The TacTip Family: Soft Optical Tactile Sensors with 3D-Printed Biomimetic Morphologies.
Tactile sensing is an essential component in human-robot interaction and object manipulation. Soft sensors allow for safe interaction and improved gripping performance. Here we present the TacTip family of sensors: a range of soft optical tactile sensors with various morphologies fabricated through dual-material 3D printing. All of these sensors are inspired by the same biomimetic design principle: transducing deformation of the sensing surface via movement of pins analogous to the function of intermediate ridges within the human fingertip. The performance of the TacTip, TacTip-GR2, TacTip-M2, and TacCylinder sensors is here evaluated and shown to attain submillimeter accuracy on a rolling cylinder task, representing greater than 10-fold super-resolved acuity. A version of the TacTip sensor has also been open-sourced, enabling other laboratories to adopt it as a platform for tactile sensing and manipulation research. These sensors are suitable for real-world applications in tactile perception, exploration, and manipulation, and will enable further research and innovation in the field of soft tactile sensing.


Population splitting of rodlike swimmers in Couette flow.
We present a quantitative analysis on the response of a dilute active suspension of self-propelled rods (swimmers) in a planar channel subjected to an imposed shear flow. To best capture the salient features of the shear-induced effects, we consider the case of an imposed Couette flow, providing a constant shear rate across the channel. We argue that the steady-state behavior of swimmers can be understood in the light of a population splitting phenomenon, occurring as the shear rate exceeds a certain threshold, initiating the reversal of the swimming direction for a finite fraction of swimmers from down- to upstream or vice versa, depending on the swimmer position within the channel. Swimmers thus split into two distinct, statistically significant and oppositely swimming majority and minority populations. The onset of population splitting translates into a transition from a self-propulsion-dominated regime to a shear-dominated regime, corresponding to a unimodal-to-bimodal change in the probability distribution function of the swimmer orientation. We present a phase diagram in terms of the swim and flow Péclet numbers showing the separation of these two regimes by a discontinuous transition line. Our results shed further light on the behavior of swimmers in a shear flow and provide an explanation for the previously reported non-monotonic behavior of the mean, near-wall, parallel-to-flow orientation of swimmers with increasing shear strength.


Metabolic alterations produced in the liver by chronic ethanol administration. Comparison between the effects produced by ethanol and by thyroid hormones.
1. Liver slices from rats treated with thyroxine show an increased rate of O(2) consumption. The extra consumption, but not the basal respiration, can be abolished by ouabain. 2. Dinitrophenol is not effective in increasing the rate of O(2) consumption of liver slices from thyroxine-treated animals but its effectiveness can be recovered in the presence of ouabain. 3. (Na(+)+K(+))-stimulated adenosine triphosphatase activity of liver was increased by administration of thyroxine in vivo. No changes were found in total Mg(2+)-stimulated adenosine triphosphatase activity. 4. Mitochondrial alpha-glycerophosphate dehydrogenase and microsomal NADPH oxidase activity were increased by both thyroxine and chronic ethanol treatment. 5. Liver slices from animals chronically treated with ethanol synthesize urea at an increased rate. 6. Mitochondrial size (section area) is markedly increased in the liver of animals chronically treated with ethanol. 7. Acute administration of ethanol in doses of 4 and 6g/kg significantly increases the uptake of (131)I-labelled thyroxine by the liver. 8. Work reported here, along with results from other investigators, indicates marked similarities between the effects produced in the liver by chronic administration of ethanol and by thyroid hormones.


Enrichment, characterization, and responsiveness of single primitive CD34 human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential.
To characterize the growth of cord blood progenitor cells, single nonadherent, low-density, T-lymphocyte-depleted CD34 cells were sorted by flow cytometer with an autoclone device into single wells containing culture medium and cytokines. These cells were evaluated for proliferation and for replating ability of their progeny. This latter effect is used as a measure of self-renewal capacity. Colony formation was assessed in 1 degree wells containing various cytokines, alone and in combination, and single colonies deriving after 21 days in semisolid medium were replated into 2 degree wells in the presence of the combination of purified preparations of recombinant human steel factor (SF, a c-kit ligand), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-3 (IL-3), and erythropoietin (Epo). Replating of single colonies was performed also for 3 degrees, 4 degrees, and 5 degrees cultures. In the presence of serum, colony formation was observed in > 66% of the wells stimulated with the combination of Epo, SF, GM-CSF, G-CSF, and IL-3, and more than 39% of the colonies formed in these 1 degree wells were very large in size (> 2.5 mm in diameter, dense in the center, and containing > 10(4) cells/colony). The replating efficiency of these large colonies was up to 93% with generation of subsequent colonies of very large size. Replating could be shown for up to five generations. The cells in these colonies were large, nonspecific esterase positive, and contained large amounts of cytoplasm with one or more nuclei containing several nucleoli per nucleus. Smaller colonies (1 to 2.5 mm in diameter and dense in the center) containing similar cells and making up an additional 14% of the colonies formed in 1 degree wells also showed extensive replating capacity, including generation of larger colonies. These colony-forming cells are likely similar to the murine macrophage high-proliferative potential colony-forming cells. The cells giving rise to these colonies are present in about eightfold higher frequency in cord blood than in adult bone marrow. These cells may at least in part be associated with the successful hematopoietic repopulating capacity of umbilical cord blood cells.


Viral-Mediated Microbe Mortality Modulated by Ocean Acidification and Eutrophication: Consequences for the Carbon Fluxes Through the Microbial Food Web.
Anthropogenic carbon emissions are causing changes in seawater carbonate chemistry including a decline in the pH of the oceans. While its aftermath for calcifying microbes has been widely studied, the effect of ocean acidification (OA) on marine viruses and their microbial hosts is controversial, and even more in combination with another anthropogenic stressor, i.e., human-induced nutrient loads. In this study, two mesocosm acidification experiments with Mediterranean waters from different seasons revealed distinct effects of OA on viruses and viral-mediated prokaryotic mortality depending on the trophic state and the successional stage of the plankton community. In the winter bloom situation, low fluorescence viruses, the most abundant virus-like particle (VLP) subpopulation comprising mostly bacteriophages, were negatively affected by lowered pH with nutrient addition, while the bacterial host abundance was stimulated. High fluorescence viruses, containing cyanophages, were stimulated by OA regardless of the nutrient conditions, while cyanobacteria of the genus Synechococcus were negatively affected by OA. Moreover, the abundance of very high fluorescence viruses infecting small haptophytes tended to be lower under acidification while their putative hosts' abundance was enhanced, suggesting a direct and negative effect of OA on viral-host interactions. In the oligotrophic summer situation, we found a stimulating effect of OA on total viral abundance and the viral populations, suggesting a cascading effect of the elevated pCO2 stimulating autotrophic and heterotrophic production. In winter, viral lysis accounted for 30 ± 16% of the loss of bacterial standing stock per day (VMMBSS) under increased pCO2 compared to 53 ± 35% in the control treatments, without effects of nutrient additions while in summer, OA had no significant effects on VMMBSS (35 ± 20% and 38 ± 5% per day in the OA and control treatments, respectively). We found that phage production and resulting organic carbon release rates significantly reduced under OA in the nutrient replete winter situation, but it was also observed that high nutrient loads lowered the negative effect of OA on viral lysis, suggesting an antagonistic interplay between these two major global ocean stressors in the Anthropocene. In summer, however, viral-mediated carbon release rates were lower and not affected by lowered pH. Eutrophication consistently stimulated viral production regardless of the season or initial conditions. Given the relevant role of viruses for marine carbon cycling and the biological carbon pump, these two anthropogenic stressors may modulate carbon fluxes through their effect on viruses at the base of the pelagic food web in a future global change scenario.


Phenotypic characterisation of colour stability of lamb meat.
A study was undertaken, using 2701 overwrapped loin samples aged for 5 days and subjected to a simulated retail display (SRD) for 3 days; sourced from lambs in the Cooperative Research Centre for Sheep Industry Innovation information nucleus flock, born 2007-2009. The ratio of reflectance of light in the wavelengths of 630 nm and 580 nm (oxy/met) was measured daily during the SRD, using a Hunterlab spectrophotometer. A series of linear mixed models was fitted to the oxy/met and time data to compare 4 breed types and identify relevant covariates, of 19, using a forward selection process. Breed type, pH at 24 h post slaughter and Linoleic acid concentration (LA) were the most important factors and covariates, in that order. Merino breed type, high pH and high LA reduced colour stability. Fitting a spline model to predict the time for oxy/met to reach a set value, represents an alternative to comparing oxy/met at a set time, for describing colour stability.


Three-dimensional silicon inverse photonic quasicrystals for infrared wavelengths.
Quasicrystals are a class of lattices characterized by a lack of translational symmetry. Nevertheless, the points of the lattice are deterministically arranged, obeying rotational symmetry. Thus, we expect properties that are different from both crystals and glasses. Indeed, naturally occurring electronic quasicrystals (for example, AlPdMn metal alloys) show peculiar electronic, vibrational and physico-chemical properties. Regarding artificial quasicrystals for electromagnetic waves, three-dimensional (3D) structures have recently been realized at GHz frequencies and 2D structures have been reported for the near-infrared region. Here, we report on the first fabrication and characterization of 3D quasicrystals for infrared frequencies. Using direct laser writing combined with a silicon inversion procedure, we achieve high-quality silicon inverse icosahedral structures. Both polymeric and silicon quasicrystals are characterized by means of electron microscopy and visible-light Laue diffraction. The diffraction patterns of structures with a local five-fold real-space symmetry axis reveal a ten-fold symmetry as required by theory for 3D structures.


