion in SBM-H is a marker for more severe anomalous brain development, which is in turn associated with poorer neurobehavioral outcomes in a wide variety of domains that determine levels of independent functioning for these children at home and school.


Scale-variant magnification for computational integral imaging and its application to 3D object correlator.
In this paper, we present a novel volumetric computational reconstruction (VCR) method for improved 3D object correlator. Basically, VCR consists of magnification and superposition. This paper presents new scale-variant magnification as a technique for VCR. To introduce our technique, we discuss an interference problem among elemental images in VCR. We find that a large magnification causes interference among elemental images when they are applied to the superposition. Thus, the resolution of reconstructed images should be limited by this interference. To overcome the interference problem, we propose a method to calculate a minimum magnification factor while VCR is still valid. Magnification by a new factor enables the proposed method to reconstruct resolution-enhanced images. To confirm the feasibility of the proposed method, we apply our method to a VCR-based 3D object correlator. Experimental results indicate that our method outperforms the conventional VCR method.


Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence.
Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk.


Hypoplasia of the Spleen: Review of Pathogenesis, Diagnosis, and Potential Clinical Implications.
Splenic aplasia is seen when the spleen is congenitally absent, has been surgically removed, or becomes atrophic secondary to episodes of arterial/venous occlusion, which result in splenic infarction. This rare condition is caused by a heterogenous group of diseases, which may present a wide spectrum of clinical manifestations. Splenic hypoplasia is defined as reduction in splenic mass and or functions caused by incomplete splenic development or secondary parenchymal involution. Splenic infarction may be clinically silent and only discovered incidentally during abdominal exploration for other conditions. We present an unusual case of hypoplastic spleen with calcifications, which was preoperatively found during radiologic workup for gastric carcinoma. An 88-year-old woman presented with coffee-ground emesis. Her past medical history was only significant for atrial fibrillation. Esophagogastroduodenoscopy demonstrated gastric carcinoma, for which a subtotal gastrectomy was planned. Preoperative computed tomography scan showed a hypoplastic spleen with calcifications in the left upper quadrant. Symptoms of immunologic deficiency were not present. During laparotomy, an atrophied and calcified spleen was identified and left in situ. The patient made an uneventful postoperative recovery. Splenic hypoplasia is an unique entity, which may be seen in the setting of atrial fibrillation and abdominal malignancy. Splenic hypoplasia may be detected incidentally during radiologic workup or abdominal exploration. Abdominal symptoms or immunologic deficiency are not always present.


When everyone goes to college: the causal effect of college expansion on earnings.
In this study, we estimate the causal effect of college expansion on earnings using the example of South Korea in the 1990s where the college enrollment rate increased from just over thirty percent to over eighty percent over a fifteen years period. We compare the pre-expansion cohort and the post-expansion cohort in order to identify those who would attend college because of the expansion but would not attend otherwise (compliers). We, then, estimate compliers' earnings gain from the college expansion relative to the earnings changes of two control groups: those who either would or would not go to college regardless of college expansion (always-takers and never-takers). We find a striking gendered pattern; for men, the earnings return to college expansion is moderate and mostly driven by the increasing skill price, whereas, for women, the return is significantly large even net of the skill price change.


The modern theory of biological evolution: an expanded synthesis.
In 1858, two naturalists, Charles Darwin and Alfred Russel Wallace, independently proposed natural selection as the basic mechanism responsible for the origin of new phenotypic variants and, ultimately, new species. A large body of evidence for this hypothesis was published in Darwin's Origin of Species one year later, the appearance of which provoked other leading scientists like August Weismann to adopt and amplify Darwin's perspective. Weismann's neo-Darwinian theory of evolution was further elaborated, most notably in a series of books by Theodosius Dobzhansky, Ernst Mayr, Julian Huxley and others. In this article we first summarize the history of life on Earth and provide recent evidence demonstrating that Darwin's dilemma (the apparent missing Precambrian record of life) has been resolved. Next, the historical development and structure of the "modern synthesis" is described within the context of the following topics: paleobiology and rates of evolution, mass extinctions and species selection, macroevolution and punctuated equilibrium, sexual reproduction and recombination, sexual selection and altruism, endosymbiosis and eukaryotic cell evolution, evolutionary developmental biology, phenotypic plasticity, epigenetic inheritance and molecular evolution, experimental bacterial evolution, and computer simulations (in silico evolution of digital organisms). In addition, we discuss the expansion of the modern synthesis, embracing all branches of scientific disciplines. It is concluded that the basic tenets of the synthetic theory have survived, but in modified form. These sub-theories require continued elaboration, particularly in light of molecular biology, to answer open-ended questions concerning the mechanisms of evolution in all five kingdoms of life.


Strong but opposing β-diversity-stability relationships in coral reef fish communities.
The 'diversity-stability hypothesis', in which higher species diversity within biological communities buffers the risk of ecological collapse, is now generally accepted. However, empirical evidence for a relationship between β-diversity (spatial turnover in community structure) and temporal stability in community structure remains equivocal, despite important implications for theoretical ecology and conservation biology. Here, we report strong β-diversity-stability relationships across a broad sample of fish taxa on Australia's Great Barrier Reef. These relationships were robust to random sampling error and spatial and environmental factors, such as latitude, reef size and isolation. While β-diversity was positively associated with temporal stability at the community level, the relationship was negative for some taxa, for example surgeonfishes (Acanthuridae), one of the most abundant reef fish families. This demonstrates that the β-diversity-stability relationship should not be indiscriminately assumed for all taxa, but that a species' risk of extirpation in response to disturbance is likely to be taxon specific and trait based. By combining predictions of spatial and temporal turnover across the study area with observations in marine-protected areas, we conclude that protection alone does not necessarily confer temporal stability and that taxon-specific considerations will improve the outcome of conservation efforts.


Neurological examination of critically ill patients: a pragmatic approach. Report of an ESICM expert panel.
Many patients admitted to the intensive care unit (ICU) have pre-existing or acquired neurological disorders which significantly affect their short-term and long-term outcomes. The ESICM Neuro Intensive Care Section convened an expert panel to establish a pragmatic approach to neurological examination (NE) of the critically ill patient. The group conducted a comprehensive review of published studies on the NE of patients with coma, delirium, seizures and neuromuscular weakness in critically ill patients. Quality of data was rated as high, moderate, low, or very low, and final recommendations as strong, weak, or best practice. The group made the following recommendations: (1) NE should be performed in all patients admitted to ICUs; (2) NE should include an assessment of consciousness and cognition, brainstem function, and motor function; (3) sedation should be managed to maximize the clinical detection of neurological dysfunction, except inpatients with reduced intracranial compliance in whom withdrawal of sedation may be deleterious; (4) the need for additional tests, including neurophysiological and neuroradiological investigations, should be guided by the NE; (5) selected features of the NE have prognostic value which should be considered in well-defined patient populations.


Shared cognitive processes underlying past and future thinking: the impact of imagery and concurrent task demands on event specificity.
Recent literature has argued that whereas remembering the past and imagining the future make use of shared cognitive substrates, simulating future events places heavier demands on executive resources. These propositions were explored in 3 experiments comparing the impact of imagery and concurrent task demands on speed and accuracy of past event retrieval and future event simulation. Results provide support for the suggestion that both past and future episodes can be constructed through 2 mechanisms: a noneffortful "direct" pathway and a controlled, effortful "generative" pathway. However, limited evidence emerged for the suggestion that simulating of future, compared with retrieving past, episodes places heavier demands on executive resources; only under certain conditions did it emerge as a more error prone and lengthier process. The findings are discussed in terms of how retrieval and simulation make use of the same cognitive substrates in subtly different ways.


