Enzymatic degradation of granular potato starch by Microbacterium aurum strain B8.A.
Microbacterium aurum strain B8.A was isolated from the sludge of a potato starch-processing factory on the basis of its ability to use granular starch as carbon- and energy source. Extracellular enzymes hydrolyzing granular starch were detected in the growth medium of M. aurum B8.A, while the type strain M. aurum DSMZ 8600 produced very little amylase activity, and hence was unable to degrade granular starch. The strain B8.A extracellular enzyme fraction degraded wheat, tapioca and potato starch at 37 °C, well below the gelatinization temperature of these starches. Starch granules of potato were hydrolyzed more slowly than of wheat and tapioca, probably due to structural differences and/or surface area effects. Partial hydrolysis of starch granules by extracellular enzymes of strain B8.A resulted in large holes of irregular sizes in case of wheat and tapioca and many smaller pores of relatively homogeneous size in case of potato. The strain B8.A extracellular amylolytic system produced mainly maltotriose and maltose from both granular and soluble starch substrates; also, larger maltooligosaccharides were formed after growth of strain B8.A in rich medium. Zymogram analysis confirmed that a different set of amylolytic enzymes was present depending on the growth conditions of M. aurum B8.A. Some of these enzymes could be partly purified by binding to starch granules.


Mental Health Service Utilization among Students and Staff in 18 Months Following Dawson College Shooting.
The aim of this study was to investigate service utilization by students and staff in the 18 months following the September 13, 2006, shooting at Dawson College, Montreal, as well as the determinants of this utilization within the context of Canada's publicly managed healthcare system. A sample of 948 from among the college's 10,091 students and staff agreed to complete an adapted computer or web-based standardized questionnaire drawn from the Statistics Canada 2002 Canadian Community Health Survey cycle 1.2 on mental health and well-being. In the 18 months following the shooting, there was a greater incidence and prevalence not only of PTSD, but also of other anxiety disorders, depression, and substance abuse. Staff and students were as likely to consult a health professional when presenting a mental or substance use disorder, with females more likely to do so than males. Results also indicated that there was relatively high internet use for mental health reasons by students and staff (14% overall). Following a major crisis event causing potential mass trauma, even in a society characterized by easy access to public, school and health services and when the population involved is generally well educated, the acceptability of consulting health professionals for mental health or substance use problems represents a barrier. However, safe internet access is one way male and female students and staff can access information and support and it may be useful to further exploit the possibilities afforded by web-based interviews in anonymous environments.


Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research.
Principles and practices of pediatric neurotoxicology are reviewed here with the purpose of guiding the design and execution of the planned National Children's Study. The developing human central nervous system is the target organ most vulnerable to environmental chemicals. An investigation of the effects of environmental exposures on child development is a complex endeavor that requires consideration of numerous critical factors pertinent to a study's concept, design, and execution. These include the timing of neurodevelopmental assessment, matters of biologic plausibility, site, child and population factors, data quality assurance and control, the selection of appropriate domains and measures of neurobehavior, and data safety and monitoring. Here we summarize instruments for the assessment of the neonate, infant, and child that are being employed in the Centers for Children's Environmental Health and Disease Prevention Research, sponsored by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency, discuss neural and neurobiologic measures of development, and consider the promises of gene-environment studies. The vulnerability of the human central nervous system to environmental chemicals has been well established, but the contribution these exposures may make to problems such as attention deficit disorder, conduct problems, pervasive developmental disorder, or autism spectrum disorder remain uncertain. Large-scale studies such as the National Children's Study may provide some important clues. The human neurodevelopmental phenotype will be most clearly represented in models that include environmental chemical exposures, the social milieu, and complex human genetic characteristics that we are just beginning to understand.


Switchable Adhesion via Subsurface Pressure Modulation.
Materials and devices with tunable dry adhesion have many applications, including transfer printing, climbing robots, and gripping in pick-and-place processes. In this paper, a novel soft device to achieve dynamically tunable dry adhesion via modulation of subsurface pneumatic pressure is introduced. Specifically, a cylindrical elastomer pillar with a mushroom-shaped cap and annular chamber that can be pressurized to tune the adhesion is investigated. Finite element-based mechanics models and experiments are used to design, understand, and demonstrate the adhesion of the device. Specifically, the device is designed using mechanics modeling such that the pressure applied inside the annular chamber significantly alters the stress distribution at the adhered interface and thus changes the effective adhesion strength. Devices made of polydimethylsiloxane (PDMS) with different elastic moduli were tested against glass, silicon, and aluminum substrates. Adhesion strengths (σ0) ranging from ∼37 kPa (between PDMS and glass) to ∼67 kPa (between PDMS and polished aluminum) are achieved for the nonpressurized state. For all cases, regardless of the material and roughness of the substrates, the adhesion strength dropped to 40% of the strength of the nonpressurized state (equivalent to a 2.5× adhesion switching ratio) by increasing the chamber pressure from 0.3σ0 to 0.6σ0. Furthermore, the strength drops to 20% of the unpressurized strength (equivalent to a 5× adhesion switching ratio) when the chamber pressure is increased to σ0.


Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling.
Wnt/beta-catenin signaling is important in stem cell biology, embryonic development, and disease, including cancer. However, the mechanism of Wnt signal transmission, notably how the receptors are activated, remains incompletely understood. We found that the prorenin receptor (PRR) is a component of the Wnt receptor complex. PRR functions in a renin-independent manner as an adaptor between Wnt receptors and the vacuolar H+-adenosine triphosphatase (V-ATPase) complex. Moreover, PRR and V-ATPase were required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system development. The results reveal an unsuspected role for the prorenin receptor, V-ATPase activity, and acidification during Wnt/beta-catenin signaling.


Experimental results using force-feedback cueing in robot-assisted stroke therapy.
Stroke is the leading cause of disability among adults in the United States. Behaviors such as learned nonuse hinder hemiplegic stroke survivors from the full use of both arms in activities of daily living. Active force-feedback cues, designed to restrain the use of the less-affected arm, were embedded into a meaningful driving simulation environment to create robot-assisted therapy device, driver's simulation environment for arm therapy (SEAT). The study hypothesized that force-feedback control mode could "motivate" stroke survivors to increase the productive use of their impaired arm throughout a bilateral steering task, by providing motivating feedback and reinforcement cues to reduce the overuse of the less-affected arm. Experimental results demonstrate that the force cues counteracted the tendency of hemiplegic subjects to produce counter-productive torques only during bilateral steering tasks (p < 0.05) that required the movement of their impaired arm in steering directions up and against gravity. Impaired arm activity was quantified in terms of torques due to the measured tangential forces on the split-steering wheel of driver's SEAT during bilateral steering. Results were verified using surface electromyograms recorded from key muscles in the impaired arm.


A catalytic asymmetric bioorganic route to enantioenriched tetrahydro- and dihydropyranones.
A conceptually novel approach to hetero Diels-Alder adducts of carbonyl compounds is described using as the key steps an antibody-mediated kinetic resolution of hydroxyenones followed by a ring-closure process. Various beta-hydroxyenones proved to be very good substrates for antibodies 84G3- and 93F3-catalyzed retro-aldol reactions, allowing the preparation of highly enantiomerically enriched (up to 99% ee) precursors of pyranones. An attractive feature of this methodology is the possibility to convert these acyclic-enantioenriched beta-hydroxyenones into tetrahydropyranones by a conventional Michael-type addition procedure or into the corresponding dihydropyranones using an alternative palladium-catalyzed oxidative ring closure. For the palladium-mediated cyclization, a biphasic system has been implemented that allows the direct preparation of enantiopure dihydropyranones from the corresponding racemic aldol precursors using a sequential antibody-resolution/palladium-cyclization strategy, without isolation of the intermediate enantioenriched hydroxyenones. This bioorganic route is best applied to the preparation of hetero Diels-Alder adducts otherwise derived from less nucleophilic dienes and unactivated dienophiles.


