Cdx ParaHox genes acquired distinct developmental roles after gene duplication in vertebrate evolution.
The functional consequences of whole genome duplications in vertebrate evolution are not fully understood. It remains unclear, for instance, why paralogues were retained in some gene families but extensively lost in others. Cdx homeobox genes encode conserved transcription factors controlling posterior development across diverse bilaterians. These genes are part of the ParaHox gene cluster. Multiple Cdx copies were retained after genome duplication, raising questions about how functional divergence, overlap, and redundancy respectively contributed to their retention and evolutionary fate. We examined the degree of regulatory and functional overlap between the three vertebrate Cdx genes using single and triple morpholino knock-down in Xenopus tropicalis followed by RNA-seq. We found that one paralogue, Cdx4, has a much stronger effect on gene expression than the others, including a strong regulatory effect on FGF and Wnt genes. Functional annotation revealed distinct and overlapping roles and subtly different temporal windows of action for each gene. The data also reveal a colinear-like effect of Cdx genes on Hox genes, with repression of Hox paralogy groups 1 and 2, and activation increasing from Hox group 5 to 11. We also highlight cases in which duplicated genes regulate distinct paralogous targets revealing pathway elaboration after whole genome duplication. Despite shared core pathways, Cdx paralogues have acquired distinct regulatory roles during development. This implies that the degree of functional overlap between paralogues is relatively low and that gene expression pattern alone should be used with caution when investigating the functional evolution of duplicated genes. We therefore suggest that developmental programmes were extensively rewired after whole genome duplication in the early evolution of vertebrates.


Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease.
The sensitivity of assays for antineutrophil cytoplasmic antibody (ANCA), anti-Saccharomyces cerevisiae antibody (ASCA), and antipancreatic antibody (PAB) in different laboratories is unknown. Likewise, the sensitivity and diagnostic usefulness of these assays in patients with inflammatory bowel disease (IBD) in the community is unknown. An incidence cohort of 290 patients with IBD were offered participation in the study. Blood was obtained from 162 patients (56%) (83 with ulcerative colitis, 79 with Crohn's disease) who agreed to participate. ANCA was determined in five laboratories. ASCA in two laboratories, and PAB in one laboratory. In ulcerative colitis, the sensitivity of ANCA determined in five laboratories varied widely, ranging from 0-63%. In Crohn's disease, the sensitivity of ASCA determined in two laboratories did not vary significantly, ranging from 39-44%; and the sensitivity of PAB determined in one laboratory was 15%. The optimal diagnostic usefulness was obtained from one laboratory where the positive predictive values of a positive ANCA assay combined with a negative ASCA assay for ulcerative colitis, and a negative ANCA combined with a positive ASCA for Crohn's disease, were 75% and 86%, respectively. In patients with IBD, the sensitivity of ANCA varied widely in different laboratories, whereas the prevalence of ASCA was similar. The positive predictive values of the ANCA assay combined with the ASCA assay for ulcerative colitis and Crohn's disease are high enough to be clinically useful.


Progress of negative symptoms over the initial 5 years of a first episode of psychosis.
Specialized early intervention (EI) following a first episode of psychosis (FEP) are effective at reducing negative symptoms, although its trajectory warrants systematic assessment. However, findings are equivocal as to whether extended gains are made post 2 years of EI and whether there is additional benefit of extending EI for an additional 3 years. Data on 178 FEP patients, from a randomized controlled trial of a 3-year extension of EI service v. transfer to regular care following 2 years of EI service, were used for this report. Repeated measures analysis of variance were conducted separately for the initial 2 years of treatment in an EI service, and for the 3-year post-randomization to examine trajectories of negative symptoms over the two periods in the two arms of the study. There were significant improvements in total negative symptoms over the first 2 years of EI F(4.612, 797.905) = 25.263, p < 0.001 and in domains of 'expressivity' and 'motivation'. In the following 3 years, there were further significant improvements in negative symptoms F(4.318, 759.908) = 4.182, p = 0.002 with no difference between groups F(4.318, 759.908) = 1.073, p = 0.371. Changes in negative symptoms over the extension period were driven by expressivity F(4.01, 674.73) = 7.19, p < 0.01, but not motivation F(6.58, 1112.18) = 0.95, p = 0.46. Negative symptoms improve significantly over the first 2 years of EI. Subsequent amelioration was largely the result of expressivity. Motivation deficits remained stable. Extended EI offered no advantage over regular care post-randomization.


Neighbourhood walkability and incidence of hypertension: Findings from the study of 429,334 UK Biobank participants.
With an estimated one billion hypertension cases worldwide, the role of the built environment in its prevention and control is still uncertain. The present study aims to examine the associations between neighbourhood walkability and hypertension in a large and diverse population-based cohort. We examined the association between neighbourhood walkability and blood pressure outcomes for N = 429,334 participants drawn from the UK Biobank and aged 38-73 years. Neighbourhood walkability was objectively modelled from detailed building footprint-level data within multi-scale functional neighbourhoods (1.0-, 1.5- and 2.0-kilometer street catchments of geocoded dwelling). A series of linear and modified Poisson regression models were employed to examine the association between walkability and outcomes of diastolic blood pressure (DBP in mmHg), systolic blood pressure (SBP in mmHg) and prevalent hypertension adjusting for socio-demographic, lifestyle and related physical environmental covariates. We also examined the relationship between walkability and change in blood pressure for a sub-sample of participants with follow-up data and tested for interaction effects of age, sex, employment status, neighbourhood SES, residential density and green exposure. Neighbourhood walkability within one-kilometer street catchment was beneficially associated with all the three blood pressure outcomes, independent of all other factors. Each interquartile increment in walkability was associated with the lower blood pressure outcomes of DBP (β = -0.358, 95% CI: -0.42, -0.29 mmHg), SBP (β = -0.833, 95% CI: -0.95, -0.72 mmHg) as well as reduced hypertension risk (RR = 0.970, 95% CI: 0.96, 0.98). The results remained consistent across spatial and temporal scales and were sensitive to sub-groups, with pronounced protective effects among female participants, those aged between 50 and 60 years, in employment, residing in deprived, high density and greener areas. This large population-based cohort found evidence of protective association between neighbourhood walkability and blood pressure outcomes. Given the enduring public health impact of community design on individual behaviour and lifestyle, of particular interest, are the targetted upstream-level interventions in city design aimed at optimizing walkability. Further long term studies are required to assess its sustained effects upon hypertension prevention and control.


Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy.
Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to co-administration of ceftriaxone- and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an "unknown" material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 μm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.


Crystal structure of cold compressed graphite.
Through a systematic structural search we found an allotrope of carbon with Cmmm symmetry which we predict to be more stable than graphite for pressures above 10 GPa. This material, which we refer to as Z-carbon, is formed by pure sp(3) bonds and it provides an explanation to several features in experimental x-ray diffraction and Raman spectra of graphite under pressure. The transition from graphite to Z-carbon can occur through simple sliding and buckling of graphene sheets. Our calculations predict that Z-carbon is a transparent wide band-gap semiconductor with a hardness comparable to diamond.


Apolipoprotein E: depressive illness, depressive symptoms, and Alzheimer's disease.
The apolipoprotein E (ApoE) epsilon 4 and epsilon 2 alleles may influence the age of onset of depressive illness. Depressive illness of late onset is also a risk factor for Alzheimer's disease (AD), and there is some evidence that the ApoE epsilon 2 allele is associated with depressive symptomatology in AD. Depressive symptomatology in AD may thus share common genetic risk factors with late-onset depressive illness. The frequency of the epsilon 2 and epsilon 4 alleles of ApoE and their effects on age of onset of disease in three independent groups of subjects, with depressive illness, with AD, and controls, were compared in a defined population from Southeast London. The frequency of the ApoE epsilon 2 allele was significantly lower in the depressive illness group compared with the control group and was associated with a later mean age at onset. Subjects with depressive symptomatology in AD had a higher frequency of the ApoE epsilon 2 allele and had a significantly later age of onset of depressive illness compared with the nondepressed AD group. The presence of the ApoE epsilon 2 allele in AD is found to be highly associated with depressive symptomatology, and it is proposed that this subgroup represents the presence of delayed depressive illness and that there are common genetic risk factors between AD and depressive illness.


Residual strain in rat left ventricle.
Residual stress in an organ is defined as the stress that remains when all external loads are removed. Residual stress has generally been ignored in published papers on left ventricular wall stress. To take residual stress into account in the analysis of stress distributions in a beating heart, one must first measure the residual strain in the no-load state of the heart. Residual strains in equatorial cross-sectional rings (2-3 mm thick) of five potassium-arrested rat left ventricles were measured. The effects of friction and external loading were reduced by submersing the specimen in fluid, and a hypothermic, hyperkalemic arresting solution containing nifedipine and EGTA was used to delay the onset of ischemic contracture. Stainless steel microspheres (60-100 microns) were lightly imbedded on the surface of the slices, and the coordinates of the microspheres were digitized from photographs taken before and after a radial cut was made through the left ventricular free wall. Two-dimensional strains computed from the deformation of a slice after one radial cut were defined as the residual strains in that slice. It was found that the distributions of the principal residual stretch ratios were asymmetric with respect to the radial cut: in areas where substantial transmural strain gradients existed, the distributions of strain components were different on the two sides of the radial cut. A second radial cut produced deformations significantly smaller than those produced from the first radial cut. Hence, a slice with one radial cut may be considered stress free.(ABSTRACT TRUNCATED AT 250 WORDS)


Emerging therapies for the treatment of relapsed or refractory follicular lymphoma.
With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.