Role of oxalic acid overexcretion in transformations of toxic metal minerals by Beauveria caledonica.
The fungus Beauveria caledonica was highly tolerant to toxic metals and solubilized cadmium, copper, lead, and zinc minerals, converting them into oxalates. This fungus was found to overexcrete organic acids with strong metal-chelating properties (oxalic and citric acids), suggesting that a ligand-promoted mechanism was the main mechanism of mineral dissolution. Our data also suggested that oxalic acid was the main mineral-transforming agent. Cadmium, copper, and zinc oxalates were precipitated by the fungus in the local environment and also in association with the mycelium. The presence of toxic metal minerals often led to the formation of mycelial cords, and in the presence of copper-containing minerals, these cords exhibited enhanced excretion of oxalic acid, which resulted in considerable encrustation of the cords by copper oxalate hydrate (moolooite). It was found that B. caledonica hyphae and cords were covered by a thick hydrated mucilaginous sheath which provided a microenvironment for chemical reactions, crystal deposition, and growth. Cryo-scanning electron microscopy revealed that mycogenic metal oxalates overgrew parental fungal hyphae, leaving a labyrinth of fungal tunnels within the newly formed mineral matter. X-ray absorption spectroscopy revealed that oxygen ligands played a major role in metal coordination within the fungal biomass during the accumulation of mobilized toxic metals by B. caledonica mycelium; these ligands were carboxylic groups in copper phosphate-containing medium and phosphate groups in pyromorphite-containing medium.


Effect of size and curvature on the enzyme activity of bionanoconjugates.
Biotic-abiotic hybrids comprised of globular proteins and functional nanostructures with complementary and synergistic properties are central to a number of bionanotechnological applications. A comprehensive understanding of the effect of physicochemical properties of abiotic nanostructures on the biological activity of the bionanoconjugates is critical in the design of these bio-nano hybrids. In this study, using size and curvature-controlled gold nanoparticles as a model abiotic system, we investigated the effect of hydrodynamic diameter and surface curvature on the activity of a model enzyme, horseradish peroxidase (HRP), adsorbed on the surface of the nanostructures. In contrast with the previous studies, we have employed a novel class of gold superstructures (gold nanoparticles on spheres) to deconvolute the effects of size and curvature on the catalytic activity of the bionanoconjugates. This study improves our understanding of the bio/nano interface and the design of bioinorganic hybrids with potential applications in biomimetic and bioenabled sensors, energy harvesting, optoelectronic components and devices, responsive and autonomous materials.


miR-294/miR-302 promotes proliferation, suppresses G1-S restriction point, and inhibits ESC differentiation through separable mechanisms.
The miR-294 and miR-302 microRNAs promote the abbreviated G1 phase of the embryonic stem cell (ESC) cell cycle and suppress differentiation induced by let-7. Here, we evaluated the role of the retinoblastoma (Rb) family proteins in these settings. Under normal growth conditions, miR-294 promoted the rapid G1-S transition independent of the Rb family. In contrast, miR-294 suppressed the further accumulation of cells in G1 in response to nutrient deprivation and cell-cell contact in an Rb-dependent fashion. We uncovered five additional miRNAs (miR-26a, miR-99b, miR-193, miR-199a-5p, and miR-218) that silenced ESC self-renewal in the absence of other miRNAs, all of which were antagonized by miR-294 and miR-302. Four of the six differentiation-inducing miRNAs induced an Rb-dependent G1 accumulation. However, all six still silenced self-renewal in the absence of the Rb proteins. These results show that the miR-294/miR-302 family acts through Rb-dependent and -independent pathways to regulate the G1 restriction point and the silencing of self-renewal, respectively.


The ELIXIR-EXCELERATE Train-the-Trainer pilot programme: empower researchers to deliver high-quality training.
One of the main goals of the ELIXIR-EXCELERATE project from the European Union's Horizon 2020 programme is to support a pan-European training programme to increase bioinformatics capacity and competency across ELIXIR Nodes. To this end, a Train-the-Trainer (TtT) programme has been developed by the TtT subtask of EXCELERATE's Training Platform, to try to expose bioinformatics instructors to aspects of pedagogy and evidence-based learning principles, to help them better design, develop and deliver high-quality training in future. As a first step towards such a programme, an ELIXIR-EXCELERATE TtT (EE-TtT) pilot was developed, drawing on existing 'instructor training' models, using input both from experienced instructors and from experts in bioinformatics, the cognitive sciences and educational psychology. This manuscript describes the process of defining the pilot programme, illustrates its goals, structure and contents, and discusses its outcomes. From Jan 2016 to Jan 2017, we carried out seven pilot EE-TtT courses (training more than sixty new instructors), collaboratively drafted the training materials, and started establishing a network of trainers and instructors within the ELIXIR community. The EE-TtT pilot represents an essential step towards the development of a sustainable and scalable ELIXIR TtT programme. Indeed, the lessons learned from the pilot, the experience gained, the materials developed, and the analysis of the feedback collected throughout the seven pilot courses have both positioned us to consolidate the programme in the coming years, and contributed to the development of an enthusiastic and expanding ELIXIR community of instructors and trainers.


Risk assessment of gene flow from genetically engineered virus resistant cassava to wild relatives in Africa: an expert panel report.
The probability and consequences of gene flow to wild relatives is typically considered in the environmental risk assessment of genetically engineered crops. This is a report from a discussion by a group of experts who used a problem formulation approach to consider existing information for risk assessment of gene flow from cassava (Manihot esculenta) genetically engineered for virus resistance to the 'wild' (naturalized) relative M. glaziovii in East Africa. Two environmental harms were considered in this case: (1) loss of genetic diversity in the germplasm pool, and (2) loss of valued species, ecosystem resources, or crop yield and quality due to weediness or invasiveness of wild relatives. Based on existing information, it was concluded that gene flow will occur, but it is not likely that this will reduce the genetic diversity in the germplasm pool. There is little existing information about the impact of the virus in natural populations that could be used to inform a prediction about whether virus resistance would lead to an increase in reproduction or survival, hence abundance of M. glaziovii. However, an increase in the abundance of M. glaziovii should be manageable, and would not necessarily lead to the identified environmental harms.


Episodic snapping of the medial head of the triceps due to weightlifting.
We describe two patients who had episodic elbow snapping and ulnar nerve dysesthesias only after weightlifting. These symptoms would disappear soon afterward. The episodic nature of their complaints and findings led to misdiagnosis. We documented by repeated clinical examinations and magnetic resonance imaging that the presence of these symptoms correlated directly with the finding of intermittent, activity-related snapping of the medial triceps. In both patients, the symptoms disappeared when the medial portion of the triceps migrated medially but did not dislocate over the medial epicondyle with elbow flexion. Thus, a minor change in the configuration of the medial portion of the triceps (fluid accumulation) in the same individual at different times can cause intermittent dislocation of the medial triceps. Previous papers dealing with patients with snapping of the medial triceps describe symptoms exacerbated by athletic activities, but the constant finding of snapping on sequential examinations.


The impact of HIV/AIDS on the living arrangements and well-being of elderly caregivers in rural Uganda.
As the HIV/AIDS epidemic continues to devastate the sub-Saharan Africa region, the demand for care and support services to persons infected and affected by the disease is proliferating. Currently providing the bulk of this much-needed care and support are elderly persons. However, limited work has been done to examine how such care and support impacts the well-being of elderly caregivers. Using qualitative data from elderly respondents in two Ugandan districts, Kamuli and Luwero, this article examines changes in the household structure and living arrangements of older persons (50 years and above) after they take on caregiving responsibilities for persons suffering from AIDS-related illnesses and orphans and vulnerable children (OVC) affected by HIV/AIDS. The findings show that elderly caregivers face drastic disruptions of living arrangements, including prolonged travels and absences from their homes to care for the sick. There is also a sharp increase in their household size as they take on more OVC. The implications of such changes on the older persons' health and well-being are discussed.