Corticosteroid modulation of interleukin-1 hematopoietic effects and toxicity in a murine system.
Interleukin-1 (IL-1) has been shown to ameliorate the hematopoietic toxicities of antitumor chemotherapeutic agents in both mice and humans. However, IL-1 toxicity in humans is considerable and is similar to the systemic inflammatory toxicities induced by IL-3, IL-6, and other cytokines with pleiotropic biologic activities, eg, fever, nausea, malaise, and hypotension. We hypothesized that corticosteroids may reduce IL-1 toxicity without reducing IL-1 hematopoietic effects in vivo. C3H/HeJ mice (female, 6 weeks) were treated for 7 days subcutaneously with cortisone acetate (CA), (0.1, 0.25, or 0.5 mg/d/mouse), intraperitoneally with IL-1 (1 or 2 micrograms/d/mouse), or both. As expected, IL-1 increased white blood cell counts, splenic granulocyte-macrophage colony-forming units, and spleen cell number, and protected mice from lethal doses of carboplatin (200 mg/kg; Paraplatin, Bristol Laboratories, Evansville, IN) administered the day after completion of the 7 days of IL-1 administration. CA did not significantly block the hematopoietic effects of IL-1 or the ability of IL-1 to protect mice from the hematopoietic toxicity of carboplatin. IL-1 administered to mice at 8 micrograms/d/mouse for 5 days induced decreased activity, roughening of hair, diarrhea, pancytopenia, multiple metabolic abnormalities, and death in 60% of mice. IL-1 at the therapeutic doses (0.5 to 2 micrograms/d) was not toxic. CA in a dose-dependent manner blocked all of the above mentioned toxicities when administered 24 hours and 30 minutes before each IL-1 injection. CA also decreased IL-1-induced increase in plasma tumor necrosis factor levels at the time point examined.


Stabilizing embedology: Geometry-preserving delay-coordinate maps.
Delay-coordinate mapping is an effective and widely used technique for reconstructing and analyzing the dynamics of a nonlinear system based on time-series outputs. The efficacy of delay-coordinate mapping has long been supported by Takens' embedding theorem, which guarantees that delay-coordinate maps use the time-series output to provide a reconstruction of the hidden state space that is a one-to-one embedding of the system's attractor. While this topological guarantee ensures that distinct points in the reconstruction correspond to distinct points in the original state space, it does not characterize the quality of this embedding or illuminate how the specific parameters affect the reconstruction. In this paper, we extend Takens' result by establishing conditions under which delay-coordinate mapping is guaranteed to provide a stable embedding of a system's attractor. Beyond only preserving the attractor topology, a stable embedding preserves the attractor geometry by ensuring that distances between points in the state space are approximately preserved. In particular, we find that delay-coordinate mapping stably embeds an attractor of a dynamical system if the stable rank of the system is large enough to be proportional to the dimension of the attractor. The stable rank reflects the relation between the sampling interval and the number of delays in delay-coordinate mapping. Our theoretical findings give guidance to choosing system parameters, echoing the tradeoff between irrelevancy and redundancy that has been heuristically investigated in the literature. Our initial result is stated for attractors that are smooth submanifolds of Euclidean space, with extensions provided for the case of strange attractors.


Carcinogenesis Bioassay of FD & C Yellow No. 6 (CAS No. 2783-94-0).
A carcinogenesis bioassay was conducted using groups of 50 male and 50 female F344 rats and B6C3F1 mice which were fed diets containing 12,500 or 25,000 ppm FD & C Yellow No. 6, a widely used food colorant, for 103 weeks. Groups of 90 male and 90 female rats and 50 male and 50 female mice served as undosed controls. Throughout the study, mean body weights of high-dose female rats and all low-dose groups were comparable with those of the controls, but mean body weights of high-dose male rats and high-dose male and female mice were slightly lower (10% or less) than those of the controls. No compound-related neoplastic or nonneoplastic lesions were observed in the rats. The incidence of hepatocellular carcinomas in low-dose male mice was significantly higher than that in the controls, but the lack of a significant increase in high-dose males and the variability of liver tumors in B6C3F1 male mice precluded clearly relating the occurrence of these tumors to the administration of FD & C Yellow No.< >6. Under the conditions of this bioassay, there was no clear evidence of the carcinogenicity of FD & C Yellow No. 6 in F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: Sunset Yellow FCF


Bladder cancer: a focus on sexuality.
A bladder cancer diagnosis and the effects of treatment can have a significant impact on a patient's physical, emotional, and psychological well-being. Because healthcare providers tend to focus on these aspects of care, a patient's concerns with changes regarding sexual health are often overlooked. The purpose of this article is to provide oncology nurses with an overview of causes of and treatment for sexual dysfunction as it relates to patients with bladder cancer. Data were extracted using key words and phrases such as bladder cancer, cystoscopy, cystectomy, pelvic exenteration, and sexual dysfunction. Oncology nurses are ideal healthcare providers to assess the sexual health concerns of patients with bladder cancer. Oncology nurses can be valuable resources for patients by giving them permission to discuss sexual health, educating them and their partners about potential implications of treatment on sexuality, reviewing treatment options, and facilitating referrals to other providers who specialize in treating sexual dysfunction.