Light-induced c-fos in melanopsin retinal ganglion cells of young and aged rodless/coneless (rd/rd cl) mice.
Non-rod, non-cone ocular photoreceptors have been shown to mediate a range of irradiance detection tasks. The strongest candidates for these receptors are melanopsin-positive retinal ganglion cells (RGCs). To provide a more complete understanding of these receptors in vivo, we have utilized a mouse that lacks rod and cone photoreceptors (rd/rd cl) and compared these animals to congenic wild-types. Using real-time polymerase chain reaction and immunohistochemistry, we address the following. (1) Is Fos expression within these RGCs driven by an input from the rods/cones or is it the product of the intrinsic photosensitivity of these neurons? We demonstrate that most Fos expression across the entire retina is due to the rods/cones, but in the absence of these photoreceptors, light will induce Fos within melanopsin RGCs. (2) Could the reported age-related decline in circadian photosensitivity of rodents be linked to changes in the population of melanopsin RGCs? We show that old mice experience an approximately 40% reduction in melanopsin RGCs. (3) Does the loss of inner retinal neurons affect the responses of melanopsin RGCs? Aged (approximately 700 days) rd/rd cl mice lose most of their inner retina but retain the retinal ganglion cell layer. In these mice, the proportion of melanopsin RGCs that express Fos in response to light is significantly reduced. Collectively, our data suggest that melanopsin RGCs form a heterogeneous population of neurons, and that most of the light-induced c-fos expression within these cells is associated with the endogenous photosensitivity of these neurons.


THERMOCOOL® SMARTTOUCH® CATHETER - The Evidence So Far for Contact Force Technology and the Role of VISITAG™ MODULE.
Catheter ablation has become an important modality in the treatment of most cardiac arrhythmias. In recent years there has been significant development of new ablation energies and technologies in an attempt to improve clinical outcomes and decrease disease burden. Ablation failure is often associated with inadequate lesion formation, and catheter-to-myocardial contact force (CF) and catheter stability are two of the parameters required to produce effective lesions during radiofrequency energy application. Recently, CF sensing catheters and tagging modules have been developed to give operators realtime data on catheter force and stability. This review describes the novel THERMOCOOL(®) SMARTTOUCH(®) CATHETER (Biosense Webster Inc., CA, US) and VISITAG™ MODULE (Biosense Webster Inc., CA, US) software, and discusses the results of several studies on CF and catheter stability during mapping and ablation of the left atrium and ventricle from our electrophysiology laboratory. We assess the short- and longer-term outcomes during mapping and ablation with and without CF data, as well as the use of the VISITAG MODULE™ software, which allows the evaluation of multiple parameters of lesion formation, then integrates and displays this as automatic tags in a relatively objective way.


In-Situ Forming pH and Thermosensitive Injectable Hydrogels to Stimulate Angiogenesis: Potential Candidates for Fast Bone Regeneration Applications.
Biomaterials that promote angiogenesis are required for repair and regeneration of bone. In-situ formed injectable hydrogels functionalised with bioactive agents, facilitating angiogenesis have high demand for bone regeneration. In this study, pH and thermosensitive hydrogels based on chitosan (CS) and hydroxyapatite (HA) composite materials loaded with heparin (Hep) were investigated for their pro-angiogenic potential. Hydrogel formulations with varying Hep concentrations were prepared by sol-gel technique for these homogeneous solutions were neutralised with sodium bicarbonate (NaHCO3) at 4 °C. Solutions (CS/HA/Hep) constituted hydrogels setting at 37 °C which was initiated from surface in 5-10 minutes. Hydrogels were characterised by performing injectability, gelation, rheology, morphology, chemical and biological analyses. Hydrogel solutions facilitated manual dropwise injection from 21 Gauge which is highly used for orthopaedic and dental administrations, and the maximum injection force measured through 19 G needle (17.191 ± 2.296N) was convenient for manual injections. Angiogenesis tests were performed by an ex-ovo chick chorioallantoic membrane (CAM) assay by applying injectable solutions on CAM, which produced in situ hydrogels. Hydrogels induced microvascularity in CAM assay this was confirmed by histology analyses. Hydrogels with lower concentration of Hep showed more efficiency in pro-angiogenic response. Thereof, novel injectable hydrogels inducing angiogenesis (CS/HA/Hep) are potential candidates for bone regeneration and drug delivery applications.


Post-Traumatic Growth in the Early Survival Phase: From Turkish Breast Cancer Survivors' Perspective.
The purpose of this descriptive phenomenological study was to explore the nature of post-traumatic growth (PTG) in Turkish breast cancer survivors in the post-treatment first two years. Semi-structured in-depth interviews were conducted with 13 breast cancer survivors. Data were collected between August 2015 and January 2016 in the medical oncology outpatient clinic of a university hospital in Turkey. Two main themes were identified. They are as follows: making sense of the cancer (questioning life and death and religious meaning) and positive restoring (changes in values and increased coping skills). Health care professionals should be aware of these positive changes in the post-treatment period in accordance with aspects of PTG and they should be designed programs directed towards facilitating and enhancing post-traumatic growth in the breast cancer survivors.


Differential diagnosis of brain lesions in a metastatic endometrial carcinosarcoma patient.
The differential diagnosis of ring-enhancing brain lesions in a patient with metastatic malignancy may initially seem straightforward, and easily attributed to brain metastases. On rare occasions, the physician needs to avoid anchoring bias by re-evaluating the entire clinical context in which these ring-enhancing brain lesions are found. We report a case of cerebral toxoplasmosis mimicking brain metastases in a patient with metastatic cancer and without a prior history of human immunodeficiency virus. A 65-year-old lady with a recently detected relapse of her endometrial carcinosarcoma presented with a 2-week history of fever with no localising symptoms or signs of infection. The initial investigations were unremarkable. She had daily fever despite empirical broad-spectrum antibiotics. A positron emission tomography-computed tomography (PET-CT) was performed to evaluate the pyrexia of unknown origin, which showed metastatic deposits in the pelvis. A magnetic resonance imaging (MRI) of the brain was subsequently performed due to fluctuating mentation, which reported metastatic disease to the brain. Her pyrexia of unknown origin was attributed to malignancy-related fever. The medical oncologist was cautious about starting systemic treatment because the PET-CT had FDG-avid diffuse ground glass opacities in both lung fields, and requested for a bronchoscopic evaluation, which returned positive for Pneumocystis jirovecii. In light of this new finding, a multi-disciplinary discussion and a review of the brain MRI were undertaken, during which it was concluded that the likelihood of cerebral toxoplasmosis was much higher than brain metastases. She was treated with high dose trimethoprim-sulfamethoxazole for both P. jirovecii pneumonia and cerebral toxoplasmosis, with clinical and radiological improvement. This case highlights the importance of (a) clinical input in interpreting imaging findings, (b) entertaining the possibility of multiple concurrent pathologies explaining a patient's symptoms, (c) being open to alternate diagnoses when new information surfaces even though the current working diagnosis is the most plausible and (d) multi-disciplinary communication when faced with diagnostic difficulty.


Sensor data acquisition and processing parameters for human activity classification.
It is known that parameter selection for data sampling frequency and segmentation techniques (including different methods and window sizes) has an impact on the classification accuracy. For Ambient Assisted Living (AAL), no clear information to select these parameters exists, hence a wide variety and inconsistency across today's literature is observed. This paper presents the empirical investigation of different data sampling rates, segmentation techniques and segmentation window sizes and their effect on the accuracy of Activity of Daily Living (ADL) event classification and computational load for two different accelerometer sensor datasets. The study is conducted using an ANalysis Of VAriance (ANOVA) based on 32 different window sizes, three different segmentation algorithm (with and without overlap, totaling in six different parameters) and six sampling frequencies for nine common classification algorithms. The classification accuracy is based on a feature vector consisting of Root Mean Square (RMS), Mean, Signal Magnitude Area (SMA), Signal Vector Magnitude (here SMV), Energy, Entropy, FFTPeak, Standard Deviation (STD). The results are presented alongside recommendations for the parameter selection on the basis of the best performing parameter combinations that are identified by means of the corresponding Pareto curve.


Specific aspects of children and adolescents undergoing lung transplantation.
Lung transplantation has evolved as an accepted therapy in carefully selected children with end-stage lung disease, offering a prolonged survival and improved quality of life. Presently, more than 100 lung transplant procedures are done in children annually worldwide. Specific aspects of children and adolescents undergoing lung transplantation will be reviewed and an update on most recent developments in the management of paediatric lung transplant recipients will be given. Certain aspects are unique to children and adolescents undergoing lung transplantation such as a challenging surgical procedure, the effects of immunosuppressant therapy, and the impact of infections on the child's developing immune system and somatic growth. The underlying diagnoses leading to lung transplantation vary considerably by age group. Early referral, careful patient selection and appropriate timing of listing are crucial to achieve the maximal survival benefit. In particular, infectious complications are a common in children. Chronic lung allograft dysfunction remains the major obstacle for a better long-term survival. Lung transplantation has successfully been performed in infants, children and adolescents with outcomes similar to that in adults. Specific aspects of paediatric lung transplantation include donor shortage for smaller recipients, somatic growth, psychosocial aspects and adherence, and transition to adult care.