The effect of acute smoking on spinal fusion: an experimental study among rabbits.
The establishment of an environment to force animals to inspire cigarette smoke is mandatory to study the true effects of smoking. This model has been used to study long-bone healing but has not yet been used to study spinal fusion. Forty male rabbits were divided into four equal groups. All the animals underwent bilateral intertransverse-process fusion at L5-L6 using the 1995 fusion model of Boden et al. The first (C8-week) group did not undergo cigarette smoke inhalation and individual rabbits were killed at 8 weeks; the second (S8-week) group underwent intermittent cigarette smoke inhalation and individual rabbits were killed at 8 weeks; the third (C6-week) group did not undergo cigarette smoke inhalation, and animals were killed at 6 weeks; and the fourth (S6-week) group underwent intermittent smoke inhalation and group-included rabbits were killed at 6 weeks. Subsequent to the animals having been killed, the fusion masses were harvested for a series of studies including manual palpation, biomechanical testing, radiographic examination, and histologic analysis. Six rabbits died shortly after the operation. Of the remaining 34 rabbits, the lumbar spine specimen was harvested for study. Manual palpation, radiographic examination, and histologic analysis of the fusion masses revealed no statistically significant difference in fusion results between the control and the corresponding smoking group killed at either 8 weeks or 6 weeks. Biomechanical testing of the fusion masses also revealed no statistically significant difference in fusion results between the control and the smoking group killed at 8 weeks, although it did indicate that smoking resulted in a 44% decrease in mean flexion stiffness and a 32% decrease in mean extension stiffness among the animals killed at 6 weeks. The former (decrease in flexion stiffness) was statistically significant (p < 0.05). The results of the biomechanical testing conducted as a part of the current study demonstrate that acute cigarette smoke inhalation delays but does not prevent the spinal fusion process for rabbits.


αβ'-NAC cooperates with Sam37 to mediate early stages of mitochondrial protein import.
The mitochondrial proteome is mostly composed of nuclear-encoded proteins. Such polypeptides are synthesized with signals that guide their intracellular transport to the surface of the organelle and later within the different mitochondrial subcompartments until they reach their functional destination. It has been suggested that the nascent-polypeptide associated complex (NAC) - a cytosolic chaperone that recognizes nascent chains on translationally active ribosomes - has a role in the import of nuclear-encoded mitochondrial proteins. However, the molecular mechanisms that regulate the NAC-mediated cotranslational import are still not clear. Here, we show that a particular NAC heterodimer formed by subunits α and β' in Saccharomyces cerevisiae is specifically involved in the process of mitochondrial import and functionally cooperates with Sam37, an outer membrane protein subunit of the sorting and assembly machinery complex. Mutants in both components display growth defects, incorrectly accumulate precursor forms of mitochondrial proteins in the cytosol, and have an altered mitochondrial protein content. We propose that αβ'-NAC and Sam37 are members of the system that recognizes mitochondrial proteins at early stages of their synthesis, escorting them to the import machinery of mitochondria.


Patients' rights in England and the United States of America: The Patient's Charter and the New Jersey Patient Bill of Rights: a comparison.
The Patient's Charter has been in effect for nearly five years. This article considers the purpose and value of the document through a comparison with the New Jersey Patient Bill of Rights. Patient rights statements have been posted in American hospitals for more than twenty years. However, the New Jersey document and the patient rights programme it established seven years ago, have proven to be economically effective, successful in their representation of patients and enforceable, due to the adoption of state legislation and regulation to oversee the process. Several examples of how the programme works are included in the comparison, with a similar review of The Patient's Charter. In the comparison the author argues that for the programme to succeed as it has done in New Jersey, the government will need to develop legislative backing to ensure enforcement, and an efficient system for monitoring compliance. The programme will need to become credible in the eyes of the health service user. The author suggests this may be best achieved by developing an efficient, accessible and user-friendly means of redress, should the patient consider his or her rights have been violated. A "mish-mash" of quality assurance standards and levels of care which patients can "expect" from the health service providers only serves to distract the health service user from the government's failure to commit the resources that would empower the patients rights portion of The Patient's Charter.


Cell-Wall-Targeting Antibiotics Cause Lag-Phase Bacteria to Form Surface-Mediated Filaments Promoting the Formation of Biofilms and Aggregates.
Antibiotics are known to promote bacterial formation of enhanced biofilms, the mechanism of which is not well understood. Here, using biolayer interferometry, we have shown that bacterial cultures containing antibiotics that target cell walls cause biomass deposition on surfaces over time with a linear profile rather than the Langmuir-like profiles exhibited by bacterial adherence in the absence of antibiotics. We observed about three times the initial rate and 12 times the final biomass deposition on surfaces for cultures containing carbenicillin than without. Unexpectedly, in the presence of antibiotics, the rate of biomass deposition inversely correlated with bacterial densities from different stages of a culture. Detailed studies revealed that carbenicillin caused faster growth of filaments that were seeded on surfaces from young bacteria (from lag phase) than those from high-density fast-growing bacteria, with rates of filament elongation of about 0.58 and 0.13 μm min-1 , respectively. With surfaces that do not support bacterial adherence, few filaments were observed even in solution. These filaments aggregated in solution and formed increased amounts of biofilms on surfaces. These results reveal the lifestyle of antibiotic-induced filamentous bacteria, as well as one way in which the antibiotics promote biofilm formation.


Plasma Lactate Levels Increase during Hyperinsulinemic Euglycemic Clamp and Oral Glucose Tolerance Test.
Insulin resistance, which plays a central role in the pathogenesis of type 2 diabetes (T2D), is an early indicator that heralds the occurrence of T2D. It is imperative to understand the metabolic changes that occur at the cellular level in the early stages of insulin resistance. The objective of this study was to determine the pattern of circulating lactate levels during oral glucose tolerance test (OGTT) and hyperinsulinemic euglycemic clamp (HIEC) study in normal nondiabetic subjects. Lactate and glycerol were determined every 30 minutes during OGTT and HIEC on 22 participants. Lactate progressively increased throughout the HIEC study period (P < 0.001). Participants with BMI < 30 had significantly higher mean M-values compared to those with BMI ≥ 30 at baseline (P < 0.05). This trend also continued throughout the OGTT. In addition, those with impaired glucose tolerance test (IGT) had significantly higher mean lactate levels compared to those with normal glucose tolerance (P < 0.001). In conclusion, we found that lactate increased during HIEC study, which is a state of hyperinsulinemia similar to the metabolic milieu seen during the early stages in the development of T2D.


Estimates for energy expenditure in free-living animals using acceleration proxies: A reappraisal.
It is fundamentally important for many animal ecologists to quantify the costs of animal activities, although it is not straightforward to do so. The recording of triaxial acceleration by animal-attached devices has been proposed as a way forward for this, with the specific suggestion that dynamic body acceleration (DBA) be used as a proxy for movement-based power. Dynamic body acceleration has now been validated frequently, both in the laboratory and in the field, although the literature still shows that some aspects of DBA theory and practice are misunderstood. Here, we examine the theory behind DBA and employ modelling approaches to assess factors that affect the link between DBA and energy expenditure, from the deployment of the tag, through to the calibration of DBA with energy use in laboratory and field settings. Using data from a range of species and movement modes, we illustrate that vectorial and additive DBA metrics are proportional to each other. Either can be used as a proxy for energy and summed to estimate total energy expended over a given period, or divided by time to give a proxy for movement-related metabolic power. Nonetheless, we highlight how the ability of DBA to predict metabolic rate declines as the contribution of non-movement-related factors, such as heat production, increases. Overall, DBA seems to be a substantive proxy for movement-based power but consideration of other movement-related metrics, such as the static body acceleration and the rate of change of body pitch and roll, may enable researchers to refine movement-based metabolic costs, particularly in animals where movement is not characterized by marked changes in body acceleration.


Reconstructing Past Admixture Processes from Local Genomic Ancestry Using Wavelet Transformation.
Admixture between long-separated populations is a defining feature of the genomes of many species. The mosaic block structure of admixed genomes can provide information about past contact events, including the time and extent of admixture. Here, we describe an improved wavelet-based technique that better characterizes ancestry block structure from observed genomic patterns. principal components analysis is first applied to genomic data to identify the primary population structure, followed by wavelet decomposition to develop a new characterization of local ancestry information along the chromosomes. For testing purposes, this method is applied to human genome-wide genotype data from Indonesia, as well as virtual genetic data generated using genome-scale sequential coalescent simulations under a wide range of admixture scenarios. Time of admixture is inferred using an approximate Bayesian computation framework, providing robust estimates of both admixture times and their associated levels of uncertainty. Crucially, we demonstrate that this revised wavelet approach, which we have released as the R package adwave, provides improved statistical power over existing wavelet-based techniques and can be used to address a broad range of admixture questions.