Prediction of residues involved in inhibitor specificity in the dihydrofolate reductase family.
Dihydrofolate reductase (DHFR) is of significant recent interest as a target for drugs against parasitic and opportunistic infections. Understanding factors which influence DHFR homolog inhibitor specificity is critical for the design of compounds that selectively target DHFRs from pathogenic organisms over the human homolog. This paper presents a novel approach for predicting residues involved in ligand discrimination in a protein family using DHFR as a model system. In this approach, the relationship between inhibitor specificity and amino acid composition for sets of protein homolog pairs is examined. Similar inhibitor specificity profiles correlate with increased sequence homology at specific alignment positions. Residue positions that exhibit the strongest correlations are predicted as specificity determinants. Correlation analysis requires a quantitative measure of similarity in inhibitor specificity (S(lig)) for a pair of homologs. To this end, a method of calculating S(lig) values using K(I) values for the two homologs against a set of inhibitors as input was developed. Correlation analysis of S(lig) values to amino acid sequence similarity scores - obtained via multiple sequence alignments - was performed for individual residue alignment positions and sets of residues on 13 DHFRs. Eighteen alignment positions were identified with a strong correlation of S(lig) to sequence similarity. Of these, three lie in the active site; four are located proximal to the active site, four are clustered together in the adenosine binding domain and five on the βFβG loop. The validity of the method is supported by agreement between experimental findings and current predictions involving active site residues.


Sensory disturbances in complex regional pain syndrome: clinical observations, autonomic interactions, and possible mechanisms.
To review mechanisms that might contribute to sensory disturbances and sympathetically-maintained pain in complex regional pain syndrome (CRPS). CRPS is associated with a range of sensory and autonomic abnormalities. In a subpopulation of patients, sympathetic nervous system arousal and intradermal injection of adrenergic agonists intensify pain. Mechanisms responsible for sensory abnormalities in CRPS include sensitization of primary afferent nociceptors and spinothalamic tract neurons, disinhibition of central nociceptive neurons, and reorganization of thalamo-cortical somatosensory maps. Proposed mechanisms of sympathetically-maintained pain include adrenergic excitation of sensitized nociceptors in the CRPS-affected limb, and interaction between processes within the central nervous system that modulate nociception and emotional responses. Central mechanisms could involve adrenergic facilitation of nociceptive transmission in the dorsal horn or thalamus, and/or depletion of bulbo-spinal opioids or tolerance to their effects. Sympathetic neural activity might contribute to pain and sensory disturbances in CRPS by feeding into nociceptive circuits at the site of injury or elsewhere in the CRPS-affected limb, within the dorsal horn, or via thalamo-cortical projections.


Perceived effectiveness of clinical pathway software: A before-after study in the Netherlands.
Clinical pathways (CPs) increase in popularity and are known to lead to several benefits in the hospital environment. Clinical pathways can be either paper-based or software-based. It is known that paper-based CPs can result in more paperwork instead of simplifying daily routines of healthcare workers. Insufficient research has been done on the acceptance of software-based CPs by different user groups. Our aim in this study was to assess the effectiveness of the software-based CPs (CPS) from the perspective of healthcare professionals in the hospital environment as well as to investigate the differences in perceived effectiveness between user groups. Using surveys and interviews, data were collected in four departments of an academic medical center. A distinction was made between decision makers (DM) and executive staff (ES). The surveys contained questions based on the Technology Acceptance Model and four objectives of the software defined by the hospital. Statistical tests were used to investigate the effectiveness of CPS and study the differences between DM and ES. Interviews were recorded and transcribed based on grounded theory principals. After implementation, monitoring protocol-based working was significantly improved (p = .026) and significantly higher efficiency on the work floor was reported (p = .046). ES perceived the software as less useful than expected (Md = 3.25 vs. Md = 2.75, p = .028) compared to DM and were less convinced of its ability to improve monitoring protocol-based working. The most important benefits of CPS as perceived by its users are the better overview of tasks it provides and facilitating documentation. Negative aspects mentioned were the lack of usability and the inflexibility of the software, and particularly ES claimed that the software did not increase their effectiveness. Our study showed that CPS is effective from healthcare professionals' perspective due to its ability to increase monitoring of protocol-based working and by enhancing the efficiency on the work floor. However, the users also acknowledge that the software lacks usability and is not flexible enough, which results in an additional workload. Policy makers should be more focused on informing and training executive staff more thoroughly when implementing a CPS. Our results strongly suggest that executive staff members need to be convinced of its usefulness and the added value a CPS provides. Preferably, they should be involved in the design phase of the software.