An introduction to the mechanics of the lasso.
Trick roping evolved from humble origins as a cattle-catching tool into a sport that delights audiences all over the world with its complex patterns or 'tricks'. Its fundamental tool is the lasso, formed by passing one end of a rope through a small loop (the honda) at the other end. Here, we study the mechanics of the simplest rope trick, the Flat Loop, in which the rope is driven by the steady circular motion of the roper's hand in a horizontal plane. We first consider the case of a fixed (non-sliding) honda. Noting that the rope's shape is steady in the reference frame rotating with the hand, we analyse a string model in which line tension is balanced by the centrifugal force and the rope's weight. We use numerical continuation to classify the steadily rotating solutions in a bifurcation diagram and analyse their stability. In addition to Flat Loops, we find planar 'coat-hanger' solutions, and whirling modes in which the loop collapses onto itself. Next, we treat the more general case of a honda that can slide due to a finite coefficient of friction of the rope on itself. Using matched asymptotic expansions, we resolve the shape of the rope in the boundary layer near the honda where the rope's bending stiffness cannot be neglected. We use this solution to derive a macroscopic criterion for the sliding of the honda in terms of the microscopic Coulomb static friction criterion. Our predictions agree well with rapid-camera observations of a professional trick roper and with laboratory experiments using a 'robo-cowboy'.


The Aedes aegypti toll pathway controls dengue virus infection.
Aedes aegypti, the mosquito vector of dengue viruses, utilizes its innate immune system to ward off a variety of pathogens, some of which can cause disease in humans. To date, the features of insects' innate immune defenses against viruses have mainly been studied in the fruit fly Drosophila melanogaster, which appears to utilize different immune pathways against different types of viruses, in addition to an RNA interference-based defense system. We have used the recently released whole-genome sequence of the Ae. aegypti mosquito, in combination with high-throughput gene expression and RNA interference (RNAi)-based reverse genetic analyses, to characterize its response to dengue virus infection in different body compartments. We have further addressed the impact of the mosquito's endogenous microbial flora on virus infection. Our findings indicate a significant role for the Toll pathway in regulating resistance to dengue virus, as indicated by an infection-responsive regulation and functional assessment of several Toll pathway-associated genes. We have also shown that the mosquito's natural microbiota play a role in modulating the dengue virus infection, possibly through basal-level stimulation of the Toll immune pathway.


Epithelial cell division - multiplying without losing touch.
Epithelia are compact tissues comprising juxtaposed cells that function as mechanical and chemical barriers between the body and the environment. This barrier relies, in part, on adhesive contacts within adherens junctions, which are formed and stabilized by E-cadherin and catenin proteins linked to the actomyosin cytoskeleton. During development and throughout adult life, epithelia are continuously growing or regenerating, largely as a result of cell division. Although persistence of adherens junctions is needed for epithelial integrity, these junctions are continually remodelled during cell division. In this Commentary, we will focus on cytokinesis, the final step of mitosis, a multiparty phenomenon in which the adherens junction belt plays an essential role and during which a new cell-cell interface is generated between daughter cells. This new interface is the site of intense remodelling, where new adhesive contacts are assembled and cell polarity is transmitted from mother to daughter cells, ultimately becoming the site of cell signalling.


Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters.
A cDNA that encodes a novel Na+-independent neutral amino acid transporter was isolated from FLC4 human hepatocarcinoma cells by expression cloning. When expressed in Xenopus oocytes, the encoded protein designated LAT3 (L-type amino acid transporter 3) transported neutral amino acids such as l-leucine, l-isoleucine, l-valine, and l-phenylalanine. The LAT3-mediated transport was Na+-independent and inhibited by 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, consistent with the properties of system L. Distinct from already known system L transporters LAT1 and LAT2, which form heterodimeric complex with 4F2 heavy chain, LAT3 was functional by itself in Xenopus oocytes. The deduced amino acid sequence of LAT3 was identical to the gene product of POV1 reported as a prostate cancer-up-regulated gene whose function was not determined, whereas it did not exhibit significant similarity to already identified transporters. The Eadie-Hofstee plots of LAT3-mediated transport were curvilinear, whereas the low affinity component is predominant at physiological plasma amino acid concentration. In addition to amino acid substrates, LAT3 recognized amino acid alcohols. The transport of l-leucine was electroneutral and mediated by a facilitated diffusion. In contrast, l-leucinol, l-valinol, and l-phenylalaninol, which have a net positive charge induced inward currents under voltage clamp, suggesting these compounds are transported by LAT3. LAT3-mediated transport was inhibited by the pretreatment with N-ethylmaleimide, consistent with the property of system L2 originally characterized in hepatocyte primary culture. Based on the substrate selectivity, affinity, and N-ethylmaleimide sensitivity, LAT3 is proposed to be a transporter subserving system L2. LAT3 should denote a new family of organic solute transporters.


Soluble urokinase-type plasminogen activator receptor improves early risk stratification in cardiogenic shock.
Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker reflecting the level of immune activation. It has been shown to have prognostic value in acute coronary syndrome and heart failure as well as in critical illness. Considering the complex pathophysiology of cardiogenic shock (CS), we hypothesized suPAR might have prognostic properties in CS as well. The aim of this study was to assess the kinetics and prognostic utility of suPAR in CS. SuPAR levels were determined in serial plasma samples (0-96 h) from 161 CS patients in the prospective, observational, multicentre CardShock study. Kinetics of suPAR, its association with 90-day mortality, and additional value in risk-stratification were investigated. The median suPAR-level at baseline was 4.4 [interquartile range (IQR) 3.2-6.6)] ng/mL. SuPAR levels above median were associated with underlying comorbidities, biomarkers reflecting renal and cardiac dysfunction, and higher 90-day mortality (49% vs. 31%; P = 0.02). Serial measurements showed that survivors had significantly lower suPAR levels at all time points compared with nonsurvivors. For risk stratification, suPAR at 12 h (suPAR12h) with a cut-off of 4.4 ng/mL was strongly associated with mortality independently of established risk factors in CS: OR 5.6 (95% CI 2.0-15.5); P = 0.001) for death by 90 days. Adding suPAR12h > 4.4 ng/mL to the CardShock risk score improved discrimination identifying high-risk patients originally categorized in the intermediate-risk category. SuPAR associates with mortality and improves risk stratification independently of other previously known risk factors in CS patients.


Tobacco smoke-related diffuse lung diseases.
Cigarette smoking has been associated with several diffuse lung diseases in which both bronchiolar and interstitial lung inflammation appear to result from chronic tobacco smoke inhalation. These diseases occur primarily in relatively young adult smokers and include desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, and pulmonary Langerhans cell histiocytosis. Although these diseases are associated with characteristic histopathologic and radiological features, there is significant overlap among these diseases, and some smokers may exhibit features indicative of the broad spectrum of smoking-related interstitial and bronchiolar lung injury patterns. Cigarette smoking has also been associated with acute eosinophilic pneumonia, and it increases the risk of developing other fibrotic interstitial lung diseases such as idiopathic pulmonary fibrosis and rheumatoid arthritis-associated interstitial lung disease. Although relatively uncommon, these smoking-related diffuse lung diseases should be recognized by clinicians as an important subset in the spectrum of interstitial lung diseases in which smoking cessation forms a central part of disease management. With the exception of acute eosinophilic pneumonia, which responds well to corticosteroid therapy, the role of corticosteroid and other immune-suppressive treatments in the management of smoking-related interstitial lung diseases is not entirely clear and is probably of limited utility, particularly in the absence of smoking cessation.


Antibody-targeted RNase fusion proteins (immunoRNases) for cancer therapy.
Ribonucleases (RNases) of the superfamily A exhibit potent antineoplastic activity yet do not mediate appreciable immunogenicity or non-specific toxicity in both animal models and cancer patients. Ranpirnase (Onconase), the first ribonuclease being evaluated as a therapeutic in humans, has progressed to phase III clinical trials in patients with unresectable mesothelioma. Conjugation of RNases to internalizing tumor-targeting monoclonal antibodies was shown to enhance specific cell killing by several orders of magnitude both in vitro and in animal models. In this review we describe the development and current status of genetically engineered 2(nd) generation immunoRNases as promising novel anti-cancer therapeutics.