Malignant lymphoma of the urinary bladder: a clinicopathological study of 11 cases.
To report the clinical and histological features and outcome of primary and secondary malignant lymphomas of the urinary bladder. Eleven cases of malignant lymphoma of the urinary bladder were obtained from the registry of cases at St Bartholomews and the Royal London Hospitals. The lymphomas were classified on the basis of their morphology and immunophenotype, and the clinical records were reviewed. There were six primary lymphomas: three extranodal marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) type and three diffuse large B cell lymphomas. Of the five secondary cases, four were diffuse large B cell lymphomas, one secondary to a systemic follicular follicle centre lymphoma, and one nodular sclerosis Hodgkins disease. Four patients with secondary lymphoma for whom follow up was available had died of disease within 13 months of diagnosis. Primary lymphomas followed a more indolent course. In one case, there was evidence of transformation from low grade MALT-type to diffuse large B cell lymphoma. The most common presenting symptom was haematuria. Cystoscopic appearances were of solid, sometimes necrotic tumours resembling transitional cell carcinoma, and in one case the tumours were multiple. These cases represented 0.2% of all bladder neoplasms. Diffuse large B cell lymphoma and MALT-type lymphoma are the most common primary malignant lymphomas of the bladder. Lymphoepithelial lesions in MALT-type lymphoma involve transitional epithelium, and their presence in high grade lymphoma suggests a primary origin owing to transformation of low grade MALT-type lymphoma. Primary and secondary diffuse large B cell lymphomas of the bladder are histologically similar, but the prognosis of the former is favourable.


Prediction of miRNA-disease associations with a vector space model.
MicroRNAs play critical roles in many physiological processes. Their dysregulations are also closely related to the development and progression of various human diseases, including cancer. Therefore, identifying new microRNAs that are associated with diseases contributes to a better understanding of pathogenicity mechanisms. MicroRNAs also represent a tremendous opportunity in biotechnology for early diagnosis. To date, several in silico methods have been developed to address the issue of microRNA-disease association prediction. However, these methods have various limitations. In this study, we investigate the hypothesis that information attached to miRNAs and diseases can be revealed by distributional semantics. Our basic approach is to represent distributional information on miRNAs and diseases in a high-dimensional vector space and to define associations between miRNAs and diseases in terms of their vector similarity. Cross validations performed on a dataset of known miRNA-disease associations demonstrate the excellent performance of our method. Moreover, the case study focused on breast cancer confirms the ability of our method to discover new disease-miRNA associations and to identify putative false associations reported in databases.


Improved T-matrix computations for large, nonabsorbing and weakly absorbing nonspherical particles and comparison with geometrical-optics approximation.
We show that the use of a matrix inversion scheme based on a special lower triangular-upper triangular factorization rather than on the standard Gaussian elimination significantly improves the numerical stability of T-matrix computations for nonabsorbing and weakly absorbing nonspherical particles. As a result, the maximum convergent size parameter for particles with small or zero absorption can increase by a factor of several and can exceed 100. We describe an improved scheme for evaluating Clebsch-Gordon coefficients with large quantum numbers, which allowed us to extend the analytical orientational averaging method developed by Mishchenko [J. Opt. Soc. Am. A 8, 871 (1991)] to larger size parameters. Comparisons of T-matrix and geometrical optics computations for large, randomly oriented spheroids and finite circular cylinders show that the applicability range of the ray-tracing approximation depends on the imaginary part of the refractive index and is different for different elements of the scattering matrix.


Platelet-derived growth factor-AA increases IL-1beta and IL-8 expression and activates NF-kappaB in rheumatoid fibroblast-like synoviocytes.
The effect of platelet-derived growth factor (PDGF)-AA on the inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA) was investigated using cultured fibroblast-like synoviocytes (FLS) obtained from RA and OA patients as well as control nonarthritic (NA) individuals. PDGF-AA increased the mRNA and protein expressions of proinflammatory cytokines, interleukin (IL)-1beta and IL-8 in RA FLS. Biological activity of IL-1 in the culture supernatant of RA FLS was also increased by PDGF-AA stimulation. Interestingly, PDGF-AA synergized with tumour necrosis factor (TNF)-alpha to upregulate the protein expressions of IL-1beta and IL-8. PDGF-induced enhancement of the IL-1beta and IL-8 mRNA expressions was also observed in OA FLS. However, the expression of these proinflammatory cytokines in NA FLS did not change by PDGF treatment, suggesting that the inflammatory condition might have modified the biological effects of PDGF. In accordance with the enhanced expression of inflammatory cytokines, the activity of nuclear factor kappaB was also induced in response to PDGF-AA in RA FLS. These results suggest that PDGF-AA plays an important role in the progression of RA inflammation, and inhibiting PDGF activity may be useful for the effective RA treatment.


Reminders Through Association.
People often fail to follow through on good intentions. While limited self-control is frequently the culprit, another cause is simply forgetting to enact intentions when opportunities arise. We introduce a novel, potent approach to facilitating follow-through: the reminders-through-association approach. This approach involves associating intentions (e.g., to mail a letter on your desk tomorrow) with distinctive cues that will capture attention when you have opportunities to act on those intentions (e.g., Valentine's Day flowers that arrived late yesterday, which are sitting on your desk). We showed that cue-based reminders are more potent when the cues they employ are distinctive relative to (a) other regularly encountered stimuli and (b) other stimuli encountered concurrently. Further, they can be more effective than written or electronic reminder messages, and they are undervalued and underused. The reminders-through-association approach, developed by integrating and expanding on past research on self-control, reminders, and prospective memory, can be a powerful tool for policymakers and individuals.


The inhibitory effects of deep-sea water on doxorubicin‑induced epithelial-mesenchymal transition.
It has been revealed that the induction of epithelial‑mesenchymal transition (EMT) is associated with drug resistance, leading to tumor recurrence and metastasis. Recent studies have shown that chemotherapeutic agents, besides their therapeutic effects, can induce EMT and enhance invasive and metastatic properties of tumor cells. Previously, we revealed that deep-sea water (DSW) exhibited antimetastatic effects in several human cancer cell lines. In the present study, we investigated the effects of DSW on doxorubicin-induced EMT in MCF-7 human breast cancer cells. When treated with doxorubicin, MCF-7 cells displayed characteristics of EMT, such as, mesenchymal markers (vimentin and fibronectin) and EMT-related transcription factors (Slug and Snail-1) in their RNA expression. However, DSW efficiently inhibited doxorubicin-induced EMT, revealing the decreased expression of vimentin, fibronectin, Slug and Snail-1. Moreover, treatment of MCF-7 cells with DSW significantly suppressed their increased migratory ability by doxorubicin as determined by wound-healing assay. We further demonstrated that the inhibitory effects of DSW on doxorubicin-induced EMT appeared to be mediated by inhibition of the ERK1/2, p38 MAPK and PI3K/AKT signaling pathways. Collectively, our data revealed that DSW has the potential to abolish undesired side-effects of doxorubicin by targeting EMT.


Methods for obtaining and analyzing whole chloroplast genome sequences.
During the past decade, there has been a rapid increase in our understanding of plastid genome organization and evolution due to the availability of many new completely sequenced genomes. There are 45 complete genomes published and ongoing projects are likely to increase this sampling to nearly 200 genomes during the next 5 years. Several groups of researchers including ours have been developing new techniques for gathering and analyzing entire plastid genome sequences and details of these developments are summarized in this chapter. The most important developments that enhance our ability to generate whole chloroplast genome sequences involve the generation of pure fractions of chloroplast genomes by whole genome amplification using rolling circle amplification, cloning genomes into Fosmid or bacterial artificial chromosome (BAC) vectors, and the development of an organellar annotation program (Dual Organellar GenoMe Annotator [DOGMA]). In addition to providing details of these methods, we provide an overview of methods for analyzing complete plastid genome sequences for repeats and gene content, as well as approaches for using gene order and sequence data for phylogeny reconstruction. This explosive increase in the number of sequenced plastid genomes and improved computational tools will provide many insights into the evolution of these genomes and much new data for assessing relationships at deep nodes in plants and other photosynthetic organisms.


Understanding beef-cattle farming management strategies by identifying motivations behind farmers' priorities.
This study aimed to identify and better understand management strategies that help livestock farmers adapt to changes in their production contexts, a fundamental challenge. A total of nine beef-cattle farmers were interviewed three times over 1 year to discuss 13 dimensions of livestock farming (e.g. reproduction, feeding, sales, etc.). Characterisation of management strategies rested on three main factors: (i) ranking of the dimensions according to the degree to which farmers desired to control them, (ii) reasons for the ranking and (iii) management guidelines. Although farmers agreed upon the rank of certain dimensions, such as herd management, they differed on that of others, such as sales and administration/regulations. Four motivation categories were identified: risk, pleasure, efficiency and ability to control the dimension. Three management guidelines were identified, which indicated that farmers managed for future survival of their farms at different scales (animal/herd v. whole-farm), involving different resources (biological v. financial) and based on different animal categories (reproductive cows v. animals sold). These results improve understanding of individual livestock farmers and their current management strategies by integrating the motivations behind their strategies. For this reason, they constitute methodological elements that agricultural advisors can use to provide relevant information to farmers while accommodating differences in farm management.


CAD mutations and uridine-responsive epileptic encephalopathy.
Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.