The plasmid-encoded urease gene cluster of the family Enterobacteriaceae is positively regulated by UreR, a member of the AraC family of transcriptional activators.
Ureolytic clinical isolates of Providencia stuartii, Salmonella spp., and some Escherichia coli strains contain large urease-encoding plasmids. Expression of urease activity from these isolates is induced at least 20-fold by urea. In order to facilitate studies on the regulatory mechanism controlling this urea-inducible expression, the plasmid-encoded urease genes were inserted into the low-copy-number vector pRK415, to form pSEF70. Deletion mutagenesis of pSEF70 demonstrated that between 1.3 and 1.6 kb of DNA upstream of ureD (the first of seven urease genes clustered in an operon-like fashion) was required for a urease-positive phenotype. An open reading frame coding for a 34.1-kDa polypeptide was found in the DNA sequence of this upstream region. This open reading frame has been designated ureR, for urease regulator. A urea-inducible promoter region was identified upstream of ureD. Transcription from this promoter was activated only when ureR was present in trans. The predicted ureR gene product contains a helix-turn-helix motif and shows significant amino acid similarity to the AraC family of transcriptional activators. We conclude that urea-dependent expression from the plasmid-encoded urease gene cluster requires ureR and that ureR codes for a positive regulatory element controlling transcription of at least one essential urease gene, ureD.


A consensus statement of the Society of Thoracic Radiology: screening for lung cancer with helical computed tomography.
This consensus statement by the Society of Thoracic Radiology is a summary of the current understanding of low dose computed tomography (CT) for screening for lung cancer. Lung cancer is the most common fatal malignancy in the industrialized world. Unlike the next three most common cancers, screening for lung cancer is not currently recommended by cancer organizations. Improvements in CT technology make lung screening feasible. Early prevalence data indicate that about two-thirds of lung cancers that are detected by CT screening are at an early stage. Other data support the postulate that patients with lung cancers detected at this early stage have better rates of survival. Whether this will translate into an improved disease specific mortality is yet to be demonstrated. The suggested technical protocols, selection criteria, and method of handling the numerous benign nodules that are detected are discussed. It is the consensus of this committee that mass screening for lung cancer with CT is not currently advocated. Suitable subjects who wish to participate should be encouraged to do so in controlled trials, so that the value of CT screening can be ascertained as soon as possible.


Learning Control Over Emotion Networks Through Connectivity-Based Neurofeedback.
Most mental functions are associated with dynamic interactions within functional brain networks. Thus, training individuals to alter functional brain networks might provide novel and powerful means to improve cognitive performance and emotions. Using a novel connectivity-neurofeedback approach based on functional magnetic resonance imaging (fMRI), we show for the first time that participants can learn to change functional brain networks. Specifically, we taught participants control over a key component of the emotion regulation network, in that they learned to increase top-down connectivity from the dorsomedial prefrontal cortex, which is involved in cognitive control, onto the amygdala, which is involved in emotion processing. After training, participants successfully self-regulated the top-down connectivity between these brain areas even without neurofeedback, and this was associated with concomitant increases in subjective valence ratings of emotional stimuli of the participants. Connectivity-based neurofeedback goes beyond previous neurofeedback approaches, which were limited to training localized activity within a brain region. It allows to noninvasively and nonpharmacologically change interconnected functional brain networks directly, thereby resulting in specific behavioral changes. Our results demonstrate that connectivity-based neurofeedback training of emotion regulation networks enhances emotion regulation capabilities. This approach can potentially lead to powerful therapeutic emotion regulation protocols for neuropsychiatric disorders.


Can artificial intelligence reduce the interval cancer rate in mammography screening?
To investigate whether artificial intelligence (AI) can reduce interval cancer in mammography screening. Preceding screening mammograms of 429 consecutive women diagnosed with interval cancer in Southern Sweden between 2013 and 2017 were analysed with a deep learning-based AI system. The system assigns a risk score from 1 to 10. Two experienced breast radiologists reviewed and classified the cases in consensus as true negative, minimal signs or false negative and assessed whether the AI system correctly localised the cancer. The potential reduction of interval cancer was calculated at different risk score thresholds corresponding to approximately 10%, 4% and 1% recall rates. A statistically significant correlation between interval cancer classification groups and AI risk score was observed (p < .0001). AI scored one in three (143/429) interval cancer with risk score 10, of which 67% (96/143) were either classified as minimal signs or false negative. Of these, 58% (83/143) were correctly located by AI, and could therefore potentially be detected at screening with the aid of AI, resulting in a 19.3% (95% CI 15.9-23.4) reduction of interval cancer. At 4% and 1% recall thresholds, the reduction of interval cancer was 11.2% (95% CI 8.5-14.5) and 4.7% (95% CI 3.0-7.1). The corresponding reduction of interval cancer with grave outcome (women who died or with stage IV disease) at risk score 10 was 23% (8/35; 95% CI 12-39). The use of AI in screen reading has the potential to reduce the rate of interval cancer without supplementary screening modalities. • Retrospective study showed that AI detected 19% of interval cancer at the preceding screening exam that in addition showed at least minimal signs of malignancy. Importantly, these were correctly localised by AI, thus obviating supplementary screening modalities. • AI could potentially reduce a proportion of particularly aggressive interval cancers. • There was a correlation between AI risk score and interval cancer classified as true negative, minimal signs or false negative.


Local destabilization of the metal-binding region in human copper-zinc superoxide dismutase by remote mutations is a possible determinant for progression of ALS.
More than 100 distinct mutations in the gene CuZnSOD encoding human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS), a fatal neuronal disease. Many studies of different mutant proteins have found effects on protein stability, catalytic activity, and metal binding, but without a common pattern. Notably, these studies were often performed under conditions far from physiological. Here, we have used experimental conditions of pH 7 and 37 °C and at an ionic strength of 0.2 M to mimic physiological conditions as close as possible in a sample of pure protein. Thus, by using NMR spectroscopy, we have analyzed amide hydrogen exchange of the fALS-associated I113T CuZnSOD variant in its fully metalated state, both at 25 and 37 °C, where (15)N relaxation data, as expected, reveals that CuZnSOD I113T exists as a dimer under these conditions. The local dynamics at 82% of all residues have been analyzed in detail. When compared to the wild-type protein, it was found that I113T CuZnSOD is particularly destabilized locally at the ion binding sites of loop 4, the zinc binding loop, which results in frequent exposure of the aggregation prone outer β-strands I and VI of the β-barrel, possibly enabling fibril or aggregate formation. A similar study (Museth, A. K., et al. (2009) Biochemistry, 48, 8817-8829) of amide hydrogen exchange at pH 7 and 25 °C on the G93A variant also revealed a selective destabilization of the zinc binding loop. Thus, a possible scenario in ALS is that elevated local dynamics at the metal binding region can result in toxic species from formation of new interactions at local β-strands.


170H-progesterone rhythms in congenital adrenal hyperplasia.
Serial blood spot and saliva samples were collected at home by 18 patients being treated for congenital adrenal hyperplasia to determine the circadian rhythm of 170H-progesterone as an index of therapeutic control. There was a strong correlation between the magnitude of the circadian fall and a single morning measurement of the plasma testosterone concentration taken near the time of the 170H-progesterone rhythm samples. Poor control in pubertal girls produced an exaggerated circadian fall in 170H-progesterone concentrations that were raised at all sampling times. Optimal control (plasma testosterone 1.5-2.5 nmol/l) was associated with blood spot and salivary 170H-progesterone concentrations at 0800 hours of between 30-70 nmol/l and 260-1000 pmol/l, respectively, falling thereafter to less than 10 nmol/l and less than 150 pmol/l, respectively. Similar results were obtained in prepubertal patients. Nomograms have been constructed to interpret the daily profiles of blood spot or salivary measurements of 170H-progesterone, or both. The analysis of 170H-progesterone circadian rhythms is useful in monitoring treatment in patients with congenital adrenal hyperplasia, particularly those who may be overtreated.


Predicting and understanding collagen remodeling in human native heart valves during early development.
The hemodynamic functionality of heart valves strongly depends on the distribution of collagen fibers, which are their main load-bearing constituents. It is known that collagen networks remodel in response to mechanical stimuli. Yet, the complex interplay between external load and collagen remodeling is poorly understood. In this study, we adopted a computational approach to simulate collagen remodeling occurring in native fetal and pediatric heart valves. The computational model accounted for several biological phenomena: cellular (re)orientation in response to both mechanical stimuli and topographical cues provided by collagen fibers; collagen deposition and traction forces along the main cellular direction; collagen degradation decreasing with stretch; and cell-mediated collagen prestretch. Importantly, the computational results were well in agreement with previous experimental data for all simulated heart valves. Simulations performed by varying some of the computational parameters suggest that cellular forces and (re)orientation in response to mechanical stimuli may be fundamental mechanisms for the emergence of the circumferential collagen alignment usually observed in native heart valves. On the other hand, the tendency of cells to coalign with collagen fibers is essential to maintain and reinforce that circumferential alignment during development. STATEMENT OF SIGNIFICANCE: The hemodynamic functionality of heart valves is strongly influenced by the alignment of load-bearing collagen fibers. Currently, the mechanisms that are responsible for the development of the circumferential collagen alignment in native heart valves are not fully understood. In the present study, cell-mediated remodeling of native human heart valves during early development was computationally simulated to understand the impact of individual mechanisms on collagen alignment. Our simulations successfully predicted the degree of collagen alignment observed in native fetal and pediatric semilunar valves. The computational results suggest that the circumferential collagen alignment arises from cell traction and cellular (re)orientation in response to mechanical stimuli, and with increasing age is reinforced by the tendency of cells to co-align with pre-existing collagen fibers.