The impact of diabetes mellitus on coronary artery disease: new therapeutic approaches.
Patients with diabetes mellitus (DM) type 2 have a high prevalence of coronary artery disease (CAD), as diabetes is implicated in the formation of atherosclerotic plaque. Hyperglycemia, elevated free fatty acid, increased amount of circulating end-glucosylated serum products and insulin resistance are the main mechanisms involved in the accelerated atherosclerotic process observed in type 2 DM patients. Novel treatments have been proposed to prevent and treat CAD in patients with diabetes, mainly in those with diabetes type 2. Several clinical trials have been designed in order to examine the effectiveness of these agents, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, glitazones, statins and antioxidants, but the results are still controversial.


Constructing interethnic conflict and cooperation: why some people harmed Jews and others helped them during the Holocaust in Romania.
The authors draw on a natural experiment to demonstrate that states can reconstruct conflictual interethnic relationships into cooperative relationships in relatively short periods of time. The article examines differences in how the gentile population in each of two neighboring territories in Romania treated its Jewish population during the Holocaust. These territories had been part of tsarist Russia and subject to state-sponsored anti-Semitism until 1917. During the interwar period one territory became part of Romania, which continued anti-Semitic policies, and the other became part of the Soviet Union, which pursued an inclusive nationality policy, fighting against inherited anti-Semitism and working to integrate its Jews. Both territories were then reunited under Romanian administration during World War II, when Romania began to destroy its Jewish population. The authors demonstrate that, despite a uniform Romanian state presence during the Holocaust that encouraged gentiles to victimize Jews, the civilian population in the area that had been part of the Soviet Union was less likely to harm and more likely to aid Jews as compared with the region that had been part of Romania. Their evidence suggests that the state construction of interethnic relationships can become internalized by civilians and outlive the life of the state itself.


The plant cannabinoid Delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice.
The phytocannabinoid, Delta(9)-tetrahydrocannabivarin (THCV), can block cannabinoid CB(1) receptors. This investigation explored its ability to activate CB(2) receptors, there being evidence that combined CB(2) activation/CB(1) blockade would ameliorate certain disorders. We tested the ability of THCV to activate CB(2) receptors by determining whether: (i) it inhibited forskolin-stimulated cyclic AMP production by Chinese hamster ovary (CHO) cells transfected with human CB(2) (hCB(2)) receptors; (ii) it stimulated [(35)S]GTPgammaS binding to hCB(2) CHO cell and mouse spleen membranes; (iii) it attenuated signs of inflammation/hyperalgesia induced in mouse hind paws by intraplantar injection of carrageenan or formalin; and (iv) any such anti-inflammatory or anti-hyperalgesic effects were blocked by a CB(1) or CB(2) receptor antagonist. THCV inhibited cyclic AMP production by hCB(2) CHO cells (EC(50)= 38 nM), but not by hCB(1) or untransfected CHO cells or by hCB(2) CHO cells pre-incubated with pertussis toxin (100 ng.mL(-1)) and stimulated [(35)S]GTPgammaS binding to hCB(2) CHO and mouse spleen membranes. THCV (0.3 or 1 mg.kg(-1) i.p.) decreased carrageenan-induced oedema in a manner that seemed to be CB(2) receptor-mediated and suppressed carrageenan-induced hyperalgesia. THCV (i.p.) also decreased pain behaviour in phase 2 of the formalin test at 1 mg.kg(-1), and in both phases of this test at 5 mg.kg(-1); these effects of THCV appeared to be CB(1) and CB(2) receptor mediated. THCV can activate CB(2) receptors in vitro and decrease signs of inflammation and inflammatory pain in mice partly via CB(1) and/or CB(2) receptor activation.


Structure learning and the posterior parietal cortex.
We propose a theory of structure learning in the primate brain. We argue that the parietal cortex is critical for learning about relations among the objects and categories that populate a visual scene. We suggest that current deep learning models exhibit poor global scene understanding because they fail to perform the relational inferences that occur in the primate dorsal stream. We review studies of neural coding in primate posterior parietal cortex (PPC), drawing the conclusion that neurons in this brain area represent potentially high-dimensional inputs on a low-dimensional manifold that encodes the relative position of objects or features in physical space, and relations among entities in abstract conceptual space. We argue that this low-dimensional code supports generalisation of relational information, even in nonspatial domains. Finally, we propose that structure learning is grounded in the actions that primates take when they reach for objects or fixate them with their eyes. We sketch a model of how this might occur in neural circuits.


Skin surface electron microscopy in Pityrosporum folliculitis. The role of follicular occlusion in disease and the response to oral ketoconazole.
The yeast Pityrosporum orbiculare is thought to cause the folliculitis associated with seborrheic eczema. However, a combination of mechanical and microbiological factors may be involved, with follicular occlusion leading to yeast overgrowth and folliculitis. Scanning electron microscopy was used to investigate this hypothesis. Skin biopsy specimens obtained from patients with Pityrosporum folliculitis were examined by scanning electron microscopy before and after oral ketoconazole therapy. Patients with active disease showed occlusion of noninflamed follicles, which resolved after ketoconazole treatment. Follicular occlusion was not present in biopsy specimens obtained from unaffected controls nor was it related to the presence of P orbiculare. These findings suggest that follicular occlusion may be a primary event in the development of this folliculitis, with yeast overgrowth a secondary occurrence. The beneficial effect of ketoconazole in this disease may be due to direct effects on the follicle.


Novel treatment from a botanical formulation Si-Miao-Yong-an decoction inhibits vasa vasorum angiogenesis and stabilizes atherosclerosis plaques via the Wnt1/β-catenin signalling pathway.
Si-Miao-Yong-An (SMYA) has been widely used for the clinical treatment of atherosclerosis (AS). Yet, its complete mechanism of action is not fully understood. To investigate the mechanism by which SMYA stabilizes AS plaques from the perspective of inhibiting vasa vasorum (VV) angiogenesis. We used male ApoE-/- mice to establish an AS model. The mice were divided into model, SMYA (11.7 mg/kg/d), and simvastatin (SVTT) (2.6 mg/kg/d) groups. Mice were given SMYA or SVTT by daily gavage for 8 weeks. HE staining, immunofluorescence double-labelling staining, and immunohistochemical staining were used to observe the pathological changes in the plaques. Finally, the protein and mRNA expression levels of the Wnt1/β-catenin signalling pathway were detected by Western blot and qRT-PCR, respectively. SMYA significantly attenuated cholesterol crystallization, and lipid accumulation in AS plaques, resulting in smaller plaque size (0.25 mm2 vs. 0.46 mm2), and lowering ratio of plaque to lumen area (20.04% vs. 38.33%) and VV density (50.64/mm2 vs. 98.02/mm2). Meanwhile, SMYA suppressed both the positive area percentage of Wnt1 (2.53 vs. 3.56), β-catenin (3.33 vs. 5.65) and Cyclin D1 (2.10 vs. 3.27) proteins in the aortic root plaques, and mRNA expression of Wnt1 (1.38 vs. 2.09), β-catenin (2.05 vs. 3.25) and Cyclin D1 (1.39 vs. 2.57). SMYA has a protective effect against AS, which may be related to its anti-VV angiogenesis in plaques, suggesting that SMYA has the potential as a novel botanical formulation in the treatment of AS.