The association between phase of illness and resource utilisation-a potential model for demonstrating clinical efficiency?
Background: Healthcare efficiency involves demonstrating flexible inter-relationships between resource utilisation and patient need. In palliative care, five phases of patient illness have been identified: stable, unstable, deteriorating, terminal and bereaved. Evaluating the association between phase of illness and nursing activities could demonstrate clinical efficiency. Aim: The aim of this study was to evaluate the association between the phase of illness and the intensity of nursing care in a specialist palliative care unit. Methods: This was a prospective, observational cohort study of consecutive admissions (n=400) to a specialist palliative care unit. Patient phase of illness was documented on admission and daily thereafter. A nursing activity tool was developed, which scored daily nursing interventions (physical, psychological, family care and symptom control). This score was called the nursing total score (NTS) and reflected the intensity of nursing activities. Data were entered into SPSS and descriptive statistics weregenerated. Results: A total of 342 (85%) patients had full data recorded on admission. Stable, unstable, deteriorating and terminal phases were associated with progressively increasing median NTSs on days 1, 2, 3 and 4 (all P<0.01). Phase stabilisation from the unstable to the stable phase during this timeframe resulted in reductions in physical care (p=0.038), symptom management (p=0.007) and near-significant reductions in family support (p=0.06). Conclusion: A significant association was demonstrated between phase of illness and intensity of nursing activities, which were sensitive to phase changes, from unstable to stable. This demonstrates technically efficient resource utilisation and identifies a potential efficiency model for future evaluations of inpatient palliative care.


Evaluating the Impact of Physical Activity Apps and Wearables: Interdisciplinary Review.
Although many smartphone apps and wearables have been designed to improve physical activity, their rapidly evolving nature and complexity present challenges for evaluating their impact. Traditional methodologies, such as randomized controlled trials (RCTs), can be slow. To keep pace with rapid technological development, evaluations of mobile health technologies must be efficient. Rapid alternative research designs have been proposed, and efficient in-app data collection methods, including in-device sensors and device-generated logs, are available. Along with effectiveness, it is important to measure engagement (ie, users' interaction and usage behavior) and acceptability (ie, users' subjective perceptions and experiences) to help explain how and why apps and wearables work. This study aimed to (1) explore the extent to which evaluations of physical activity apps and wearables: employ rapid research designs; assess engagement, acceptability, as well as effectiveness; use efficient data collection methods; and (2) describe which dimensions of engagement and acceptability are assessed. An interdisciplinary scoping review using 8 databases from health and computing sciences. Included studies measured physical activity, and evaluated physical activity apps or wearables that provided sensor-based feedback. Results were analyzed using descriptive numerical summaries, chi-square testing, and qualitative thematic analysis. A total of 1829 abstracts were screened, and 858 articles read in full. Of 111 included studies, 61 (55.0%) were published between 2015 and 2017. Most (55.0%, 61/111) were RCTs, and only 2 studies (1.8%) used rapid research designs: 1 single-case design and 1 multiphase optimization strategy. Other research designs included 23 (22.5%) repeated measures designs, 11 (9.9%) nonrandomized group designs, 10 (9.0%) case studies, and 4 (3.6%) observational studies. Less than one-third of the studies (32.0%, 35/111) investigated effectiveness, engagement, and acceptability together. To measure physical activity, most studies (90.1%, 101/111) employed sensors (either in-device [67.6%, 75/111] or external [23.4%, 26/111]). RCTs were more likely to employ external sensors (accelerometers: P=.005). Studies that assessed engagement (52.3%, 58/111) mostly used device-generated logs (91%, 53/58) to measure the frequency, depth, and length of engagement. Studies that assessed acceptability (57.7%, 64/111) most often used questionnaires (64%, 42/64) and/or qualitative methods (53%, 34/64) to explore appreciation, perceived effectiveness and usefulness, satisfaction, intention to continue use, and social acceptability. Some studies (14.4%, 16/111) assessed dimensions more closely related to usability (ie, burden of sensor wear and use, interface complexity, and perceived technical performance). The rapid increase of research into the impact of physical activity apps and wearables means that evaluation guidelines are urgently needed to promote efficiency through the use of rapid research designs, in-device sensors and user-logs to assess effectiveness, engagement, and acceptability. Screening articles was time-consuming because reporting across health and computing sciences lacked standardization. Reporting guidelines are therefore needed to facilitate the synthesis of evidence across disciplines.


Cloning of genes involved in carbazole degradation of Pseudomonas sp. strain CA10: nucleotide sequences of genes and characterization of meta-cleavage enzymes and hydrolase.
The DNA fragment encoding meta-cleavage enzymes and the meta-cleavage compound hydrolase, involved in carbazole degradation, was cloned from the carbazole-utilizing bacterium Pseudomonas sp. strain CA10. DNA sequence analysis of this 2.6-kb SmaI-SphI fragment revealed that there were three open reading frames (ORF1, ORF2, and ORF3, in this gene order). ORF1 and ORF2 were indispensable for meta-cleavage activity for 2'-aminobiphenyl-2,3-diol and its easily available analog, 2,3-dihydroxybiphenyl, and were designated carBa and carBb, respectively. The alignment of CarBb with other meta-cleavage enzymes indicated that CarBb may have a non-heme iron cofactor coordinating site. On the basis of the phylogenetic tree, CarBb was classified as a member of the protocatechuate 4,5-dioxygenase family. This unique extradiol dioxygenase, CarB, had significantly higher affinity and about 20-times-higher meta-cleavage activity for 2,3-dihydroxybiphenyl than for catechol derivatives. The putative polypeptide encoded by ORF3 was homologous with meta-cleavage compound hydrolases in other bacteria, and ORF3 was designated carC. The hydrolase activity of CarC for 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid, the meta-cleavage compound of 2,3-dihydroxybiphenyl, was 40 times higher than that for 2-hydroxy-6-oxohepta-2,4-dienoic acid, the meta-cleavage compound of 3-methylcatechol. Alignment analysis and the phylogenetic tree indicate that CarC has greatest homologies with hydrolases involved in the monoaromatic compound degradation pathway. These results suggest the possibility that CarC is a novel type of hydrolase.


Correction of enzyme deficiency in mice by allogeneic bone marrow transplantation with total lymphoid irradiation.
Enzyme deficiency was corrected in mice after allogeneic bone marrow transplantation with occurrence of graft versus host disease. beta-Glucuronidase-deficient C3H/HeJ mice were treated with total lymphoid irradiation. Normal bone marrow cells (30 X 10(6)) from BALB/c to C3H/HeJ chimeras (>90 percent circulating donor-type cells) without graft versus host disease. beta-Glucuronidase activity increases to normal levels in all chimeras as measured in the liver and in the plasma. Activity was maintained throughout an observation period of 7 months.


Genetic characterization of the Asian Taenia, a newly described taeniid cestode of humans.
Recent studies on the epidemiologic pattern of taeniasis in Southeast Asia have indicated the existence of a third form of human Taenia, distinguishable from Taenia saginata and T. solium. Originally termed Taiwan Taenia, and first described in Taiwanese aboriginals, this newly recognized taeniid is now generally referred to as Asian Taenia since it has since been recorded in a number of other Asian countries. Here we have used a genetic yardstick approach to determine whether the Asian Taenia should most appropriately be considered as a new, distinct species or as a subspecies, strain, or variant of T. saginata, which previous studies have shown it closely resembles. Sequence variation in the 28S rRNA and mitochondrial cytochrome c oxidase I (COI) genes of a range of taeniid cestodes and the COI and rDNA internal transcribed spacer I polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) pattern differences in the Asian Taenia, T. saginata, and T. solium were used as markers of genetic identity. The PCR-RFLP approaches proved useful for rapid and unambiguous discrimination of Asian Taenia from the other two human species, whereas the mitochondrial and nuclear sequence comparisons indicate that the Asian Taenia is much more closely related to T. saginata than recognized taeniid species are to each other. The results support earlier conclusions that the Asian Taenia is a genetically distinct entity but is closely related to T. saginata, and suggest that its taxonomic classification as a subspecies or strain of T. saginata is more appropriate than formal designation as a new species. The very close relationship between Asian Taenia and T. saginata has public health implications in that the Asian form is unlikely to be an important cause of human cysticercosis because T. saginata cysticercosis, if it occurs at all in humans, is an extremely rare phenomenon.


Establishment of five immortalized human ovarian surface epithelial cell lines via SV40 T antigen or HPV E6/E7 expression.
Human ovarian surface epithelial (HOSE) cells are a critical cell source for ovarian cancer research; however, they are difficult to obtain and maintain under standard laboratory conditions in large quantities. The aim of this study was to generate immortalized HOSE (IHOSE) cells with maintained properties to the original cell source, thereby guaranteeing a sufficiently large cell quantity for ovarian cancer research. HOSE cells isolated from four non-cancer patients and five IHOSE cell lines were established by induction of HPV-E6/E7 expression or SV40 large T antigen using a lenti-viral system. Each of IHOSE cells was confirmed to be distinct by STR profiling. RNA-sequencing was used to compare gene expression profiles in HOSE, IHOSE and ovarian cancer cells. RNA-sequencing results revealed a stronger linear correlation in gene expression between IHOSE and HOSE cells (R2 = 0.9288) than between IHOSE or HOSE cells and ovarian cancer cells (R2 = 0.8562 and R2 = 0.7982, respectively). The gene expression pattern of 319 differentially expressed genes revealed minimal differences between HOSE and IHOSE cells, while a strong difference between ovarian cancer cells and HOSE or IHOSE cells was observed. Furthermore, the five IHOSE cell lines displayed morphological characteristics typical of epithelial cells but showed a lower level of EpCAM, CD133 and E-cadherin, as cancer stem marker, than ovarian cancer cells. Moreover, unlike cancer cells, IHOSE cells could not form colonies in the anchorage-independent soft agar growth assay. These findings demonstrate that five newly established IHOSE cell lines have characteristics of progenitor HOSE cells while exhibiting continuous growth, and thus, should be highly useful as control cells for ovarian cancer research.