Komodo dragons are not ecological analogs of apex mammalian predators.
Apex predators can have substantial and complex ecological roles in ecosystems. However, differences in species-specific traits, population densities, and interspecific interactions are likely to determine the strength of apex predators' roles. Here we report complementary studies examining how interactions between predator per capita metabolic rate and population density influenced the biomass, population energy use, and ecological effects of apex predators on their large mammalian prey. We first investigated how large mammal prey resources and field metabolic rates of terrestrial apex predators, comprising large mammals and the Komodo dragon (Varanus komodoensis), influenced their biomass densities and population energy use requirements. We next evaluated whether Komodo dragons, like apex mammalian predators, exerted top-down regulation of their large mammal prey. Comparison of results from field studies demonstrates that Komodo dragons attain mean population biomass densities that are 5.75-231.82 times higher than that of apex mammalian predator species and their guilds in Africa, Asia, and North America. The high biomass of Komodo dragons resulted in 1.96-108.12 times greater population energy use than that of apex mammalian predators. Nevertheless, substantial temporal and spatial variation in Komodo dragon population energy use did not regulate the population growth rates of either of two large mammal prey species, rusa deer (Rusa timorensis) and wild pig (Sus scrofa). We suggest that multiple processes weaken the capacity of Komodo dragons to regulate large mammal prey populations. For example, a low per capita metabolic rate requiring an infrequent and inactive hunting strategy (including scavenging), would minimize lethal and nonlethal impacts on prey populations. We conclude that Komodo dragons differ in their predatory role from, including not being the ecological analogs of, apex mammalian predators.


Understanding attitudes toward people with Down syndrome.
Understanding attitudes of the public toward people with Down syndrome is important because negative attitudes might create barriers to social integration, which can affect their success and quality of life. We used data from two 2008 U.S. surveys (HealthStyles(c) survey of adults 18 years or older and YouthStyles(c) survey of youth ages 9-18) that asked about attitudes toward people with Down syndrome, including attitudes toward educational and occupational inclusion and toward willingness to interact with people with Down syndrome. Results showed that many adults continue to hold negative attitudes toward people with Down syndrome: A quarter of respondents agreed that students with Down syndrome should go to special schools, nearly 30% agreed that including students with Down syndrome in typical educational settings is distracting, and 18% agreed that persons with Down syndrome in the workplace increase the chance for accidents. Negative attitudes were also held by many youth: 30% agreed that students with Down syndrome should go to separate schools, 27% were not willing to work with a student with Down syndrome on a class project, and nearly 40% indicated they would not be willing to spend time with a student with Down syndrome outside of school. Among both adult and youth, female sex and respondents with previous relationships with people with Down syndrome were consistently associated with more positive attitudes. These results may be helpful in the development of educational materials about Down syndrome and in guiding policies on educational and occupational inclusion.


Split-face comparison of ultrapulse-mode and superpulse-mode fractionated carbon dioxide lasers on photoaged skin.
Both ultrapulse-mode and superpulse-mode fractional CO2 lasers (UPCO2 and SPCO2) could be successfully used in treating photoaged skin. This evidence-based study was intended to compare the therapeutic and adverse effects of UPCO2 and SPCO2 in treating photoaged skin in Chinese subjects. Eighteen Chinese subjects with Fitzpatrick skin type IV were enrolled in a randomized, split-face trial. Subjects received SPCO2 on one half of the face and UPCO2 on the other half. Before and after photos, skin color, epidermal water content, sebum level, periorbital wrinkles, skin roughness, and self-esteem questionnaires were used. Global evaluation and subjects' self-esteem assessments showed a similar trend at 1-month and 3-month follow-up visits on both sides. The UPCO2 laser has a shorter downtime of 6.25±2.71 days compared with 6.41±2.67 days for SPCO2, but has a higher incidence of edema, spot bleeding, prolonged redness and postinflammatory hyperpigmentation. More subjects prefer SPCO2 treatment because of similar efficacy and fewer adverse effects. The effectiveness of the SPCO2 laser in treating photoaged skin is very similar to the UPCO2 laser, with less erythema, but more crusting and longer downtime.


Gastric mill activity in the lobster. III. Effects of proctolin on the isolated central pattern generator.
1. The response of the isolated gastric central pattern generator (CPG) to bath application of proctolin is characterized and compared with the previously analyzed behavioral response. 2. Proctolin had an excitatory effect on the ongoing spontaneous rhythm of "combined" preparations, in which the stomatogastric ganglion (STG) is connected to the esophageal and commissural ganglia by the stomatogastric nerve (STN). The effect started between 20 s and 5 min and was characterized by strongly increased burst durations as well as increased spike rates in all units except the two lateral posterior gastric (LPG) motoneurons. The effect was strongest in the dorsal gastric (DG) and lateral gastric (LG) motoneurons and was accompanied by a phase change of the DG burst. DG continued spiking throughout large parts of the burst of LG and of the gastric mill (GM) motoneurons, which are antagonists of DG. 3. The threshold concentration was approximately 10(-10) M, and the effects were dose dependent and reversible. 4. LG and DG were identified as target cells for the action of proctolin. In LG regenerative plateau properties were induced, as revealed by its long-lasting plateau potentials, sensitivity for triggering inputs, and the occurrence of oscillatory prepotentials. An induction of endogenous bursting in DG was concluded from preparations, in which DG was cycling alone or bursting with a much shorter period duration than other gastric neurons. Hyperpolarization of DG, which normally has no or weak driving power within the gastric network, demonstrated that under the influence of proctolin, firing of DG can accelerate the gastric rhythm from a 27- to a 9-s period duration. 5. Proctolin does not only have a modulatory influence on an ongoing rhythm, but it also can trigger gastric activity. This function was first concluded from proctolin-treated STGs, which, unlike normal preparations, continue bursting if inputs via the STN are blocked. Finally, triggering was demonstrated directly, since isolated STGs that were not oscillating started a gastric rhythm after 20-30 min of perfusion with proctolin. 6. The proctolin-induced changes of the CPG activity in isolated preparations are in agreement with the effect on gastric mill chewing in the intact animal, in which, depending on the dose, different modes of chewing could be elicited.


[Autoimmune processes in diseases of the thyroid gland].
The previous knowledge related to auto-immune occurrences in thyroid gland disease are described in the review, showing main antigens, auto-antibodies, the inclusion of humoral and cellular immunity in the most frequent thyroid gland diseases. In spite of many learnings, which are broadened every day, the exact sequence of events and roles of external factors in genetically predisposed persons is still unknown. An identification of auto-antibodies gives direct evidence about the auto-immune process, as they are present among the majority of patients with Graves' hyperthyroid and Hashimoto's thyroiditis. Immuno globulins, created by plasma cells, linked with cytokinins from lymphocyte CD4 T, engage the cell auto-immune reaction in these diseases. Being acquainted with all events in the auto-immune process, we can understand better why these frequent diseases occur, why do they have chronic and recidivous course, why they are more frequent with women and within some families, and why they enable us to make a better diagnosis and treatment of these patients.


Assessment of oral health related quality of life.
In Dentistry, as in other branches of Medicine, it has been recognised that objective measures of disease provide little insight into the impact of oral disorders on daily living and quality of life. A significant body of development work has been undertaken to provide health status measures for use as outcome measures in dentistry. In descriptive population studies, poor oral health related quality of life is associated with tooth loss. There is a less extensive literature of longitudinal clinical trials, and measurement of change and interpretation of change scores continues to pose a challenge. This paper reviews the literature regarding the development and use of these oral health related QoL measures and includes an appraisal of future research needs in this area.


COMT genotype influences prefrontal response to emotional distraction.
Early studies of genetic effects on brain activity have been conducted to investigate primarily either the influence of polymorphisms in dopaminergic genes, especially the catechol-O-methyltransferase (COMT) gene, on prefrontal cognitive processes such as working memory, or that of polymorphisms in the serotonin transporter gene on the amygdala response to threatening stimuli. Here, we address genetic influences on the neural systems underlying cognitive-affective interactions. Specifically, we assess the effect of the CO MT val158met polymorphism onfrontal regulation of attentionunder emotional distraction. Healthy volunteers were scanned while performing a house-matching task with affectively negative versus neutral distractors. Effects of val allele load were examined on frontal regions associated with attentional control and emotion regulation, and on parahippocampal regions associated with perception of houses. As we predicted, val load correlated positively with activity in control- and task-related regions during performance under emotional distraction. These findings provide an initial step toward identifying genetic contributions to interindividual variability in recruitment of mechanisms that regulate affective processing.


N-acetyl-L-cysteine protects against delta-aminolevulinic acid-induced 8-hydroxydeoxyguanosine formation.
5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in acute intermittent porphyria and lead poisoning. It has been shown that ALA induces free radical generation and may cause damage to proteins and DNA. In the present study, the effects of ALA on DNA damage and its prevention by N-acetyl-L-cysteine (NAC) and the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) are investigated. Oxidative damage to DNA was quantitated by measuring the increase in 8-hydroxy-2'-deoxyguanosine (oh8dG) formation. The time-course study demonstrated that ALA causes a linear increase in oh8dG levels in Chinese hamster ovary (CHO) cells. However, direct lead exposure did not cause any measurable increase in oh8dG levels. In the presence of either NAC (1 mM) or antioxidant enzymes (10 u/ml SOD and 10 u/ml CAT), oh8dG levels returned to the corresponding control levels. This suggests a protective role for NAC and the antioxidant enzymes. To determine the effect of ALA on cell proliferation, cell numbers were counted at the end of 24 h of incubation in the presence and absence of ALA at different concentrations. Results showed that levels of ALA up to 5 mM do not inhibit cell proliferation.