Effects of prostaglandins on gastrin release from canine antral mucosal cells in primary culture.
Evidence in vivo indicates that endogenous and exogenous prostaglandins can alter gastrin secretion. We have used primary cultures containing canine antral G-cells to study the cellular actions of prostaglandins on gastrin secretion, comparing the effects of prostaglandin E2 (PGE2) and its synthetic analogue enprostil. Enprostil (10(-10)-10(-6) M) inhibited gastrin secretion in response to bombesin, carbachol, and forskolin, the latter a receptor-independent activator of adenylate cyclase. This inhibition by enprostil was reversed by treatment with pertussis toxin (200 ng/ml, 8 h). However, enprostil did not inhibit the postreceptor stimuli 8-bromoadenosine 3',5'-cyclic monophosphate (10(-3) M), calcium ionophore A-23187 (10(-7) M), or 4 beta-phorbol 12-myristate 13-acetate (10(-8) M). In contrast, whereas PGE2 inhibited forskolin-stimulated gastrin release, PGE2 did not inhibit the response to carbachol or bombesin in control cultures. However, in pertussis toxin-treated cultures, PGE2 inhibition was reversed and, in contrast, the responses to bombesin, carbachol, and possibly forskolin were augmented. Indomethacin at a dose of 10(-5) M did not alter basal or bombesin-stimulated gastrin secretion. However, the somatostatin antibody CURE-S6 enhanced the response to forskolin and enhanced inhibition by PGE2, suggesting that endogenous somatostatin produced an inhibitory tone in these cultures and excluding the possibility that PGE2 acted via release of endogenous somatostatin. Our data suggest that in cultured antral cells gastrin release is regulated by inhibitory and stimulatory prostaglandin mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)


Free radical-mediated endothelial damage in blood vessels after electrical stimulation.
The endothelium plays an important role in mediating vasodilator effects of several agents (acetylcholine, thrombin, A23187, etc.). The goal of this study was to determine the ability of oxygen free radicals generated by electrical field stimulation to alter endothelial function in isolated tissue systems. Tail artery strips and the mesenteric microvasculature isolated from Sprague-Dawley rats were used. Following smooth muscle contraction induced by norepinephrine, these preparations relaxed in response to acetylcholine chloride or ionophore A23187. All vessels were then subjected to electrical stimulation (9 V, 1-2 ms, 4 Hz) of the physiological buffer in which they were bathed or perfused. In some of these preparations, an antioxidant, (10(-4) M sodium ascorbate, 3.6 X 10(-5) M glutathione, 1.3 X 10(-2) M dimethyl sulfoxide) was included in the buffer. Relaxation responses persisted in vessels where an antioxidant had been included in the electrically stimulated buffer. Tissues stimulated without this protection did not relax on subsequent exposures to endothelium-dependent vasodilators. Scanning-electron microscopy of the tissues revealed significant endothelial damage (cell membrane pitting) in tissues exposed to electrical stimulation without antioxidant protection. These results suggest that electrical stimulation causes endothelial damage in isolated vascular preparations. This seemingly adverse effect proves to be a useful tool for removing the endothelium in studies of isolated vascular tissues.


Getting to the top of Google: search engine optimization.
Search engine optimization is the process of making your Web site appear at or near the top of popular search engines such as Google, Yahoo, and MSN. This is not done by luck or knowing someone working for the search engines but by understanding the process of how search engines select Web sites for placement on top or on the first page. This article will review the process and provide methods and techniques to use to have your site rated at the top or very near the top.


Haemophilia A home therapy in the United Kingdom 1975-6.
Data on home treatment for patients with haemophilia A (factor VIII deficient haemophilia) were compiled for 1975 and 1976 from questionnaires answered by directors of haemophilia centres throughout the United Kingdom. There were 48 haemophilia centres in 1975 and 71 in 1976. The number of patients on or in training for home treatment increased from 267 to 488 in the two years, and a further 241 haemophiliacs were considered suitable for home therapy by the end of 1976. Apart from a small (but increasing) number of haemophiliacs on prophylactic treatment, most patients were on low-dose (250-500 units) on-demand regimens, using a mean of 20 000 factor VIII units per patient per year in 1976. An estimated 55% of the blood product used for home therapy in the UK in 1976 was imported from commercial sources. Despite the fact that the numbers of patients on home treatment have increased, so that about 60% of the potential population were receiving or being considered for home treatment in 1976, inadequacies in the service still remain. In some centres follow-up is clearly inadequate; about 15% of patients still rely on cryoprecipitate; and too little money has been invested in making the NHS self-sufficient in factor VIII production.


Invasive procedures in the elderly after stage IV cancer diagnosis.
Invasive procedures are resource intense and may be associated with substantial morbidity. These harms must be carefully balanced with the benefits gained in life expectancy and quality of life. Prior research has demonstrated an increasing aggressiveness of care in cancer patients at the end-of-life. To better characterize surgical care in this setting, we sought to examine trends in the use of invasive procedures in patients diagnosed with metastatic cancer on presentation. Using Surveillance Epidemiology and End Results -Medicare data, we identified invasive procedure claims from 1994-2009 for patients diagnosed with incident stage IV breast, colorectal, lung, and prostate cancer patients in 1995-2006. We grouped procedures into surgically relevant categories, using an adaptation of the Clinical Classifications Software, and measured utilization and relative changes over time. Of stage IV patients diagnosed in 2002-2006, 96% underwent a procedure during the course of their cancer care including 63% after the diagnostic period, and 25% in the last month of life. Between 1996 and 2006, minimal change was observed in utilization during the diagnostic period (+1.5%). However, there were significant increases during continuing care (+20.7%) and the last month of life (+21.5%). Procedures consistent with primary tumor resection decreased, whereas those with probable palliative intent and those unrelated to cancer increased. Nearly all patients who present with metastatic cancer undergo invasive procedures. Although overall utilization is increasing, the specific procedure types indicate that it may be appropriate, enhancing the quality of life in this vulnerable population.


Construct validity of UroSim® simulator for learning transurethral resection of bladder tumor.
There is an increasing trend to incorporate Simulator-based training in urology residency programs. The study was designed to determine the construct validity of UroSim® for that we compared the performance of transurethral resection of bladder tumor (TURBT) between experts and novices. We conducted a cross sectional study at a university hospital to determine the construct validity of UroSim® for TURBT. We compared the outcome measures between experts (urology consultants) and novices (residents) to determine relationship between clinical experience and performance on simulator. Primary outcome measure was resection time and secondary outcome measures were safety, bleeding, and visualization during TURBT on UroSim. We requested participant to resect three tumors to assess the test content of the simulator. Comparison of continuous variables such as resection time, resection, bleeding control, and visualization and blood loss using student t test. Comparison of categorical variable, i.e. perforation of bladder, using Fischer exact test. We included 30 experts and 30 novices. There was a statistically significant difference in the mean resection time between the groups (196±67.4 sec versus 374.6±179.7 sec; p=0.01), suggesting a positive relationship between clinical experience and performance on simulator. Additionally, safety parameters, namely, bleeding control, inadvertent cuts into bladder wall, ureteric orifices, and bladder perforations varied between the two groups. We observed significant differences of parameters in performance between experts and novices. Simulator is a useful tool for teaching TURBT as it demonstrates good construct validity and recommended in urology training for teaching psychomotor skills.


Optogenetic Modulation of Intraocular Pressure in a Glucocorticoid-Induced Ocular Hypertension Mouse Model.
Steroid-induced glaucoma is a common form of secondary open angle glaucoma characterized by ocular hypertension (elevated intraocular pressure [IOP]) in response to prolonged glucocorticoid exposure. Elevated IOP occurs with increased outflow resistance and altered trabecular meshwork (TM) function. Recently, we used an optogenetic approach in TM to regulate the 5-phosphatase, OCRL, which contributes to regulating PI(4,5)P2 levels. Here, we applied this system with the aim of reversing compromised outflow function in a steroid-induced ocular hypertension mouse model. Elevated IOP was induced by chronic subconjunctival dexamethasone injections in wild-type C57Bl/6j mice. AAV2 viruses containing optogenetic modules of cryptochrome 2 (Cry2)-OCRL-5ptase and CIBN-GFP were injected into the anterior chamber. Four weeks after viral expression and dexamethasone exposure, IOP was measured by tonometer and outflow facility was measured by perfusion apparatus. Human TM cells were treated with dexamethasone, stimulated by light and treated with rhodamine-phalloidin to analyze actin structure. Dexamethasone treatment elevated IOP and decreased outflow facility in wild-type mice. Optogenetic constructs were expressed in the TM of mouse eyes. Light stimulation caused CRY2-OCRL-5ptase to translocate to plasma membrane (CIBN-CAAX-GFP) and cilia (CIBN-SSTR3-GFP) in TM cells, which rescued the IOP and outflow facility. In addition, aberrant actin structures formed by dexamethasone treatment were reduced by optogenetic stimulation in human TM cells in culture. Subcellular targeting of inositol phosphatases to remove PIP2 represents a promising strategy to reverse defective TM function in steroid-induced ocular hypertension. Targeted modulation of OCRL may be used to decrease steroid-induced elevated IOP.