Levan based fibrous scaffolds electrospun via co-axial and single-needle techniques for tissue engineering applications.
This represents the first systematic study where levan polysaccharide was used to fabricate fibrous matrices by co-axial and single-needle electrospinning techniques. For this, hydrolyzed (hHL) and sulfated hydrolyzed (ShHL) Halomonas levan were chemically synthesized and used together with polycaprolactone (PCL) and polyethyleneoxide (PEO) for the spinning process. In co-axially spun matrices, ultimate tensile strength (UTS) were found to increase with increasing ShHL concentration and elongation at break of PCL + ShHL matrices increased up to ten-fold when compared to PCL matrices. Similarly, in single-needle spun matrices, higher elongation at break values were obtained by blending HL and ShHL with PEO pointing to the effective energy absorbing features. Dense and fine fibers were characterized by FTIR and SEM. Cell viability and fluorescence imaging of L929 fibroblasts and HUVECs as well as heparin mimetic activity of the matrices pointed to their high potential to be used in decreasing neointimal proliferation and thrombogenicity of grafts and prosthesis.


Telomeres and Longevity: A Cause or an Effect?
Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.


Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis.
Schizophrenia is characterized by altered prefrontal activity and elevated striatal dopaminergic function. To investigate the relationship between these abnormalities in the prodromal phase of the illness, we combined functional Magnetic Resonance Imaging and (18)F-Dopa Positron Emission Tomography. When performing a verbal fluency task, subjects with an At-Risk Mental State showed greater activation in the inferior frontal cortex than controls. Striatal dopamine function was greater in the At-Risk group than in controls. Within the At-Risk group, but not the control group, there was a direct correlation between the degree of left inferior frontal activation and the level of striatal dopamine function. Altered prefrontal activation in subjects with an At-Risk Mental State for psychosis is related to elevated striatal dopamine function. These changes reflect an increased vulnerability to psychosis and predate the first episode of frank psychosis.


Neurologists' perspectives on medical cannabis for pediatric drug-resistant epilepsy in Canada: A qualitative interview study.
To understand the experiences with and perspectives of neurologists about the use of medical cannabis in the treatment of pediatric drug-resistant epilepsy. In this qualitative study, we interviewed neurologists who provide care to children with drug-resistant epilepsy in Canada. Through semi-structured telephone interviews, we sought participants' views about and experiences with medical cannabis for the treatment of drug-resistant epilepsy in children. Here we present a thematic summary of the interviews. The 12 interviewed neurologists generally perceived medical cannabis as a viable treatment option for children with drug-resistant epilepsy; however, participants identified important gaps in the evidence and implications for their practices. Six themes were generated from the content of the interviews: learning about medical cannabis; perceptions about medical cannabis; discussing medical cannabis with parents; experiences with medical cannabis authorization; barriers to authorizing medical cannabis; and the impact of medical cannabis on clinical care. Of note, while some neurologists took on all aspects of the children's care, including medical cannabis, others referred interested families to non-neurology health care professionals. Our findings highlight the diverse opinions and experiences of neurologists in Canada with medical cannabis for the treatment of drug-resistant epilepsy in children, including with the authorization process and caring for children using medical cannabis. Additional education about medical cannabis may be warranted, in order to better prepare neurologists to have informed and open conversations with parents about this treatment option and to provide care for children using medical cannabis.


Aneurysm rupture after EVAR: can the ultimate failure be predicted?
To provide insight into the causes and timing of AAA rupture after EVAR. Original data regarding AAA ruptures following EVAR were collected from MEDLINE and EMBASE databases. Data were extracted systematically and patient and procedural characteristics were analyzed. 270 patients with AAA ruptures after EVAR were identified. Causes of rupture included endoleaks (in 160: type IA 57, type IB 31, type II 23, type III 26, type IV 0, endotension 9, unspecified 14), graft migration 41, graft disconnection 11 and infection 6. Most of the described AAA ruptures occurred within 2-3 years after EVAR. Mean initial AAA diameter was relatively large (65 mm). No abnormalities were present in 41 patients during follow-up before rupture. Structural graft failure was described in 96 and a fatal course in 119 patients. Focus of surveillance on the first 2-3 years after EVAR may possibly reduce the AAA rupture rate, especially in patients with increased risk of early rupture (relatively large initial AAA diameter or presence of endoleak or graft migration). Better stent-graft durability and longevity is required to further reduce the AAA rupture risk after EVAR. Complete prevention will however remain challenging since AAA rupture may occur even if no predisposing abnormalities are present.


Molecular analysis of ATP-sensitive K channel gating and implications for channel inhibition by ATP.
The beta cell KATP channel is an octameric complex of four pore-forming subunits (Kir6.2) and four regulatory subunits (SUR1). A truncated isoform of Kir6.2 (Kir6.2DeltaC26), which expresses independently of SUR1, shows intrinsic ATP sensitivity, suggesting that this subunit is primarily responsible for mediating ATP inhibition. We show here that mutation of C166, which lies at the cytosolic end of the second transmembrane domain, to serine (C166S) increases the open probability of Kir6.2DeltaC26 approximately sevenfold by reducing the time the channel spends in a long closed state. Rundown of channel activity is also decreased. Kir6.2DeltaC26 containing the C166S mutation shows a markedly reduced ATP sensitivity: the Ki is reduced from 175 microM to 2.8 mM. Substitution of threonine, alanine, methionine, or phenylalanine at position C166 also reduced the channel sensitivity to ATP and simultaneously increased the open probability. Thus, ATP does not act as an open channel blocker. The inhibitory effects of tolbutamide are reduced in channels composed of SUR1 and Kir6.2 carrying the C166S mutation. Our results are consistent with the idea that C166 plays a role in the intrinsic gating of the channel, possibly by influencing a gate located at the intracellular end of the pore. Kinetic analysis suggests that the apparent decrease in ATP sensitivity, and the changes in other properties, observed when C166 is mutated is largely a consequence of the impaired transition from the open to the long closed state.


Ultrathin nickel oxide film as a hole buffer layer to enhance the optoelectronic performance of a polymer light-emitting diode.
In order to promote a polymer LED (PLED), we fabricated and introduced an ultrathin nickel oxide (NiO) buffer layer (<10 nm) between the indium tin oxide (ITO) anode and the poly (3, 4-ethylenedioxythiophene) hole injection layer in the PLED. The NiO buffer layer was easily formed on the ITO anode by electron-beam deposition of a nickel (Ni) metal source and an oxygen plasma treatment process. As a result, the PLED device with the NiO buffer layer on its ITO anode had the same turn-on voltage as conventional PLED devices without the NiO buffer layer, and the luminance of the PLED device with the NiO buffer layer was doubled, compared with the conventional PLED devices without the NiO buffer layer. Improvement of the optoelectronic performance of the PLED can be attributed to the increase of the current driven into the diode, resulting from the NiO buffer layer, which can enhance the hole injection and balance the injection of the two types of carriers (holes and electrons). Thus it is an excellent choice to introduce the NiO buffer layer onto the ITO anode of the PLED devices in order to enhance the optoelectronic performance of PLED devices.


Health-promoting hospitals in Estonia: what are they doing differently?
The health-promoting hospitals (HPH) movement in Estonia was initiated in 1999. This study aimed to compare the implementation of health-promoting and quality-related activities in HPH and those which have not joined the HPH network (non-HPH). In the beginning of 2005, a postal survey was conducted among the top managers of 54 Estonian hospitals. The questionnaire was based on the WHO standards for HPH and on the set of the national quality assurance (QA) requirements for health services. The study demonstrated some significant differences in the uptake of health promotion and QA activities between HPH and non-HPH. For example, regular patient satisfaction studies were conducted in 83% of HPH and 46% of non-HPH (P < 0.03) and 65% of HPH and 46% of non-HPH cooperated with various patient organizations (P < 0.03). Systems for reporting and analysis of complications were implemented in 71% of HPH and 33% of non-HPH (P < 0.03); also, the implementation of various guidelines was more developed in HPH. All HPH have carried out a risk analysis on the workplace and staff job satisfaction studies were conducted in 89% of HPH and 41% non-HPH (P < 0.05). This study indicates that the concepts of HPH and QA are closely related. Making progress in health promotion is accompanied with QA and vice versa. Implementation of health-promoting activities in hospitals will promote the well-being and health of patients and hospital staff, and creates a supportive environment to provide safe and high-quality health services.


Neurobiological, cognitive, and emotional mechanisms in melodic intonation therapy.
Singing has been used in language rehabilitation for decades, yet controversy remains over its effectiveness and mechanisms of action. Melodic Intonation Therapy (MIT) is the most well-known singing-based therapy; however, speculation surrounds when and how it might improve outcomes in aphasia and other language disorders. While positive treatment effects have been variously attributed to different MIT components, including melody, rhythm, hand-tapping, and the choral nature of the singing, there is uncertainty about the components that are truly necessary and beneficial. Moreover, the mechanisms by which the components operate are not well understood. Within the literature to date, proposed mechanisms can be broadly grouped into four categories: (1) neuroplastic reorganization of language function, (2) activation of the mirror neuron system and multimodal integration, (3) utilization of shared or specific features of music and language, and (4) motivation and mood. In this paper, we review available evidence for each mechanism and propose that these mechanisms are not mutually exclusive, but rather represent different levels of explanation, reflecting the neurobiological, cognitive, and emotional effects of MIT. Thus, instead of competing, each of these mechanisms may contribute to language rehabilitation, with a better understanding of their relative roles and interactions allowing the design of protocols that maximize the effectiveness of singing therapy for aphasia.