The clinical features of bulimia nervosa.
The clinical features of 35 patients with bulimia nervosa are described. All the patients came from the Oxford area and each fulfilled conservative operational diagnostic criteria. Standardised assessment procedures were used including a structured interview designed to assess the psychopathology characteristic of patients with eating disorders. It was confirmed that these patients have grossly disturbed eating habits accompanied by morbid beliefs and values concerning their shape and weight. Although the majority had a weight within the normal range, a history of weight disturbance was common. There was a high degree of psychiatric morbidity with depressive symptoms being particularly prominent. A quarter of the sample had previously fulfilled diagnostic criteria for anorexia nervosa, and this group closely resembled those patients with no such history.


Natural radioactivity and trace metals in crude oils: implication for health.
Crude oil samples were collected from six different fields in the central Niger Delta in order to determine their natural radioactivity and trace element contents, with the aim of assessing the radiological health implications and environmental health hazard of the metals, and also to provide natural radioactivity baseline data that could be used for more comprehensive future study in this respect. The activity concentrations of the radionuclides were measured using a well, accurately calibrated and shielded vertical cryostat, Canberra coaxial high-purity germanium (HPGe) detector system, and the derived doses were evaluated. The metal concentrations were determined by the graphite furnace atomic absorption spectroscopic (GFAAS) method. The radionuclides identified with reliable regularity belong to the decay series of naturally occurring radionuclides headed by (238)U and (232)Th along with the non-decay series radionuclide, (40)K. The averaged activity concentrations obtained were 10.52 +/- 0.03 Bq kg(-1), 0.80 +/- 0.37 Bq kg(-1) and 0.17 +/- 0.09 Bq kg(-1) for (40)K, (238)U and (232)Th, respectively. The equivalent doses were very low, ranging from 0.0028 to 0.012 mSv year(-1) with a mean value of 0.0070 mSv year(-1). The results obtained were low, and hence, the radioactivity content from the crude oils in the Niger delta oil province of Nigeria do not constitute any health hazard to occupationally exposed workers, the public and the end user. The concentrations of the elements (As, Cd, Co, Fe, Mn, Ni, Se and V) determined ranged from 0.73 to 202.90 ppb with an average of 74.35 ppb for the oil samples analysed. The pattern of occurrence of each element agreed with the earlier studies from other parts of the Niger Delta. It was obvious from this study and previous ones that the Niger Delta oils have low metal contents. However, despite the low concentrations, they could still pose an intrinsic health hazard considering their cumulative effects in the environment. Also, various studies on the impact of oil spillage and activities of oil exploration and production on organisms in the immediate environment suggest this.


Hepatic stellate cells and liver fibrosis.
Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer.


The tail sheath structure of bacteriophage T4: a molecular machine for infecting bacteria.
The contractile tail of bacteriophage T4 is a molecular machine that facilitates very high viral infection efficiency. Its major component is a tail sheath, which contracts during infection to less than half of its initial length. The sheath consists of 138 copies of the tail sheath protein, gene product (gp) 18, which surrounds the central non-contractile tail tube. The contraction of the sheath drives the tail tube through the outer membrane, creating a channel for the viral genome delivery. A crystal structure of about three quarters of gp18 has been determined and was fitted into cryo-electron microscopy reconstructions of the tail sheath before and after contraction. It was shown that during contraction, gp18 subunits slide over each other with no apparent change in their structure.


Understanding metropolitan patterns of daily encounters.
Understanding of the mechanisms driving our daily face-to-face encounters is still limited; the field lacks large-scale datasets describing both individual behaviors and their collective interactions. However, here, with the help of travel smart card data, we uncover such encounter mechanisms and structures by constructing a time-resolved in-vehicle social encounter network on public buses in a city (about 5 million residents). Using a population scale dataset, we find physical encounters display reproducible temporal patterns, indicating that repeated encounters are regular and identical. On an individual scale, we find that collective regularities dominate distinct encounters' bounded nature. An individual's encounter capability is rooted in his/her daily behavioral regularity, explaining the emergence of "familiar strangers" in daily life. Strikingly, we find individuals with repeated encounters are not grouped into small communities, but become strongly connected over time, resulting in a large, but imperceptible, small-world contact network or "structure of co-presence" across the whole metropolitan area. Revealing the encounter pattern and identifying this large-scale contact network are crucial to understanding the dynamics in patterns of social acquaintances, collective human behaviors, and--particularly--disclosing the impact of human behavior on various diffusion/spreading processes.