Is use of fall risk-increasing drugs in an elderly population associated with an increased risk of hip fracture, after adjustment for multimorbidity level: a cohort study.
Risk factors for hip fracture are well studied because of the negative impact on patients and the community, with mortality in the first year being almost 30% in the elderly. Age, gender and fall risk-increasing drugs, identified by the National Board of Health and Welfare in Sweden, are well known risk factors for hip fracture, but how multimorbidity level affects the risk of hip fracture during use of fall risk-increasing drugs is to our knowledge not as well studied. This study explored the relationship between use of fall risk-increasing drugs in combination with multimorbidity level and risk of hip fracture in an elderly population. Data were from Östergötland County, Sweden, and comprised the total population in the county aged 75 years and older during 2006. The odds ratio (OR) for hip fracture during use of fall risk-increasing drugs was calculated by multivariate logistic regression, adjusted for age, gender and individual multimorbidity level. Multimorbidity level was estimated with the Johns Hopkins ACG Case-Mix System and grouped into six Resource Utilization Bands (RUBs 0-5). 2.07% of the study population (N = 38,407) had a hip fracture during 2007. Patients using opioids (OR 1.56, 95% CI 1.34-1.82), dopaminergic agents (OR 1.78, 95% CI 1.24-2.55), anxiolytics (OR 1.31, 95% CI 1.11-1.54), antidepressants (OR 1.66, 95% CI 1.42-1.95) or hypnotics/sedatives (OR 1.31, 95% CI 1.13-1.52) had increased ORs for hip fracture after adjustment for age, gender and multimorbidity level. Vasodilators used in cardiac diseases, antihypertensive agents, diuretics, beta-blocking agents, calcium channel blockers and renin-angiotensin system inhibitors were not associated with an increased OR for hip fracture after adjustment for age, gender and multimorbidity level. Use of fall risk-increasing drugs such as opioids, dopaminergic agents, anxiolytics, antidepressants and hypnotics/sedatives increases the risk of hip fracture after adjustment for age, gender and multimorbidity level. Fall risk-increasing drugs, high age, female gender and multimorbidity level, can be used to identify high-risk patients who could benefit from a medication review to reduce the risk of hip fracture.


Guided bone augmentation using ceramic space-maintaining devices: the impact of chemistry.
The purpose of the study was to evaluate histologically, whether vertical bone augmentation can be achieved using a hollow ceramic space maintaining device in a rabbit calvaria model. Furthermore, the chemistry of microporous hydroxyapatite and zirconia were tested to determine which of these two ceramics are most suitable for guided bone generation. 24 hollow domes in two different ceramic materials were placed subperiosteal on rabbit skull bone. The rabbits were sacrificed after 12 weeks and the histology results were analyzed regarding bone-to-material contact and volume of newly formed bone. The results suggest that the effect of the microporous structure of hydroxyapatite seems to facilitate for the bone cells to adhere to the material and that zirconia enhance a slightly larger volume of newly formed bone. In conclusion, the results of the current study demonstrated that ceramic space maintaining devices permits new bone formation and osteoconduction within the dome.


Extracellular domain of TGFbeta type III receptor inhibits angiogenesis and tumor growth in human cancer cells.
TGFbeta overexpression in human cancer cells has been shown to promote tumor progression. In the present study, we sought to determine whether sequestration of endogenous TGFbeta by the expression of a soluble TGFbeta type III receptor (sRIII), can reduce malignancy in human carcinoma cells and whether the tumor-suppressive activity of sRIII is associated with the inhibition of angiogenesis. Ectopic expression of sRIII significantly inhibited the growth of tumors formed by human colon carcinoma HCT116 and breast carcinoma MDA-MB-435 cells in nude mice. It also reduced the metastatic potential of the MDA-MB-435 cells. Thus, endogenous TGFbeta appears to be necessary for the progression of these two carcinomas. Furthermore, when the tumor cells were mixed with Matrigel and embedded subcutaneously in nude mice, the blood volume in Matrigel plugs containing sRIII-expressing cells as indicated by hemoglobin levels was significantly lower than that in Matrigel plugs containing the respective control cells. Blood vessel counts in paraffin sections of the Matrigel plugs containing sRIII-expressing cells were also significantly lower than those in paraffin sections of the Matrigel plugs containing control cells. Treatment of human endothelial cells with a recombinant sRIII significantly inhibited their ability to form a capillary web structure on Matrigel. These results for the first time indicate that the sRIII-induced tumor suppression appears to be in part due to the inhibition of angiogenesis.


Exploring patient and family involvement in the lifecycle of an orphan drug: a scoping review.
Patients and their families have become more active in healthcare systems and research. The value of patient involvement is particularly relevant in the area of rare diseases, where patients face delayed diagnoses and limited access to effective therapies due to the high level of uncertainty in market approval and reimbursement decisions. It has been suggested that patient involvement may help to reduce some of these uncertainties. This review explored existing and proposed roles for patients, families, and patient organizations at each stage of the lifecycle of therapies for rare diseases (i.e., orphan drug lifecycle). A scoping review was conducted using methods outlined by Arksey and O'Malley. To validate the findings from the literature and identify any additional opportunities that were missed, a consultative webinar was conducted with members of the Patient and Caregiver Liaison Group of a Canadian research network. Existing and proposed opportunities for involving patients, families, and patient organizations were reported throughout the orphan drug lifecycle and fell into 12 themes: research outside of clinical trials; clinical trials; patient reported outcomes measures; patient registries and biorepositories; education; advocacy and awareness; conferences and workshops; patient care and support; patient organization development; regulatory decision-making; and reimbursement decision-making. Existing opportunities were not described in sufficient detail to allow for the level of involvement to be assessed. Additionally, no information on the impact of involvement within specific opportunities was found. Based on feedback from patients and families, documentation of existing opportunities within Canada is poor. Opportunities for patient, family, and patient organization involvement exist throughout the orphan drug lifecycle. However, based on the information found, it is not possible to determine which opportunities would be most effective at each stage.


[CINE-MRT for the study of the effects of regional left ventricular wall motion disorders on global heart function after a myocardial infarct and revascularization].
To determine changes in global cardiac function and mass caused by infarct-associated regional wall motion abnormalities and to compare the changes after revascularization in patients with and without improvement of regional contractility. 21 patients with regional left ventricular wall motion abnormalities and associated coronary artery stenoses requiring revascularization were examined with a Cine FLASH-2D sequence 26 +/- 12 days after their first myocardial infarction and re-examined three months after revascularization. Regional contractility and volumes and masses of both ventricles were determined. After revascularization, regional wall motion improvement led to decreased left ventricular volumes and improved ejection fractions, whereas patients with persisting wall motion defects showed unchanged left ventricular functional parameters. Comparing both groups of patients, the patients with improvement of regional contractility revealed lower end-systolic volumes and higher ejection fractions at follow-up. Cardiac masses and right ventricular parameters were not different, patients with a depressed right ventricular ejection fraction showed improvement at follow-up. After myocardial infarction, revascularization of the infarct-related coronary artery leads to an improvement of left ventricular function only if there is also an improvement of regional contractility. An effect on right ventricular function was not observed three months after the first small- or middle-sized myocardial infarction.


Extended molecular dynamics of a c-kit promoter quadruplex.
The 22-mer c-kit promoter sequence folds into a parallel-stranded quadruplex with a unique structure, which has been elucidated by crystallographic and NMR methods and shows a high degree of structural conservation. We have carried out a series of extended (up to 10 μs long, ∼50 μs in total) molecular dynamics simulations to explore conformational stability and loop dynamics of this quadruplex. Unfolding no-salt simulations are consistent with a multi-pathway model of quadruplex folding and identify the single-nucleotide propeller loops as the most fragile part of the quadruplex. Thus, formation of propeller loops represents a peculiar atomistic aspect of quadruplex folding. Unbiased simulations reveal μs-scale transitions in the loops, which emphasizes the need for extended simulations in studies of quadruplex loops. We identify ion binding in the loops which may contribute to quadruplex stability. The long lateral-propeller loop is internally very stable but extensively fluctuates as a rigid entity. It creates a size-adaptable cleft between the loop and the stem, which can facilitate ligand binding. The stability gain by forming the internal network of GA base pairs and stacks of this loop may be dictating which of the many possible quadruplex topologies is observed in the ground state by this promoter quadruplex.