Surface treatment of flexor tendon autografts with carbodiimide-derivatized hyaluronic Acid. An in vivo canine model.
Clinical and experimental studies have demonstrated that restrictive adhesions and poor digital motion are common complications after extrasynovial tendon grafting in an intrasynovial environment. The purpose of this study was to test the hypothesis that surface modification of an extrasynovial tendon with use of a carbodiimide-derivatized hyaluronic acid-gelatin polymer (cd-HA) improves gliding ability and digital function after tendon grafting in a canine model in vivo. The peroneus longus tendons from both hindpaws of twenty-four dogs were harvested and transplanted to replace the flexor digitorum profundus tendons in the second and fifth digits of one forepaw. Prior to grafting, one of the peroneus longus tendons was coated with cd-HA, which consists of 1% hyaluronic acid, 10% gelatin, 0.25% 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), and 0.25% N-hydroxysuccinimide (NHS), while the other was immersed in saline solution only. Eight dogs were killed at one, three, and six weeks. Digital normalized work of flexion, tendon gliding resistance, and hyaluronic acid quantification (with the hyaluronic acid-binding-protein staining technique) were the outcome measures. The normalized work of flexion of the tendons treated with cd-HA was significantly lower than that of the saline-solution-treated controls at each time-point (p < 0.05). The gliding resistance of the cd-HA group was significantly lower than that of the saline-solution group at three and six weeks (p < 0.05). The ratio between the intensity of staining of the cd-HA-treated tendons with that of the saline-solution-treated controls was significantly greater at time-0 than at three or six weeks (p < 0.05), but there was no significant difference between time-0 and one-week values. Treating the surface of an extrasynovial tendon autograft with a carbodiimide-derivatized hyaluronic acid-gelatin polymer decreases digital work of flexion and tendon gliding resistance in this flexor tendon graft model in vivo. cd-HA gelatin may provide surgeons with a new and useful method to improve the quality of tendon graft surgery.


Evolution and phenotypic selection of cancer stem cells.
Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behavior. Transformation into cancer cells will inherit these kinetics that determine initial cell and tumor population progression dynamics. Subject to genetic mutation and epigenetic alterations, cancer cell kinetics can change, and favorable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. We set out to investigate the emerging intratumoral heterogeneity and to determine the evolutionary trajectories of the combination of cell-intrinsic kinetics that yield aggressive tumor growth. We develop a cellular automaton model that tracks the temporal evolution of the malignant subpopulation of so-called cancer stem cells(CSC), as these cells are exclusively able to initiate and sustain tumors. We explore orthogonal cell traits, including cell migration to facilitate invasion, spontaneous cell death due to genetic drift after accumulation of irreversible deleterious mutations, symmetric cancer stem cell division that increases the cancer stem cell pool, and telomere length and erosion as a mitotic counter for inherited non-stem cancer cell proliferation potential. Our study suggests that cell proliferation potential is the strongest modulator of tumor growth. Early increase in proliferation potential yields larger populations of non-stem cancer cells(CC) that compete with CSC and thus inhibit CSC division while a reduction in proliferation potential loosens such inhibition and facilitates frequent CSC division. The sub-population of cancer stem cells in itself becomes highly heterogeneous dictating population level dynamics that vary from long-term dormancy to aggressive progression. Our study suggests that the clonal diversity that is captured in single tumor biopsy samples represents only a small proportion of the total number of phenotypes.


The shared signal hypothesis and neural responses to expressions and gaze in infants and adults.
Event-related potentials were recorded from adults and 4-month-old infants while they watched pictures of faces that varied in emotional expression (happy and fearful) and in gaze direction (direct or averted). Results indicate that emotional expression is temporally independent of gaze direction processing at early stages of processing, and only become integrated at later latencies. Facial expressions affected the face-sensitive ERP components in both adults (N170) and infants (N290 and P400), while gaze direction and the interaction between facial expression and gaze affected the posterior channels in adults and the frontocentral channels in infants. Specifically, in adults, this interaction reflected a greater responsiveness to fearful expressions with averted gaze (avoidance-oriented emotion), and to happy faces with direct gaze (approach-oriented emotions). In infants, a larger activation to a happy expression at the frontocentral negative component (Nc) was found, and planned comparisons showed that it was due to the direct gaze condition. Taken together, these results support the shared signal hypothesis in adults, but only to a lesser extent in infants, suggesting that experience could play an important role.


Evaluation of absolute serum α-fetoprotein levels in liver transplant for hepatocellular cancer.
An elevated serum α-fetoprotein (AFP) level before orthotopic liver transplant (OLT) is predictive of mortality after OLT for hepatocellular carcinoma (HCC). Retrospective analysis of a population-based cohort. United Network for Organ Sharing registry (2003-2008). We identified 2253 patients who underwent OLT for HCC with available pre-OLT serum AFP values. Patients were stratified by AFP levels into low (<20 ng/mL), medium (20-399 ng/mL), or high (≥400 ng/mL) groups. Clinical and pathological characteristics were compared among groups. Survival curves were constructed by the Kaplan-Meier method, and univariate and multivariate Cox-regression analysis was performed. Of the 2253 patients, 1210 (53.7%), 805 (35.7%), and 238 (10.6%) were in the low, medium, and high AFP groups, respectively. On univariate analysis, the low AFP group demonstrated the best 4-year survival (76%) compared with the medium (65%; P = .001) and high (57%; P < .001) AFP groups. When AFP levels in patients with only stage II HCC underwent assessment, improved survival in the low AFP group was still observed (P < .001). On multivariate analysis, the medium and high AFP groups were associated with higher mortality (hazard ratios, 1.50 [95% confidence interval, 1.19-1.89; P = .001] and 2.11 [1.55-2.88; P < .001], respectively). Serum AFP level is an independent prognostic predictor of outcome after OLT for HCC. The association between serum AFP value and post-OLT survival warrants further investigation to potentially better allocate donor allografts for HCC.


Commodity risk assessment of Acer spp. plants from New Zealand.
The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as 'High risk plants, plant products and other objects'. This Scientific Opinion covers all plant health risks posed by dormant and free of leaves, 1- to 3-year-old bare root plants for planting of Acer spp. imported from New Zealand, taking into account the available scientific information, including the technical information provided by New Zealand. The relevance of an EU-quarantine pest for this opinion was based on evidence that: (i) the pest is present in New Zealand; (ii) Acer spp. are hosts of the pest and (iii) the pest can be associated with the commodity. The relevance for this opinion of any other pest, not regulated in the EU, was based on evidence that: (i) the pest is present in New Zealand; (ii) the pest is absent from the EU; (iii) Acer spp. are hosts of the pest; (iv) the pest can be associated with the commodity and (v) the pest may have an impact and can pose a potential risk for the EU territory. Four pests (Eotetranychus sexmaculatus, Meloidogyne fallax, Oemona hirta and Platypus apicalis) that fulfilled all relevant criteria were selected for further evaluation. For the selected pests, the risk mitigation measures proposed in the technical dossier from New Zealand were evaluated taking into account the possible limiting factors. For the selected pests, an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. Based on the outcome of Expert Knowledge Elicitation, the degree of pest freedom varies among the pests evaluated. The mite, Eotetranychus sexmaculatus, was the pest most likely to cause plants to fail pest freedom status. The Panel is 95% sure that at least 9,240 plants per 10,000 will be free from E. sexmaculatus.


Prognostic factors of differentiated thyroid cancer patients in Hospital Universiti Sains Malaysia.
The aim of this study was to identify the prognostic factors that influence the survival of differentiated thyroid cancer patients treated at Hospital Universiti Sains Malaysia (HUSM). A total of 178 patients diagnosed with and treated for differentiated thyroid cancer in HUSM between January 1974 and July 2003 were included in this retrospective cohort study. The additional follow-up period was one year after the end of the recruitment phase. The data was collected from the medical records of the patients. The overall five- and ten-year relative survivals of differentiated thyroid cancer patients in HUSM were 90.6 percent (95 percent confidence interval [CI] 84.4-94.4) and 85.3 percent (95 percent CI 76.0-91.2), respectively. The significant prognostic factors for differentiated thyroid cancer were age (hazard ratio [HR] 6.9; 95 percent CI 1.7-28.6), loss of appetite (HR 10.9; 95 percent CI 2.7-43.7), tumour size (HR 3.7; 95 percent CI 1.1-13.8), regional recurrences (HR 3.2; 95 percent CI 1.1-9.8), high-risk stage (HR 19.9; 95 percent CI 4.4-90.4), and treatment (HR 0.2; 95 percent CI: 0.1-0.5). The survival rates obtained in this study were slightly lower than other studies but the pattern of survival rates between groups were similar. Prognostic factors identified in this study were similar to those of other studies, suggesting that the experience of HUSM was almost similar with that of other institutions.


Breast tumor developed in a pregnant rat after treatment with the teratogen Cycloheximide.
To describe histochemically and immunohistochemically a breast tumor presented in a pregnant rat given Cycloheximide to examine its teratogenic and embryotoxic effect on the embryos. Cycloheximide was injected in pregnant Wistar rats at a dose of 3 mg/kg.b.w. on both 10th and 11th gestational days. In one of the rats, a large breast tumor developed rapidly. Histochemical staining with Hematoxylin-Eosin and Masson Trichrome and immunohistochemical identification with mouse monoclonal antibodies: a) Estrogen Receptor A and b) Estrogen Receptor B was performed. Analysis with A-receptor and B-receptor showed that the breast tumor which was developed after treatment with Cycloheximide was malignant. Positive immunohistochemical reaction was evident especially with A-receptor indicating the malignancy of the tumor. Cycloheximide is a known toxic and teratogenic agent and potentially a carcinogenic drug. Thus it should be used with extreme caution as a pesticide.