Changes in plasma bile acids, plasma amino acids, and hepatic enzyme pools as indices of functional impairment in liver-damaged sheep.
Plasma bile acids, plasma amino acids, and the total hepatic pools of aspartate aminotransferase, gamma glutamyltransferase, glutamate dehydrogenase, and sorbitol dehydrogenase were compared in control sheep (Group 1), sheep with subclinical pyrrolizidine alkaloid toxicosis (Group 2), and in sheep with acute hepatocellular necrosis associated with the hemolytic phase of chronic copper poisoning (Group 3). Subclinical pyrrolizidine alkaloid toxicosis was not associated with any changes in bile acid or amino acid status but was associated with a significant decline in the hepatic pools of sorbitol dehydrogenase and aspartate aminotransferase. This observation could not be explained in terms of enzyme leakage from damaged hepatocytes and suggested that pyrrolizidine alkaloids might specifically inhibit hepatocellular enzyme synthesis. Group 3 sheep also had reduced hepatic enzyme pools which were at least partly referable to enzyme leakage from damaged hepatocytes. In these sheep, increases in plasma bile acids were a more sensitive index of hepatic function than were either increased aromatic amino acid concentration or the ratio between branched chain and aromatic amino acids.


Effects of recall time on cause-of-death findings using verbal autopsy: empirical evidence from rural South Africa.
Verbal autopsy (VA) is a widely used technique for assigning causes to non-medically certified deaths using information gathered from a close caregiver. Both operational and cultural factors may cause delays in follow-up of deaths. The resulting time lag-from death to VA interview-can influence ways in which terminal events are remembered, and thus affect cause-of-death assignment. This study investigates the impact of recall period on causes of death determined by VA. A total of 10,882 deaths from the Agincourt Health and Demographic Surveillance System (HDSS) with complete VAs, including recall period, were incorporated in this study. To measure seasonal effect, cause specific mortality fractions (CSMFs) were calculated and compared by every cause for VAs undertaken within six months of death and those undertaken from six to 12 months of death. All causes were classified into eight broad categories and entered in a multiple logistic regression to explore outcome by recall period in relation to covariates. The majority of deaths (83 %) had VAs completed within 12 months. There was a tendency towards longer recall periods for deaths of those under one year or over 65 years of age. Only the acute respiratory, diarrhoeal and other unspecified non-communicable disease groups showed a CSMF ratio significantly different from unity at the 99 % confidence level between the two recall periods. Only neonatal deaths showed significantly different OR for recall exceeding 12 months (OR 1.69; p value = 0.004) and this increased when adjusting for background factors (OR 2.58; p value = 0.000). A recall period of up to one year between death and VA interview did not have any consequential effects on the cause-of-death patterns derived, with the exception of neonatal causes. This is an important operational consideration given the planned widespread use of the VA approach in civil registration, HDSS sites and occasional surveys.


Therapeutic relationship in the context of perceived coercion in a psychiatric population.
The relationship between patient and therapist in mental health care is one of the most important treatment factors. It is a reliable predictor of treatment outcome, regardless of diagnosis, setting or of the type of therapy used. On the other hand, influence and coercion occur in patient-physician relationships in psychiatry. We investigated the associations between patients' perceived coercion and the therapeutic relationship. A total of 116 psychiatric patients, who have been admitted to the Psychiatric University Hospital Zurich, were interviewed using a structured interview. Data were collected by using Scale To Assess the Therapeutic Relationship (STAR) (therapeutic relationship) and Mac Arthur Admission Experience Survey (AES) (perceived coercion). Associations were investigated using bivariate and multivariate methods. Perceived coercion predicts the patients' appraisal of the therapeutic relationship. We found a moderate relation between the patients' and the clinicians' view of their relationship. Perceived coercion is related to a higher symptom level and a lower level of global functioning at admission, and higher perceived coercion is related to a more negative patient-therapist relationship rated by the patient. Perceived loss of autonomy goes hand in hand with a more negative relationship between the patient and the clinician. This phenomenon has to be impeded, regarding the unambiguous impact relationship quality has on treatment outcome.


Oocyte activation procedures and influence of serum on porcine oocyte maturation and subsequent parthenogenetic and nuclear transfer embryo development.
The viability of SCNT embryos is poor, with an extremely low cloned piglet production rate. In the present work, we studied the effect of three activation protocols based on ionomycin treatment (5 microM ionomycin for 5 min and incubated in 2 mM 6-DMAP for 3.5 h) or electric stimuli (two square wave electrical DC pulses of 1.2 kV/cm for 30 micros) combined or not with 6-DMAP on parthenogenetic embryo development. Oocytes activated by ionomycin plus 6-DMAP showed lower cleavage (47.2 vs. 78.5-81.5; p < 0.05) and blastocyst rates (11.3 vs. 29.2-32.1; p < 0.05) than those activated by electrical and electrical plus 6-DMAP treatments. Also, we studied the effect of addition of serum to maturation medium (0% vs. 10%) on nuclear maturation and further parthenogenetic and SCNT embryo development. We observed in the parthenogenetic embryos that cleavage rates in the serum-free group were significantly higher than in the serum-supplemented group (81.8 vs. 69.6% respectively; p < 0.05), although these differences were not detected in blastocyst rates or blastocyst nuclei numbers. Regarding SCNT embryos, no significant differences were observed in cleavage or blastocyst rates between different experimental groups of SCNT embryos. In conclusion, electrical pulse followed or not by 6-DMAP was found to be an efficient procedure to artificially activate MII porcine oocytes. Moreover, the addition of serum to oocyte maturation media did not seem to improve parthenogenetic or SCNT porcine embryo development.


Maternal body mass index, gestational weight gain, and the risk of overweight and obesity across childhood: An individual participant data meta-analysis.
Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.


'Roll-your-own' cigarette smoking in South Africa between 2007 and 2010.
The prevalence of smoking and consumption of cigarettes have decreased in South Africa over the last 20 years. This decrease is a result of comprehensive tobacco control legislation, particularly large cigarette tax increases. However, little attention has been given to the potential use of 'roll-your-own' cigarettes as cheaper alternatives, especially among the socio-economically disadvantaged population. This study therefore sought to determine socio-demographic correlates of 'roll-your-own' cigarette use among South African adults (2007-2010). This secondary data analysis used a merged dataset from two nationally representative samples of 2 907 and 3 112 South African adults (aged ≥16 years) who participated in the 2007 and 2010 annual South African Social Attitude Surveys respectively. The surveys used a face-to-face interviewer-administered questionnaire. The overall response rates were 83.1% for 2007 and 88.9% for 2010. Data elicited included socio-demographic data, current smoking status, type of tobacco products used, past quit attempts and self-efficacy in quitting. Data analysis included chi-square statistics and multi-variable adjusted logistic regression analysis. Of the 1 296 current smokers in this study, 24.1% (n = 306) reported using roll-your-own cigarettes. Some of whom also smoked factory-made cigarettes. Roll-your-own cigarette smoking was most common among black Africans and was more common among male smokers than among female smokers (27% vs 15.8%; p < 0.01). Compared to smokers who exclusively used factory-made cigarettes, roll-your-own cigarette smokers were less confident that they could quit, more likely to be less educated, and more likely to reside in rural areas. The odds of use of roll-your-own cigarette were significantly higher in 2010 than in 2007 (OR = 1.24; 95% CI: 1.07-1.44). Despite an aggregate decline in smoking prevalence, roll-your-own cigarette smoking has increased and is particularly common among smokers in the lower socio-economic group. The findings also suggest the need for a more intensive treatment intervention to increase self-efficacy to quit among roll-your-own cigarette smokers.


A cooperative study of epirubicin with cyclophosphamide, vincristine and prednisone (CEOP) in non-Hodgkin's lymphoma.
The purpose of our cooperative trial was to investigate whether epirubicin (EPI) at 90 mg/m2 in a CHOP-like combination (called CEOP) could increase complete response (CR) and survival rates in non-Hodgkin lymphoma (NHL) patients while maintaining a tolerable degree of toxicity. Between September 1986 and July 1992, 218 patients from 12 Centers in Lombardy entered this study. The inclusion criteria were: a histological diagnosis of intermediate or diffuse large cell (DLC) NHL and no previous radio-chemotherapy. The patients in stages IA and IIA (both intermediate and DLC) received four CEOP courses followed by local/regional radiotherapy; those with intermediate NHL in stages IB, IIB, III A and B and IV A and B received six CEOP courses and, if they achieved CR, three further courses as consolidation. Among the 160 evaluable patients, CR was observed in 90% of the subjects with DLC-NHL (stages IA and IIA) and in 59% of those with intermediate-grade NHL (all clinical stages). If the clinical stages are considered separately, the CR rates were 92% for stages IA, IIA and 53% for stages IB, IIB, III A and B, IV A and B. Relapses occurred in 20% of the patients treated with four CEOP courses plus radiotherapy and in 31% of those who received nine CEOP courses because of the advanced stage of their disease. As of May 1994, the median follow-up was 42 months. If all of the patients are considered together, the 7-year overall survival (OS) probability was 64% and the 7-year disease-free survival (DFS) probability 67%. In comparison with stages III/IV, the patients in stages I-II had better DFS (7-year chance 77% vs 56%, p < 0.03). Hematological toxicity was acceptable, and a delay in the administration of CEOP chemotherapy was required in only three patients. No life-threatening infections were recorded. Our cooperative study of the use of the CEOP combination in NHL patients shows that response rates and the length of DFS are equal to the best results obtained with CHOP and more intensive programs, although further confirmation must be provided by means of a longer follow-up and a more careful analysis of prognostic factors according to the recently proposed international index. In our experience, an EPI dose of 90 mg/m2 has negligible toxicity (particularly on bone marrow), even in elderly patients. These findings are interesting since it is well known that myelotoxicity is the principal limiting factor for the majority of anthracycline-containing regimens used in the treatment of potentially curable NHL.