Global research priorities for interpersonal violence prevention: a modified Delphi study.
To establish global research priorities for interpersonal violence prevention using a systematic approach. Research priorities were identified in a three-round process involving two surveys. In round 1, 95 global experts in violence prevention proposed research questions to be ranked in round 2. Questions were collated and organized according to the four-step public health approach to violence prevention. In round 2, 280 international experts ranked the importance of research in the four steps, and the various substeps, of the public health approach. In round 3, 131 international experts ranked the importance of detailed research questions on the public health step awarded the highest priority in round 2. In round 2, "developing, implementing and evaluating interventions" was the step of the public health approach awarded the highest priority for four of the six types of violence considered (i.e. child maltreatment, intimate partner violence, armed violence and sexual violence) but not for youth violence or elder abuse. In contrast, "scaling up interventions and evaluating their cost-effectiveness" was ranked lowest for all types of violence. In round 3, research into "developing, implementing and evaluating interventions" that addressed parenting or laws to regulate the use of firearms was awarded the highest priority. The key limitations of the study were response and attrition rates among survey respondents. However, these rates were in line with similar priority-setting exercises. These findings suggest it is premature to scale up violence prevention interventions. Developing and evaluating smaller-scale interventions should be the funding priority.


Recombinant human platelet-activating factor acetylhydrolase reduces the frequency of diabetes in the diabetes-prone BB rat.
Platelet-activating factor (PAF) has been implicated in the development of type 1 diabetes. Our previous studies have suggested that PAF inhibitors reduce insulitis and the frequency of diabetes in BB rats. In this study, serum PAF levels were reduced to address the hypothesis that PAF is important for the development of insulitis. From the age of 35 days on, DP-BB rats were treated with human recombinant PAF acetylhydrolase (rPAF-AH), which efficiently inactivates PAF. Our data indicate that intraperitoneal injections of rPAF-AH reduce the incidence of diabetes in the DP-BB rat. Daily intraperitoneal injections of 6.0 mg/kg body wt rPAF-AH reduced the frequency of diabetes in saline-injected rats from 90% (27/30) to 57% (17/30) (P = 0.004). As found by morphometric analysis on pancreatic islets, DP-BB rats protected from diabetes had less severe degrees of insulitis in a dose-dependent manner. DP-BB rats protected by rPAF-AH also had a higher percentage of insulin-positive cells in pancreas sections compared with those from diabetic animals. We therefore speculated that the beta-cells were protected from insulitis by rPAF-AH.


Stratified meta-analysis of intermittent pneumatic compression of the lower limbs to prevent venous thromboembolism in hospitalized patients.
Optimal thromboprophylaxis for patients at risk of bleeding remains uncertain. This meta-analysis assessed whether intermittent pneumatic compression (IPC) of the lower limbs was effective in reducing venous thromboembolism and whether combining pharmacological thromboprophylaxis with IPC would enhance its effectiveness. Two reviewers searched MEDLINE, EMBASE, and the Cochrane controlled trial register (1966-February 2013) for randomized, controlled trials and assessed the outcomes and quality of the trials independently. Trials comparing IPC with pharmacological thromboprophylaxis, thromboembolic deterrent stockings, no prophylaxis, and a combination of IPC and pharmacological thromboprophylaxis were considered. Trials that used IPC <24 hours or compared different types of IPC were excluded. A total of 16 164 hospitalized patients from 70 trials met the inclusion criteria and were subjected to meta-analysis. IPC was more effective than no IPC prophylaxis in reducing deep vein thrombosis (7.3% versus 16.7%; absolute risk reduction, 9.4%; 95% confidence interval [CI], 7.9-10.9; relative risk, 0.43; 95% CI, 0.36-0.52; P<0.01; I(2)=34%) and pulmonary embolism (1.2% versus 2.8%; absolute risk reduction, 1.6%; 95% CI, 0.9-2.3; relative risk, 0.48; 95% CI, 0.33-0.69; P<0.01; I(2)=0%). IPC was also more effective than thromboembolic deterrent stockings in reducing deep vein thrombosis and appeared to be as effective as pharmacological thromboprophylaxis but with a reduced risk of bleeding (relative risk, 0.41; 95% CI, 0.25-0.65; P<0.01; I(2)=0%). Adding pharmacological thromboprophylaxis to IPC further reduced the risk of deep vein thrombosis (relative risk, 0.54; 95% CI, 0.32-0.91; P=0.02; I(2)=0%) compared with IPC alone. IPC was effective in reducing venous thromboembolism, and combining pharmacological thromboprophylaxis with IPC was more effective than using IPC alone.


Cesarean Section Delivery Is Not a Risk Factor for Development of Inflammatory Bowel Disease: A Population-based Analysis.
Mode of birth affects development of the intestinal microbiota, and microbial dysbiosis has been associated with inflammatory bowel disease (IBD). We performed a population-based analysis to determine whether mode of delivery (cesarean section vs. vaginal delivery) affects risk of IBD. We collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010. Starting in 1970, 6-digit family health registration numbers were used in Manitoba to link mothers with their offspring. Maternal health records, including dates and modes of delivery and siblings of individuals with IBD, were identified. We obtained data on 1671 individuals with IBD and 10,488 controls (individuals without IBD, matched by age, sex, and area of residence at IBD diagnosis) linked to mothers' obstetrical records. Higher proportions of urban than rural residents were delivered by cesarean section for IBD cases (12.8% vs. 9.7%, P = .05) and controls (13.3% vs. 9.4%, P < .0001). A higher percentage of men with Crohn's disease than women with Crohn's disease were born via cesarean section (13.5% vs. 8.4%, P = .01). Overall, there was no difference in the percentage of IBD cases born by cesarean section (11.6%) vs. controls (11.7%, P = .93). In multivariate analysis, birth by cesarean section was not associated with an increased risk of subsequent IBD, controlling for age, sex, urban residence, and income (odds ratio, 1.04; 95% confidence interval, 0.89-1.23). Persons with IBD were no more likely to have been born by cesarean section than their siblings without IBD (1740 siblings from 1615 families) (11.6% vs. 11.3%; odds ratio, 1.14; 95% confidence interval, 0.72-1.80; P = .79). People with IBD were not more likely to have been born via cesarean section than controls or siblings without IBD. These findings indicate that events of the immediate postpartum period that shape the developing intestinal microbiome do not affect risk for IBD.


Effect of polyamine depletion on chromatin structure in U-87 MG human brain tumour cells.
The chromatin structure of polyamine-depleted U-87 MG human brain tumour cells was studied by following the kinetics of digestion of cell nuclei by micrococcal nuclease and bovine pancreatic DNAase I. Cells growing in monolayers were treated with either alpha-difluoromethylornithine (DFMO), to deplete putrescine and spermidine, or N1,N14-bis(ethyl)homospermine (BE-4-4-4), to deplete putrescine, spermidine and spermine. BE-4-4-4 increased the initial rates of digestion and the magnitudes of limit digest by both enzymes; DFMO increased the limit digests without affecting initial digestion rates. Addition of 1 mM-putrescine 1 day after addition of DFMO reversed the effect of DFMO on limit digests. (Because polyamine uptake is low in cells treated with BE-4-4-4, and because putrescine does not reverse the growth-inhibitory effects of BE-4-4-4, reversal of the effects of BE-4-4-4 with putrescine was not attempted.) The increases in initial rates and limit digests did not result from changes in the lengths of nucleosomal or linker DNA, from blocks in cell-cycle progression, or from growth inhibition caused by DFMO or BE-4-4-4. Thus, because the limit digest is highest in cells with the lowest polyamine levels, it seems clear that the enhanced enzymic digestion of nuclei is caused by polyamine depletion and its possible effect on chromatin structure.