Domesticated animals and human infectious diseases of zoonotic origins: domestication time matters.
The rate of emergence for emerging infectious diseases has increased dramatically over the last century, and research findings have implicated wildlife as an importance source of novel pathogens. However, the role played by domestic animals as amplifiers of pathogens emerging from the wild could also be significant, influencing the human infectious disease transmission cycle. The impact of domestic hosts on human disease emergence should therefore be ascertained. Here, using three independent datasets we showed positive relationships between the time since domestication of the major domesticated mammals and the total number of parasites or infectious diseases they shared with humans. We used network analysis, to better visualize the overall interactions between humans and domestic animals (and amongst animals) and estimate which hosts are potential sources of parasites/pathogens for humans (and for all other hosts) by investigating the network architecture. We used centrality, a measure of the connection amongst each host species (humans and domestic animals) in the network, through the sharing of parasites/pathogens, where a central host (i.e. high value of centrality) is the one that is infected by many parasites/pathogens that infect many other hosts in the network. We showed that domesticated hosts that were associated a long time ago with humans are also the central ones in the network and those that favor parasites/pathogens transmission not only to humans but also to all other domesticated animals. These results urge further investigation of the diversity and origin of the infectious diseases of domesticated animals in their domestication centres and the dispersal routes associated with human activities. Such work may help us to better understand how domesticated animals have bridged the epidemiological gap between humans and wildlife.


A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity.
The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.


What do we know about the neurogenic potential of different stem cell types?
Cell therapies, based on transplantation of immature cells, are being considered as a promising tool in the treatment of neurological disorders. Many efforts are being concentrated on the development of safe and effective stem cell lines. Nevertheless, the neurogenic potential of some cell lines, i.e., the ability to generate mature neurons either in vitro or in vivo, is largely unknown. Recent evidence indicate that this potential might be distinct among different cell lines, therefore limiting their broad use as replacement cells in the central nervous system. Here, we have reviewed the latest advancements regarding the electrophysiological maturation of stem cells, focusing our attention on fetal-derived-, embryonic-, and induced pluripotent stem cells. In summary, a large body of evidence supports the biological safety, high neurogenic potential, and in some diseases probable clinical efficiency related to fetal-derived cells. By contrast, reliable data regarding embryonic and induced pluripotent stem cells are still missing.


Evidence for generalized hyperalgesia in chronic fatigue syndrome: a case control study.
Several studies provided evidence for generalized hyperalgesia in fibromyalgia or whiplash-associated disorders. In chronic fatigue syndrome, however, pain is a frequently reported complaint, but up to now, evidence for generalized hyperalgesia is lacking. The aim of this study is to examine whether the pressure pain thresholds (PPTs) at both symptomatic and asymptomatic sites differ in chronic fatigue syndrome (CFS) patients with chronic pain, compared to healthy controls. Therefore, 30 CFS patients with chronic pain and 30 age- and gender-matched healthy controls indicated on a Margolis Pain Diagram where they felt pain lasting longer than 24 h in the past 4 weeks. After completing a test battery of questionnaires evaluating pain cognitions, functional status and symptomatology, a blinded researcher assessed PPTs bilaterally at seven nonspecific sites on both trunk and extremities. PPTs were compared for the two complete groups. In addition, PPTs of patients and controls who did not report pain in a respective zone were compared. PPTs of the patients were significantly lower (p<0.001) compared to those of the control group, also when pain-free samples per zone were compared (p<0.001). The mean PPT was 3.30 kg/cm2 in all CFS patients and 8.09 kg/cm2 in the controls. No confounding factors responsible for the observed differences, as, e.g., catastrophizing and depression, could be revealed. These findings provide evidence for the existence of hyperalgesia even in asymptomatic areas (generalized secondary hyperalgesia). The generalized hyperalgesia may represent the involvement of a sensitized central nervous system.


Widespread mitochondrial depletion via mitophagy does not compromise necroptosis.
Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.


Toward a critical ethical reflexivity: phenomenology and language in Maurice Merleau-Ponty.
Working within the tradition of continental philosophy, this article argues in favour of a phenomenological understanding of language as a crucial component of bioethical inquiry. The authors challenge the 'commonsense' view of language, in which thinking appears as prior to speaking, and speech the straightforward vehicle of pre-existing thoughts. Drawing on Maurice Merleau-Ponty's (1908-1961) phenomenology of language, the authors claim that thinking takes place in and through the spoken word, in and through embodied language. This view resituates bioethics as a matter of bodies that speak. It also refigures the meaning of ethical self-reflexion, and in so doing offers an alternative view on reflexivity and critique. Referring to the Kantian critical tradition and its reception by Hannah Arendt and Michel Foucault, we advance a position we call 'critical ethical reflexivity'. We contend that Merleau-Ponty's phenomenology of language offers valuable insight into ethical reflexivity and subject formation. Moreover, his understanding of language may foster new qualitative empirical research in bioethics, lead to more nuanced methods for interpreting personal narratives, and promote critical self-reflexion as necessary for bioethical inquiry.


Substrate and metal ion promiscuity in mannosylglycerate synthase.
The enzymatic transfer of the sugar mannose from activated sugar donors is central to the synthesis of a wide range of biologically significant polysaccharides and glycoconjugates. In addition to their importance in cellular biology, mannosyltransferases also provide model systems with which to study catalytic mechanisms of glycosyl transfer. Mannosylglycerate synthase (MGS) catalyzes the synthesis of α-mannosyl-D-glycerate using GDP-mannose as the preferred donor species, a reaction that occurs with a net retention of anomeric configuration. Past work has shown that the Rhodothermus marinus MGS, classified as a GT78 glycosyltransferase, displays a GT-A fold and performs catalysis in a metal ion-dependent manner. MGS shows very unusual metal ion dependences with Mg(2+) and Ca(2+) and, to a lesser extent, Mn(2+), Ni(2+), and Co(2+), thus facilitating catalysis. Here, we probe these dependences through kinetic and calorimetric analyses of wild-type and site-directed variants of the enzyme. Mutation of residues that interact with the guanine base of GDP are correlated with a higher k(cat) value, whereas substitution of His-217, a key component of the metal coordination site, results in a change in metal specificity to Mn(2+). Structural analyses of MGS complexes not only provide insight into metal coordination but also how lactate can function as an alternative acceptor to glycerate. These studies highlight the role of flexible loops in the active center and the subsequent coordination of the divalent metal ion as key factors in MGS catalysis and metal ion dependence. Furthermore, Tyr-220, located on a flexible loop whose conformation is likely influenced by metal binding, also plays a critical role in substrate binding.


Estimating EQ-5D utility values for major health behavioural risk factors in England.
Major behavioural risk factors, namely obesity, alcohol consumption, smoking, lack of fruit and vegetable intake and physical inactivity negatively impact on self-reported quality of life. However, little is known about their impact on preference-based measures of health-related quality of life commonly used to inform economic evaluations. Preference-based health-related quality of life outcomes associated with major behavioural risk factors were estimated using the EuroQol EQ-5D responses of 14 117 participants, aged ≥16 years, in the 2008 Health Survey for England. Multivariable linear regression was used to model the relationship between the five risk factors and EQ-5D utility scores. In addition, logistic regression was used to model their relationship to dichotomous reports of problems for each of the five EQ-5D dimensions. Only one-third of participants had a body mass index within normal range, never drank alcohol, consumed at least five portions of fruit or vegetable/day or exercised regularly, while nearly half of participants were smokers or ex-smokers. In the fully adjusted multivariable analyses, reductions in EQ-5D utility scores (95% CI) of 0.105 (0.072 to 0.137), 0.062 (0.042 to 0.082) and 0.142 (0.129 to 0.155) were estimated for a body mass index ≥40 kg/m(2), heavy smoking (≥20 cigarettes/day) and physical inactivity, respectively. Hazardous alcohol consumption (men >4 and ≤8 units/day; women >3 and ≤6 units/day) and daily fruit and vegetable intake between three and less than five portions were associated with small positive effects on EQ-5D utility scores (p<0.05). The high prevalence and substantial utility loss associated with obesity, smoking and physical inactivity highlight the potential impact that interventions aimed at their prevention or alleviation may have on population health.


Coordination of DNA replication and histone modification by the Rik1-Dos2 complex.
Histone modification marks have an important role in many chromatin processes. During DNA replication, both heterochromatin and euchromatin are disrupted ahead of the replication fork and are then reassembled into their original epigenetic states behind the fork. How histone marks are accurately inherited from generation to generation is still poorly understood. In fission yeast (Schizosaccharomyces pombe), RNA interference (RNAi)-mediated histone methylation is cell cycle regulated. Centromeric repeats are transiently transcribed in the S phase of the cell cycle and are processed into short interfering RNAs (siRNAs) by the complexes RITS (RNA-induced initiation of transcriptional gene silencing) and RDRC (RNA-directed RNA polymerase complex). The small RNAs together with silencing factors-including Dos1 (also known as Clr8 and Raf1), Dos2 (also known as Clr7 and Raf2), Rik1 and Lid2-promote heterochromatic methylation of histone H3 at lysine 9 (H3K9) by a histone methyltransferase, Clr4 (refs 8-13). The methylation of H3K9 provides a binding site for Swi6, a structural and functional homologue of metazoan heterochromatin protein 1 (HP1). Here we characterize a silencing complex in fission yeast that contains Dos2, Rik1, Mms19 and Cdc20 (the catalytic subunit of DNA polymerase-ε). This complex regulates RNA polymerase II (RNA Pol II) activity in heterochromatin and is required for DNA replication and heterochromatin assembly. Our findings provide a molecular link between DNA replication and histone methylation, shedding light on how epigenetic marks are transmitted during each cell cycle.