Treatment of erythema chronicum migrans of Lyme disease.
Between June 1981 and July 1987 the efficacy of antibiotic treatment of 215 patients with erythema chronicum migrans of Lyme disease was evaluated in terms of the necessity for retreatment and the prevention of the late manifestations of Lyme disease. The principal antibiotics utilized to treat 161 patients through 1986 were varying doses of tetracycline, or penicillin alone or in combination with probenecid. Two of 80 patients with a minor form of the illness and 17 of 81 patients with a major form of the illness required retreatment. There were four patients who did not respond to retreatment with their original medication. A 15- to 30-day course of amoxicillin (500 mg q.i.d.) and probenecid (500 mg q.i.d.) or doxycycline (100 mg t.i.d.), and on three occasions ceftriaxone (2-4 g/day i.v.), were used to treat 54 patients in 1987. Although it is too early to judge the efficacy of treatment in these patients, increases in the incidence of Herxheimer reactions and drug eruptions were observed. Strict compliance with treatment protocols and the possibility of reactions to medications should be thoroughly discussed with patients.


Near real-time monitoring of HIV transmission hotspots from routine HIV genotyping: an implementation case study.
HIV evolves rapidly and therefore infections with similar genetic sequences are likely linked by recent transmission events. Clusters of related infections can represent subpopulations with high rates of transmission. We describe the implementation of an automated near real-time system to monitor and characterise HIV transmission hotspots in British Columbia, Canada. In this implementation case study, we applied a monitoring system to the British Columbia drug treatment database, which holds more than 32 000 anonymised HIV genotypes for nearly 9000 residents of British Columbia living with HIV. On average, five to six new HIV genotypes are deposited in the database every day, which triggers an automated reanalysis of the entire database. We extracted clusters of five or more individuals with short phylogenetic distances between their respective HIV sequences. The system generated monthly reports of the growth and characteristics of clusters that were distributed to public health officers. In June, 2014, the monitoring system detected the expansion of a cluster by 11 new cases during 3 months, including eight cases with transmitted drug resistance. This cluster generally comprised young men who have sex with men. The subsequent report precipitated an enhanced public health follow-up to ensure linkage to care and treatment initiation in the affected subpopulation. Of the nine cases associated with this follow-up, all had already been linked to care and five cases had started treatment. Subsequent to the follow-up, three additional cases started treatment and most cases achieved suppressed viral loads. During the next 12 months, we detected 12 new cases in this cluster with reduction in the onward transmission of drug resistance. Our findings show the first application of an automated phylogenetic system monitoring a clinical database to detect a recent HIV outbreak and support the ensuing public health response. By making secondary use of routinely collected HIV genotypes, this approach is cost-effective, attains near real-time monitoring of new cases, and can be implemented in all settings in which HIV genotyping is the standard of care. BC Centre for Excellence in HIV/AIDS, the Canadian Institutes for Health Research, the Genome Canada-CIHR Partnership in Genomics and Personalized Health, and the US National Institute on Drug Abuse.


Successful treatment and management of large superficial basal cell carcinomas with topical imiquimod 5% cream: a case series and review.
Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer in the Caucasian population and its incidence is increasing worldwide. Although surgical procedures show a high cure rate with acceptable morbidity, non-surgical, pharmacotherapeutic approaches have been regarded as appropriate alternatives, and/or first-line treatments, in selected cases. Imiquimod (IQ) is a synthetic imidazoquinoline amine that locally enhances, through cytokine induction, both innate and acquired immune pathways, resulting in immunomodulating, antiviral and antitumor effects. Topical IQ 5% cream is approved by the FDA and the European Union for the treatment of small superficial BCCs (<2.0 cm); however, published data highlight the possibility of successful outcomes in larger lesions. We report three patients, each one presenting with a large BCC and successfully treated with IQ 5% cream. Although our cases and those from the literature do not rise to the level of evidence, IQ may be a reliable, efficacious and safe non-surgical option for selected cases of large superficial BCCs. Histological examination should occur at baseline and at the end of treatment along with clinical and dermatoscopic examination at least monthly during the course of the treatment and every 6 months for 2 years following the treatment.


Plant dehydrins--tissue location, structure and function.
Dehydrins (DHNs) are part of a large group of highly hydrophilic proteins known as LEA (Late Embryogenesis Abundant). They were originally identified as group II of the LEA proteins. The distinctive feature of all DHNs is a conserved, lysine-rich 15-amino acid domain, EKKGIMDKIKEKLPG, named the K-segment. It is usually present near the C-terminus. Other typical dehydrin features are: a track of Ser residues (the S-segment); a consensus motif, T/VDEYGNP (the Y-segment), located near the N-terminus; and less conserved regions, usually rich in polar amino acids (the Phi-segments). They do not display a well-defined secondary structure. The number and order of the Y-, S-and K-segments define different DHN sub-classes: Y(n)SK(n), Y(n)Kn, SK(n), K(n) and K(n)S. Dehydrins are distributed in a wide range of organisms including the higher plants, algae, yeast and cyanobacteria. They accumulate late in embryogenesis, and in nearly all the vegetative tissues during normal growth conditions and in response to stress leading to cellular dehydration (e.g. drought, low temperature and salinity). DHNs are localized in different cell compartments, such as the cytosol, nucleus, mitochondria, vacuole, and the vicinity of the plasma membrane; however, they are primarily localized to the cytoplasm and nucleus. The precise function of dehydrins has not been established yet, but in vitro experiments revealed that some DHNs (YSK(n)-type) bind to lipid vesicles that contain acidic phospholipids, and others (K(n)S) were shown to bind metals and have the ability to scavenge hydroxyl radicals [Asghar, R. et al. Protoplasma 177 (1994) 87-94], protect lipid membranes against peroxidation or display cryoprotective activity towards freezing-sensitive enzymes. The SK(n)-and K-type seem to be directly involved in cold acclimation processes. The main question arising from the in vitro findings is whether each DHN structural type could possess a specific function and tissue distribution. Much recent in vitro data clearly indicates that dehydrins belonging to different subclasses exhibit distinct functions.


Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011.
The CBTRUS Statistical Report: Alex's Lemonade Stand Foundation Infant and Childhood Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011 comprehensively describes the current population-based incidence of primary malignant and non-malignant brain and CNS tumors in children ages 0–14 years, collected and reported by central cancer registries covering approximately 99.8% of the United States population (for 2011 only, data were available for 50 out of 51 registries). Overall, brain and CNS tumors are the most common solid tumor, the most common cancer, and the most common cause of cancer death in infants and children 0–14 years. This report aims to serve as a useful resource for researchers, clinicians, patients, and families.


Systems analysis of bioenergetics and growth of the extreme halophile Halobacterium salinarum.
Halobacterium salinarum is a bioenergetically flexible, halophilic microorganism that can generate energy by respiration, photosynthesis, and the fermentation of arginine. In a previous study, using a genome-scale metabolic model, we have shown that the archaeon unexpectedly degrades essential amino acids under aerobic conditions, a behavior that can lead to the termination of growth earlier than necessary. Here, we further integratively investigate energy generation, nutrient utilization, and biomass production using an extended methodology that accounts for dynamically changing transport patterns, including those that arise from interactions among the supplied metabolites. Moreover, we widen the scope of our analysis to include phototrophic conditions to explore the interplay between different bioenergetic modes. Surprisingly, we found that cells also degrade essential amino acids even during phototropy, when energy should already be abundant. We also found that under both conditions considerable amounts of nutrients that were taken up were neither incorporated into the biomass nor used as respiratory substrates, implying the considerable production and accumulation of several metabolites in the medium. Some of these are likely the products of forms of overflow metabolism. In addition, our results also show that arginine fermentation, contrary to what is typically assumed, occurs simultaneously with respiration and photosynthesis and can contribute energy in levels that are comparable to the primary bioenergetic modes, if not more. These findings portray a picture that the organism takes an approach toward growth that favors the here and now, even at the cost of longer-term concerns. We believe that the seemingly "greedy" behavior exhibited actually consists of adaptations by the organism to its natural environments, where nutrients are not only irregularly available but may altogether be absent for extended periods that may span several years. Such a setting probably predisposed the cells to grow as much as possible when the conditions become favorable.


Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages.
Mutations in membrane frizzled-related protein (MFRP) are associated with nanophthalmia, hyperopia, foveoschisis, irregular patches of RPE atrophy, and optic disc drusen in humans. Mouse mfrp mutants show retinal degeneration but no change in eye size or refractive state. The goal of this work was to generate zebrafish mutants to investigate the loss of Mfrp on eye size and refractive state, and to characterize other phenotypes observed. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 methods were used to generate multiple frameshift mutations in zebrafish mfrp causing premature translational stops in Mfrp. Spectral-domain optical coherence tomography (SD-OCT) was used to measure eye metrics and refractive state, and immunohistochemistry was used to study adult eyes. Gene expression levels were measured using quantitative PCR. Zebrafish Mfrp was shown to localize to apical and basal regions of RPE cells, as well as the ciliary marginal zone. Loss of Mfrp in mutant zebrafish was verified histologically. Zebrafish eyes that were mfrp mutant showed reduced axial length causing hyperopia, RPE folding, and macrophages were observed subretinally. Visual acuity was reduced in mfrp mutant animals. Mutation of zebrafish mfrp results in hyperopia with subretinal macrophage infiltration, phenocopying aspects of human and mouse Mfrp deficiency. These mutant zebrafish will be useful in studying the onset and progression of Mfrp-related nanophthalmia, the cues that initiate the recruitment of macrophages, and the mechanisms of Mfrp function.