Silica colloidal crystals as porous substrates for total internal reflection fluorescence microscopy of live cells.
Total internal reflection fluorescence (TIRF) microscopy is a powerful means of probing biological cells because it reduces autofluorescence, but the need for direct contact between the cell surface and the microscope slide hinders chemical access to the cell surface. In this work, a submicrometer crystalline layer of colloidal silica on the microscope coverslip is shown to allow TIRF microscopy while also allowing chemical access to the cell surface. A 750 nm layer of 165 nm silica colloidal crystals was sintered onto a fused silica coverslip, and Chinese hamster ovary cells were successfully grown on this surface. This cell line over-expresses the human delta-opioid receptor, which enabled probing of the binding of a labeled ligand to the receptors on the cell surface. Total internal reflection and chemical access to the cell surface are demonstrated. The range of angles for total internal reflection is reduced only by 1/3 due to the lower index of refraction of the colloidal multilayer relative to fused silica.


Future waste treatment and energy systems--examples of joint scenarios.
Development and use of scenarios for large interdisciplinary projects is a complicated task. This article provides practical examples of how it has been carried out in two projects addressing waste management and energy issues respectively. Based on experiences from the two projects, recommendations are made for an approach concerning development of scenarios in projects dealing with both waste management and energy issues. Recommendations are given to develop and use overall scenarios for the project and leave room for sub-scenarios in parts of the project. Combining different types of scenarios is recommended, too, in order to adapt to the methods and tools of different disciplines, such as developing predictive scenarios with general equilibrium tools and analysing explorative scenarios with energy system analysis tools. Furthermore, as marginals identified in differing future background systems determine the outcomes of consequential life cycle assessments (LCAs), it is considered advisable to develop and use explorative external scenarios based on possible marginals as a framework for consequential LCAs. This approach is illustrated using an on-going Danish research project.


Ruminant Milk-Derived Extracellular Vesicles: A Nutritional and Therapeutic Opportunity?
Milk has been shown to contain a specific fraction of extracellular particles that are reported to resist digestion and are purposefully packaged with lipids, proteins, and nucleic acids to exert specific biological effects. These findings suggest that these particles may have a role in the quality of infant nutrition, particularly in the early phase of life when many of the foundations of an infant's potential for health and overall wellness are established. However, much of the current research focuses on human or cow milk only, and there is a knowledge gap in how milk from other species, which may be more commonly consumed in different regions, could also have these reported biological effects. Our review provides a summary of the studies into the extracellular particle fraction of milk from a wider range of ruminants and pseudo-ruminants, focusing on how this fraction is isolated and characterised, the stability and uptake of the fraction, and the reported biological effects of these fractions in a range of model systems. As the individual composition of milk from different species is known to differ, we propose that the extracellular particle fraction of milk from non-traditional and minority species may also have important and distinct biological properties that warrant further study.


Dietary licorice root supplementation reduces diet-induced weight gain, lipid deposition, and hepatic steatosis in ovariectomized mice without stimulating reproductive tissues and mammary gland.
We studied the impact of dietary supplementation with licorice root components on diet-induced obesity, fat accumulation, and hepatic steatosis in ovariectomized C57BL/6 mice as a menopause model. We evaluated the molecular and physiological effects of dietary licorice root administered to ovariectomized C57BL/6 mice as root powder (LRP), extracts (LRE), or isolated isoliquiritigenin (ILQ) on reproductive (uterus and mammary gland) and nonreproductive tissues important in regulating metabolism (liver, perigonadal, perirenal, mesenteric, and subcutaneous fat). Quantitative outcome measures including body weight, fat distribution (magnetic resonance imaging), food consumption, bone density and weight (Dual-energy X-ray absorptiometry), and gene expression were assessed by the degree of restoration to the preovariectomized health state. We characterized histological (H&E and oil red O staining) and molecular properties (expression of certain disease markers) of these tissues, and correlated these with metabolic phenotype as well as blood levels of bioactives. Although LRE and ILQ provided some benefit, LRP was the most effective in reducing body weight gain, overall fat deposition, liver steatosis, and expression of hepatic lipid synthesis genes following ovariectomy. Our data demonstrate that licorice root provided improvement of multiple metabolic parameters under conditions of low estrogen and high-fat diets without stimulating reproductive tissues.


Delivering medical education for future healthcare needs: a community-focused challenge.
Medical schools are required to train the workforce needed to care for the population they serve. In the UK, we are expected to produce more graduates choosing to be general practitioners and to equip all graduates with the ability to care for an ageing population with increasingly complex care needs. These doctors need to be effective members of multi-professional teams, possessing generalist skills including an understanding of uncertainty and risk. Curricula where a significant proportion of clinical learning is based in general practice are best placed to address this pedagogic need. The authors evaluate the sociocultural factors which impede the expansion of undergraduate medical education in general practice. These include historic cultural divides between secondary and primary care, medical school leadership, funding, contractual arrangements and capacity in general practice to deliver increasing education of medical students alongside other established and emerging health professions. The piece concludes with two recommendations: undergraduate student teaching should be incorporated into contract negotiations and there must be urgent UK-wide investment in appropriate placement tariff for students. Furthemore, there is an imperative to pilot and evaluate novel collaborative approaches to the education of undergraduate medical and other health professions students.


Distribution of malaria exposure in endemic countries in Africa considering country levels of effective treatment.
Malaria prevalence, clinical incidence, treatment, and transmission rates are dynamically interrelated. Prevalence is often considered a measure of malaria transmission, but treatment of clinical malaria reduces prevalence, and consequently also infectiousness to the mosquito vector and onward transmission. The impact of the frequency of treatment on prevalence in a population is generally not considered. This can lead to potential underestimation of malaria exposure in settings with good health systems. Furthermore, these dynamical relationships between prevalence, treatment, and transmission have not generally been taken into account in estimates of burden. Using prevalence as an input, estimates of disease incidence and transmission [as the distribution of the entomological inoculation rate (EIR)] for Plasmodium falciparum have now been made for 43 countries in Africa using both empirical relationships (that do not allow for treatment) and OpenMalaria dynamic micro-simulation models (that explicitly include the effects of treatment). For each estimate, prevalence inputs were taken from geo-statistical models fitted for the year 2010 by the Malaria Atlas Project to all available observed prevalence data. National level estimates of the effectiveness of case management in treating clinical attacks were used as inputs to the estimation of both EIR and disease incidence by the dynamic models. When coverage of effective treatment is taken into account, higher country level estimates of average EIR and thus higher disease burden, are obtained for a given prevalence level, especially where access to treatment is high, and prevalence relatively low. These methods provide a unified framework for comparison of both the immediate and longer-term impacts of case management and of preventive interventions.


Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth.
Multiple myeloma (MM) causes lytic bone lesions due to increased bone resorption and concomitant marked suppression of bone formation. Sclerostin (Scl), an osteocyte-derived inhibitor of Wnt/β-catenin signaling, is elevated in MM patient sera and increased in osteocytes in MM-bearing mice. We show here that genetic deletion of Sost, the gene encoding Scl, prevented MM-induced bone disease in an immune-deficient mouse model of early MM, and that administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreases osteolysis in immune-competent mice with established MM. Sost/Scl inhibition increased osteoblast numbers, stimulated new bone formation and decreased osteoclast number in MM-colonized bone. Further, Sost/Scl inhibition did not affect tumor growth in vivo or anti-myeloma drug efficacy in vitro. These results identify the osteocyte as a major contributor to the deleterious effects of MM in bone and osteocyte-derived Scl as a promising target for the treatment of established MM-induced bone disease. Further, Scl did not interfere with efficacy of chemotherapy for MM, suggesting that combined treatment with anti-myeloma drugs and Scl-Ab should effectively control MM growth and bone disease, providing new avenues to effectively control MM and bone disease in patients with active MM.