Cardiac arrest outside and inside hospital in a community: mechanisms behind the differences in outcome and outcome in relation to time of arrest.
The aim was to compare characteristics and outcome after cardiac arrest where cardiopulmonary resuscitation was attempted outside and inside hospital over 12 years. All out-of-hospital cardiac arrests (OHCAs) in Göteborg between 1994 and 2006 and all in-hospital cardiac arrests (IHCAs) in 1 of the city's 2 hospitals for whom the rescue team was called between 1994 and 2006 were included in the survey. The study included 2,984 cases of OHCA and 1,478 cases of IHCA. Patients with OHCA differed from those with an IHCA; they were younger, included fewer women, were less frequently found in ventricular fibrillation, and were treated later. If patients were found in a shockable rhythm, survival to 1 month/discharge was 18% after OHCA and 61% after IHCA (P < .0001). Corresponding values for a nonshockable rhythm were 3% and 21% (P < .0001). Survival was higher on daytime and weekdays as compared with nighttime and weekends after IHCA but not after OHCA. Among patients found in a shockable rhythm, a multivariate analysis considering age, gender, witnessed status, delay to defibrillation, time of day, day of week, and location showed that IHCA was associated with increased survival compared with OHCA (adjusted odds ratio 3.18, 95% CI 2.07-4.88). Compared with OHCA, the survival of patients with IHCA increased 3-fold for shockable rhythm and 7-fold for nonshockable rhythm in our practice setting. If patients were found in a shockable rhythm, the higher survival after IHCA was only partly explained by a shorter treatment delay. The time and day of CA were associated with survival in IHCA but not OHCA.


Machine learning amplifies the effect of parental family history of Alzheimer's disease on list learning strategy.
Identification of preclinical Alzheimer's disease (AD) is an essential first step in developing interventions to prevent or delay disease onset. In this study, we examine the hypothesis that deeper analyses of traditional cognitive tests may be useful in identifying subtle but potentially important learning and memory differences in asymptomatic populations that differ in risk for developing Alzheimer's disease. Subjects included 879 asymptomatic higher-risk persons (middle-aged children of parents with AD) and 355 asymptotic lower-risk persons (middle-aged children of parents without AD). All were administered the Rey Auditory Verbal Learning Test at baseline. Using machine learning approaches, we constructed a new measure that exploited finer differences in memory strategy than previous work focused on serial position and subjective organization. The new measure, based on stochastic gradient descent, provides a greater degree of statistical separation (p = 1.44 × 10-5) than previously observed for asymptomatic family history and non-family history groups, while controlling for apolipoprotein epsilon 4, age, gender, and education level. The results of our machine learning approach support analyzing memory strategy in detail to probe potential disease onset. Such distinct differences may be exploited in asymptomatic middle-aged persons as a potential risk factor for AD.


Atrioventricular Valve Regurgitation in Single Ventricle Heart Disease: A Common Problem Associated With Progressive Deterioration and Mortality.
The Fontan procedure has provided patients with single ventricle physiology extended survival into adulthood and in many cases has improved their quality of life. Atrioventricular valve regurgitation (AVVR) is common in single ventricle patients and is associated with increased risk of mortality. AVVR is more common in patients with a systemic tricuspid or common atrioventricular valve but is generally progressive irrespective of underlying valve morphology. AVVR can be attributable to diverse structural and functional abnormalities at multiple levels of the valvar apparatus, as well as ventricular dysfunction and dilation. Multiple imaging modalities including recent advances in 3-dimensional echocardiography and cross-sectional imaging have been used to further understand AVVR. Surgery to address AVVR must be tailored to the underlying mechanism and the timing of surgical repair should be chosen carefully. In this review, we discuss the etiologies, treatment options, surgical timing, and outcomes of valve repair or replacement for AVVR in patients with single ventricle congenital heart disease, with a focus on those with a Fontan circulation as AVVR is associated with increased risk for Fontan failure and mortality. In-depth understanding of the current literature will help guide clinicians in their approach and management of AVVR in this population.


Mild endothelial dysfunction in Sirt3 knockout mice fed a high-cholesterol diet: protective role of a novel C/EBP-β-dependent feedback regulation of SOD2.
Sirtuin 3 (Sirt3) is an NAD(+)-dependent mitochondrial deacetylase associated with superoxide dismutase 2 (SOD2)-mediated protection from oxidative stress. We have reported accelerated weight gain and impaired metabolic flexibility in atherosclerotic Sirt3 (-/-) mice. Oxidative stress is a hallmark of endothelial dysfunction. Yet, the role of Sirt3 in this context remains unknown. Thus, we aimed to unravel the effects of endogenous Sirt3 on endothelial function and oxidative stress. Knockdown of Sirt3 in human aortic endothelial cells (HAEC) increased intracellular mitochondrial superoxide accumulation, as assessed by electron spin resonance spectroscopy and fluorescence imaging. Endothelium-dependent relaxation of aortic rings from Sirt3 (-/-) mice exposed to a normal diet did not differ from wild-type controls. However, following 12 weeks of high-cholesterol diet and increasing oxidative stress, endothelial function of Sirt3 (-/-) mice was mildly impaired compared with wild-type controls. Relaxation was restored upon enhanced superoxide scavenging using pegylated superoxide dismutase. Knockdown of Sirt3 in cultured HAEC diminished SOD2 specific activity, which was compensated for by a CCAAT/enhancer binding protein beta (C/EBP-β)-dependent transcriptional induction of SOD2. Abrogation of this feedback regulation by simultaneous knockdown of C/EBP-β and Sirt3 exacerbated mitochondrial superoxide accumulation and culminated into endothelial cell death upon prolonged culture. Taken together, Sirt3 deficiency induces a mild, superoxide-dependent endothelial dysfunction in mice fed a high-cholesterol diet. In cultured endothelial cells, a novel C/EBP-β-dependent rescue mechanism maintains net SOD2 activity upon transient knockdown of Sirt3.


Neuronal glycogen synthesis contributes to physiological aging.
Glycogen is a branched polymer of glucose and the carbohydrate energy store for animal cells. In the brain, it is essentially found in glial cells, although it is also present in minute amounts in neurons. In humans, loss-of-function mutations in laforin and malin, proteins involved in suppressing glycogen synthesis, induce the presence of high numbers of insoluble polyglucosan bodies in neuronal cells. Known as Lafora bodies (LBs), these deposits result in the aggressive neurodegeneration seen in Lafora's disease. Polysaccharide-based aggregates, called corpora amylacea (CA), are also present in the neurons of aged human brains. Despite the similarity of CA to LBs, the mechanisms and functional consequences of CA formation are yet unknown. Here, we show that wild-type laboratory mice also accumulate glycogen-based aggregates in the brain as they age. These structures are immunopositive for an array of metabolic and stress-response proteins, some of which were previously shown to aggregate in correlation with age in the human brain and are also present in LBs. Remarkably, these structures and their associated protein aggregates are not present in the aged mouse brain upon genetic ablation of glycogen synthase. Similar genetic intervention in Drosophila prevents the accumulation of glycogen clusters in the neuronal processes of aged flies. Most interestingly, targeted reduction of Drosophila glycogen synthase in neurons improves neurological function with age and extends lifespan. These results demonstrate that neuronal glycogen accumulation contributes to physiological aging and may therefore constitute a key factor regulating age-related neurological decline in humans.


Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo.
Axin proteins are key negative regulators of the canonical Wnt signal transduction pathway. Although Axin2 null mice are viable, we identified an unusual ENU-induced recessive allele of Axin2, canp, that causes midgestation lethality in homozygotes. We show that the Axin2(canp) mutation is a V26D substitution in an invariant N-terminal sequence motif and that the Axin2(canp) protein is more stable than wild type. As predicted for an increased level of a negative regulator, the Axin2(canp) mutation leads to decreased Wnt signaling in most tissues, and this can account for most of the morphological phenotypes of Axin2(canp) mutants. In contrast, there is a paradoxical increase in canonical Wnt activity in the late primitive streak of all Axin2(canp) mutant embryos that is associated with the formation of an ectopic tail in some mutants. Treatment of wild-type embryos with an inhibitor of Tankyrase that stabilizes Axin proteins also causes inhibition of Wnt signaling in anterior regions of the embryo and a gain of Wnt signaling in the primitive streak. The results indicate that although increased stability of Axin2 leads to a loss of canonical Wnt signaling in most tissues, stabilized Axin2 enhances Wnt pathway activity in a specific progenitor population in the late primitive streak.