A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder.
To investigate the safety and efficacy of aripiprazole in preventing relapse of a mood episode in recently manic- or mixed-episode patients with bipolar I disorder stabilized on aripiprazole. This randomized, double-blind, parallel-group, placebo-controlled, multicenter study enrolled patients from 76 centers in 3 countries (Argentina, Mexico, United States) from March 2000 to June 2003. Bipolar I disorder (DSM-IV) patients who had recently been hospitalized and treated for a manic or mixed episode entered an open-label stabilization phase (aripiprazole monotherapy: 15 or 30 mg/day, 6-18 weeks). After meeting stabilization criteria (Young Mania Rating Scale score of < or = 10 and Montgomery-Asberg Depression Rating Scale score of < or = 13 for 6 consecutive weeks), 161 patients were randomly assigned to aripiprazole or placebo for the 26-week, double-blind phase. The primary endpoint was time to relapse for a manic, mixed, or depressive episode (defined by discontinuation caused by lack of efficacy). Aripiprazole was superior to placebo in delaying the time to relapse (p = .020). Aripiprazole-treated patients had significantly fewer relapses (25%) than placebo patients (43%; p = .013). Aripiprazole was superior to placebo in delaying the time to manic relapse (p = .01); however, no significant differences were observed in time to depressive relapse (p = .68). Weight gain (> or = 7% increase) occurred in 7 (13%) aripiprazole-treated and 0 placebo-treated patients. Adverse events (> or = 5% incidence and twice that of placebo) reported by aripiprazole-treated patients were akathisia, pain in the extremities, tremor, and vaginitis. Aripiprazole, 15 or 30 mg/day, was superior to placebo in maintaining efficacy in patients with bipolar I disorder with a recent manic or mixed episode who were stabilized and maintained on aripiprazole treatment for 6 weeks, as shown by a longer time to relapse.


Tinea incognito due to Trichophyton rubrum--a case report.
Tinea incognito is a dermatophyte infection modified by inappropriate and often prolonged use of topical steroids. We present a case of tinea incognito in a 72-year-old woman, referred by her family physician who had unsuccessfully treated the lesions for 3 weeks with topical steroid cream. Physical examination revealed multiple nummular scaly papules and plaques which spread over her arms and trunk. The lesions were circular, erythematous, sharply demarcated with raised scaly edge some coalescing to form moderately infiltrated areas. Direct microscopy was positive for fungal hyphae. Fungal culture on Sabouraud's agar grew Trichophyton rubrum. The patient was successfully treated with oral terbinafine 250 mg daily and 1% clotrimazole cream twice daily. The present case highlights the importance of considering a dermatophytosis when clinical presentation of dermatosis is atypical. Disseminated scaly infiltrate lesions should be investigated for fungal infection in patients previously treated with steroids, as to avoid misdiagnosis and spread of infection.


Surface morphology of the gastroduodenal mucosa in duodenal ulceration.
Endoscopic biopsies from the duodenal cap and prepyloric areas of 25 patients have been examined with the scanning electron microscope. Eleven patients had duodenal ulceration. Bacteria are related only to the surface of gastric type epithelial cells whether these cells are located at areas of gastric metaplasia in the duodenal bulb or in the pre-pyloric region of the stomach. The bacteria are not associated with the surface of intestinal type epithelial cells. The bacteria are absent from the biopsies of those patients with a normal stomach and duodenum. Of those patients with duodenal ulceration, 73% have bacteria related to the epithelial surface. The bacteria are of two morphological types - a kidney shaped bacillus and an S-shaped bacillus.


Structures of enveloped virions determined by cryogenic electron microscopy and tomography.
Enveloped viruses enclose their genomes inside a lipid bilayer which is decorated by membrane proteins that mediate virus entry. These viruses display a wide range of sizes, morphologies and symmetries. Spherical viruses are often isometric and their envelope proteins follow icosahedral symmetry. Filamentous and pleomorphic viruses lack such global symmetry but their surface proteins may display locally ordered assemblies. Determining the structures of enveloped viruses, including the envelope proteins and their protein-protein interactions on the viral surface, is of paramount importance. These structures can reveal how the virions are assembled and released by budding from the infected host cell, how the progeny virions infect new cells by membrane fusion, and how antibodies bind surface epitopes to block infection. In this chapter, we discuss the uses of cryogenic electron microscopy (cryo-EM) in elucidating structures of enveloped virions. Starting from a detailed outline of data collection and processing strategies, we highlight how cryo-EM has been successfully utilized to provide unique insights into enveloped virus entry, assembly, and neutralization.


Failure to achieve immunological recovery in HIV-infected patients with clinical and virological success after 10 years of combined ART: role of treatment course.
We assessed factors, including treatment course, associated with failure to obtain a 10 year immunological response after starting first-generation PI-containing combined ART (cART). In the prospective COPILOTE cohort of HIV-infected patients started on a first-generation PI-containing regimen in 1997-99, the impact of cART history on the failure to achieve immunological response measured at 10 years was assessed by multivariate logistic regression models in the 399 patients with clinical and virological success of cART. Failure of CD4 response (CD4 >500/mm3) was associated with age ≥40 years at baseline (P < 0.001), CD4 cell counts ≤500/mm3 at month 4 (P = 0.016) or month 12 (P < 0.001) and ≥3 months of cART interruption (P = 0.016). Factors associated with failure to achieve complete immunological response (CD4 >500/mm3 and CD4:CD8 ratio >1) were CD4:CD8 ratio ≤0.8 at month 8 (P < 0.001) or month 12 (P < 0.001), ≥3 months of cumulative cART interruption (P = 0.011), ≥3 antiretroviral regimens (P = 0.009) and ≤4 treatment lines (P = 0.015). Baseline CD4 and CD4:CD8 ratio were not predictors of the 10 year immunological outcomes. In this therapeutic cohort of patients starting first-generation PI-containing cART in 1997-99, poor initial immunological response had a negative impact on 10 year CD4 and CD4 plus CD4:CD8 ratio response, despite prolonged virological success. Lack of treatment interruption may improve long-term immunological outcome in HIV infection.


Regulatory design governing progression of population growth phases in bacteria.
It has long been noted that batch cultures inoculated with resting bacteria exhibit a progression of growth phases traditionally labeled lag, exponential, pre-stationary and stationary. However, a detailed molecular description of the mechanisms controlling the transitions between these phases is lacking. A core circuit, formed by a subset of regulatory interactions involving five global transcription factors (FIS, HNS, IHF, RpoS and GadX), has been identified by correlating information from the well- established transcriptional regulatory network of Escherichia coli and genome-wide expression data from cultures in these different growth phases. We propose a functional role for this circuit in controlling progression through these phases. Two alternative hypotheses for controlling the transition between the growth phases are first, a continuous graded adjustment to changing environmental conditions, and second, a discontinuous hysteretic switch at critical thresholds between growth phases. We formulate a simple mathematical model of the core circuit, consisting of differential equations based on the power-law formalism, and show by mathematical and computer-assisted analysis that there are critical conditions among the parameters of the model that can lead to hysteretic switch behavior, which--if validated experimentally--would suggest that the transitions between different growth phases might be analogous to cellular differentiation. Based on these provocative results, we propose experiments to test the alternative hypotheses.


A carboxylate oxygen of the substrate bridges the magnesium ions at the active site of enolase: structure of the yeast enzyme complexed with the equilibrium mixture of 2-phosphoglycerate and phosphoenolpyruvate at 1.8 A resolution.
The equilibrium mixture of yeast enolase with substrate, 2-phospho-D-glycerate (2-PGA), and product, phosphoenolpyruvate (P-enolpyruvate), has been crystallized from solutions of poly(ethylene glycol) (PEG) at pH 8.0. Crystals belong to the space group C2 and have unit cell dimensions a = 121.9 A, b = 73.2 A, c = 93.9 A, and beta = 93.3 degrees. The crystals have one dimer per asymmetric unit. Crystals of the equilibrium mixture and of the enolase complex of phosphonoacetohydroxamate (PhAH) are isomorphous, and the structure of the former complex was solved from the coordinates of enolase-(Mg2+)2-PhAH [Wedekind, J. E., Poyner, R. R., Reed, G. H., & Rayment, I. (1994) Biochemistry 33, 9333-9342]. The current crystallographic R-factor is 17.7% for all recorded data (92% complete) to 1.8 A resolution. The electron density map is unambiguous with respect to the positions and liganding of both magnesium ions and with respect to the stereochemistry of substrate/product binding. Both magnesium ions are complexed to functional groups of the substrate/product. The higher affinity Mg2+ coordinates to the carboxylate side chains of Asp 246, Glu 295, and Asp 320, both carboxylate oxygens of the substrate/product, and a water molecule. One of the carboxylate oxygens of the substrate/product also coordinates to the lower affinity Mg2+-thus forming a mu-carboxylato bridge. The other ligands of the second Mg2+ are a phosphoryl oxygen of the substrate/product, two water molecules, and the carbonyl and gamma-oxygens of Ser 39 from the active site loop. The intricate coordination of both magnesium ions to the carboxylate group suggests that both metal ions participate in stabilizing negative charge in the carbanion (aci-carboxylate) intermediate. The epsilon-amino group of Lys 345 is positioned to serve as the base in the forward reaction whereas the carboxylate side chain of Glu 211 is positioned to interact with the 3-OH of 2-PGA. The structure provides a candid view of the catalytic machinery of enolase.