A support vector machine for predicting defibrillation outcomes from waveform metrics.
Algorithms to predict shock success based on VF waveform metrics could significantly enhance resuscitation by optimising the timing of defibrillation. To investigate robust methods of predicting defibrillation success in VF cardiac arrest patients, by using a support vector machine (SVM) optimisation approach. Frequency-domain (AMSA, dominant frequency and median frequency) and time-domain (slope and RMS amplitude) VF waveform metrics were calculated in a 4.1Y window prior to defibrillation. Conventional prediction test validity of each waveform parameter was conducted and used AUC>0.6 as the criterion for inclusion as a corroborative attribute processed by the SVM classification model. The latter used a Gaussian radial-basis-function (RBF) kernel and the error penalty factor C was fixed to 1. A two-fold cross-validation resampling technique was employed. A total of 41 patients had 115 defibrillation instances. AMSA, slope and RMS waveform metrics performed test validation with AUC>0.6 for predicting termination of VF and return-to-organised rhythm. Predictive accuracy of the optimised SVM design for termination of VF was 81.9% (± 1.24 SD); positive and negative predictivity were respectively 84.3% (± 1.98 SD) and 77.4% (± 1.24 SD); sensitivity and specificity were 87.6% (± 2.69 SD) and 71.6% (± 9.38 SD) respectively. AMSA, slope and RMS were the best VF waveform frequency-time parameters predictors of termination of VF according to test validity assessment. This a priori can be used for a simplified SVM optimised design that combines the predictive attributes of these VF waveform metrics for improved prediction accuracy and generalisation performance without requiring the definition of any threshold value on waveform metrics.


Synthesis, structure and conformation of partially-modified retro- and retro-inverso psi[NHCH(CF3)]Gly peptides.
Partially modified retro- (PMR) and retro-inverso (PMRI) psi[NHCH(CF(3))]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure alpha-amino esters and peptides with enantiomerically and geometrically pure N-4,4,4-trifluorocrotonoyl-oxazolidin-2-ones. The factors underlying the observed moderate to good diastereocontrol have been investigated. The conformations of model PMR-psi[NHCH(CF(3))]Gly tripeptides have been studied in solution by (1)H NMR spectroscopy supported by MD calculations, as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp(3) bonds in the [CO-CH(2)-CH(CF(3))-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF(3) group and the R side chain; 2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl(3) solution and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramolecular hydrogen bonding. The relative configuration of the -C*H(CF(3))NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochemistry. X-ray diffraction and ab initio computational studies showed that the [-CH(CF(3))NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analogue, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF(3))-NH-CH backbone angle close to 120 degrees, C-CF(3) bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O(-))NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron density on the CF(3) group, tetrahedral backbone carbon).


Pseudotumor cerebri presenting with visual failure in promyelocytic leukemia: a case report.
Pseudotumor cerebri secondary to all-trans retinoic acid in acute promyelocytic leukemia is a reported but rare complication of the therapy. Most cases improve following the discontinuation of all-trans retinoic acid. There is no published literature on how to manage such patients if severe symptoms of increased intracranial pressure continue after discontinuation of the drug. We report the case of a 16-year-old Afro-Caribbean woman with aggressive secondary pseudotumor cerebri who presented to our facility with visual failure that persisted despite discontinuation of all-trans retinoic acid. A lumbar drain was inserted for 11 days resulting in symptomatic relief of headaches and objective improvement of visual failure. Pressure settings were titrated regularly to ensure optimal symptomatic relief. The use of a lumbar drain for continuous drainage of cerebrospinal fluid in patients with all-trans retinoic acid-induced pseudotumor cerebri resistant to all-trans retinoic acid discontinuation is a feasible management option. This method can be used when other less invasive measures have failed to improve signs and symptoms. Permanent drainage of cerebrospinal fluid with a shunt may also provide a long-term viable management strategy but the use of a lumbar drain may be preferable if the cause of pseudotumor cerebri is known to be self-limiting.


The Ontology-Epistemology Divide: A Case Study in Medical Terminology.
Medical terminology collects and organizes the many different kinds of terms employed in the biomedical domain both by practitioners and also in the course of biomedical research. In addition to serving as labels for biomedical classes, these names reflect the organizational principles of biomedical vocabularies and ontologies. Some names represent invariant features (classes, universals) of biomedical reality (i.e., they are a matter for ontology). Other names, however, convey also how this reality is perceived, measured, and understood by health professionals (i.e., they belong to the domain of epistemology). We analyze terms from several biomedical vocabularies in order to throw light on the interactions between ontological and epistemological components of these terminologies. We identify four cases: 1) terms containing classification criteria, 2) terms reflecting detectability, modality, uncertainty, and vagueness, 3) terms created in order to obtain a complete partition of a given domain, and 4) terms reflecting mere fiat boundaries. We show that epistemology-loaded terms are pervasive in biomedical vocabularies, that the "classes" they name often do not comply with sound classification principles, and that they are therefore likely to cause problems in the evolution and alignment of terminologies and associated ontologies.


Photorefractive spatial mode converter for multimode-to-single-mode fiber-optic coupling.
We report what is to our knowledge the first experimental demonstration of a photorefractive spatial mode converter (based on mutually pumped phase conjugation) that couples light efficiently from a multimode fiber into a singlemode fiber with an extremely large degree of tolerance to misalignment. Using an argon laser (514.5 nm) and a barium titanate crystal, we have demonstrated that the laser light can be coupled from a multimode fiber (core diameter 100 microm, numerical aperture 0.37) into a single-mode fiber (core diameter 2.9 microm, numerical aperture 0.11), with an efficiency of ~15% and an alignment tolerance of ~100 microm. The coupling efficiency is more than 2 orders of magnitude, and the tolerance to misalignments is more than 30 times better than the corresponding values achievable by conventional techniques.


Post-traumatic growth in adults following a burn.
It is well established that a burn can result in negative psychological consequences. Throughout the literature there is also reference to individuals reporting positive changes post-burn. The concept of 'post-traumatic growth' (PTG) refers to such individuals, whose recovery exceeds pre-trauma levels of well-being. To date there has only been one quantitative analysis directly examining PTG post-burn. The present study builds on this, examining the prevalence of PTG and related constructs, including: social support, coping styles, dispositional optimism, functioning, post-traumatic stress symptoms, severity and time since burn. Seventy-four participants recruited through a regional burns unit completed a battery of self-report questionnaires. Burn survivors were found to experience PTG, although to a lesser degree than previous research suggests (GM=1.26, range=0-4.67). Severity of burn, post-burn functioning and trauma symptoms significantly correlated with PTG. Regression analysis proposed a model explaining 51.7% of the variance, with active coping, perceived social support and avoidance coping as significant predictors of PTG. Results support the theory that distress and trauma symptoms act as a catalyst for PTG. Coping styles and social support appear to facilitate this process. Clinical implications are discussed.


Disability-adjusted life-year burden of abusive head trauma at ages 0-4.
We estimated the disability-adjusted life-year (DALY) burden of abusive head trauma (AHT) at ages 0 to 4 years in the United States. DALYs are computed by summing years of productive life that survivors lost to disability plus life-years lost to premature death. Surveying a convenience sample of 170 caregivers and pediatricians yielded health-related disability over time according to severity of AHT (measured with the Health Utilities Index, Mark 2). Incidence estimates for 2009 came from Vital Statistics for Mortality, Healthcare Cost and Utilization Program Kids' Inpatient Database for hospitalized survivors, and published ratios of 0.894 case treated and released and 0.340 case not diagnosed/treated while in the acute phase per survivor admitted. Survival probability over time after discharge came from published sources. An estimated 4824 AHT cases in 2009 included 334 fatalities within 30 days. DALYs per surviving child averaged 0.555 annually for severe AHT (95% confidence interval: 0.512-0.598) and 0.155 (95% confidence interval: 0.120-0.190) for other cases. Including life-years lost to premature mortality, estimated lifetime burden averaged 4.7 DALYs for mild AHT, 5.4 for moderate AHT, 24.1 for severe AHT, and 29.8 for deaths. On average, DALY loss per 30-day survivor included 7.6 years of lost life expectancy and 5.7 years lived with disability. Estimated burden of AHT incidents in 2009 was 69 925 DALYs or 0.017 DALYs per US live birth. AHT is extremely serious, often resulting in severe physical damage or death. The annual DALY burden several years after mild AHT exceeds the DALY burden of a severe burn.


A comparison between unifocal papillary thyroid microcarcinoma with noninvasive follicular thyroid neoplasm with papillary-like nuclear features and other patterns: A retrospective clinicopathological study.
Papillary thyroid microcarcinoma (mPTC) is defined as a tumor with low malignancy potential. Different treatment protocols have been used at different centers for analyzing this tumor which has common recurrence and metastasis rates. Consequently, in 2016, the definition of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was accepted which included the lesions > cm. It is important to explain the clinical course and appropriate treatment options for mPTC and its subtypes. In this study, we aimed to describe the clinical course of mPTC with and without NIFTP and to determine different risk groups among these subtypes. We performed microscopic reexamination of about 280 unifocal mPTCs retrieved from our archives between 2007-2018 and analyzed the results of morphological and clinical comparison among these cases that had 0-11-years of clinical follow-up. Among 280 unifocal mPTCs, 127 cases (45.4%) had classical morphology, 58 (20.7%) had NIFTP, 53 (18.9%) had infiltrative pattern, 27 (9.6%) had oncocytic pattern, 12 (4.3%) showed capsular invasion, and 3 (1.1%) showed other morphologies. Seven patients were detected with lymph node metastasis and one with distant metastasis at diagnosis. Lymph node metastasis (recurrence) was postoperatively detected in five patients. All patients with recurrence were women. Moreover, three of these patients were in their 30s and two in 70s. The median diameter of the tumor was 3 mm. Both invasive and noninvasive cases have recurred. Contrary to the results of the previous studies, the results of our study did not confirm the indolent course of mPTC with NIFTP. However, metastasis was detected both at the time of diagnosis and during the postoperative period. The malignancy potential of these tumors may not be low. Therefore, more clinicopathological and molecular studies are needed to determine the biological behavior of mPTC cases with different histology.