Exploratory analysis of fast-food chain restaurant menus before and after implementation of local calorie-labeling policies, 2005-2011.
Since 2008, several states and municipalities have implemented regulations requiring provision of nutrition information at chain restaurants to address obesity. Although early research into the effect of such labels on consumer decisions has shown mixed results, little information exists on the restaurant industry's response to labeling. The objective of this exploratory study was to evaluate the effect of menu labeling on fast-food menu offerings over 7 years, from 2005 through 2011. Menus from 5 fast-food chains that had outlets in jurisdictions subject to menu-labeling laws (cases) were compared with menus from 4 fast-food chains operating in jurisdictions not requiring labeling (controls). A trend analysis assessed whether case restaurants improved the healthfulness of their menus relative to the control restaurants. Although the overall prevalence of "healthier" food options remained low, a noteworthy increase was seen after 2008 in locations with menu-labeling laws relative to those without such laws. Healthier food options increased from 13% to 20% at case locations while remaining static at 8% at control locations (test for difference in the trend, P = .02). Since 2005, the average calories for an à la carte entrée remained moderately high (approximately 450 kilocalories), with less than 25% of all entrées and sides qualifying as healthier and no clear systematic differences in the trend between chain restaurants in case versus control areas (P ≥ .50). These findings suggest that menu labeling has thus far not affected the average nutritional content of fast-food menu items, but it may motivate restaurants to increase the availability of healthier options.


Bayes classification of online arabic characters by Gibbs modeling of class conditional densities.
This study investigates Bayes classification of online Arabic characters represented by histograms of tangent differences and Gibbs modeling of the class-conditional probability density functions. The parameters of these Gibbs density functions are estimated following the Zhu, Wu, and Mumford constrained maximum entropy formalism, originally introduced for image and shape synthesis. We investigate two partition function estimation methods: one uses the training sample and the other draws from a reference distribution. The efficiency of the corresponding Bayes decision methods, and of a combination of these, is shown in experiments using a database of 9504 freely written samples by 22 scriptors. Comparisons to the nearest neighbor rule method and Kohonen neural network methods are provided.


Remodeling of the Basal Labyrinth of Retinal Pigment Epithelial Cells With Osmotic Challenge, Age, and Disease.
The basal surface of the retinal pigment epithelium (RPE) is folded into a complex basal labyrinth thought to facilitate solute and water transport. We aimed to analyze and define the structural organization of the basal labyrinth of the RPE to enable quantitative analysis of structural changes in age and disease and to better understand the relationship between basal labyrinth structure and efficiency of transepithelial transport. Conventional transmission and serial block-face scanning electron microscopy and electron tomography were used to examine the structure of the basal labyrinth in mouse eyes of different ages and genotypes and with and without osmotic shock before fixation. We identified structurally distinct zones (stacked and ribbon-like) within the RPE basal labyrinth that are largely organelle free and cisternal elements that make contact with the endoplasmic reticulum (ER) and mitochondria. These zones are lost in a hierarchic fashion with age and prematurely in a model of the progressive retinal degenerative disease, choroideremia. Junctional complexes crosslink closely opposed infoldings. Spacing between the basal infoldings was affected by subtle osmotic changes while osmotic shock induced dramatic remodeling of the infoldings. The basal labyrinth has complex but ordered structural elements that break down with age and in choroideremia. The geometry of these elements and site of contact with ER and mitochondria likely facilitate the ion transport that drives water transport across the basal RPE surface. Changes in structure in response to local osmotic variation may allow transport to be modulated in order to maintain RPE volume.


Optical coherence tomography as a diagnostic tool for retinal pathologies in avian ophthalmology.
Optical coherence tomography (OCT) is an established diagnostic tool for retinal pathologies in human eyes and has been adapted to small animal models. However, there have been only a few attempts to use OCT for examination of avian eyes, and little is known about structural details of healthy or pathologically affected retinas in living birds. We used SD-OCT (high-resolution spectral domain OCT) to investigate eyes of various avian species including birds of prey. The birds were anesthetized by isoflurane application during OCT examination. Eyes of a common buzzard (Buteo buteo) could be used for a comparative analysis of OCT images and histologic/immunohistochemical examinations. We investigated 45 wild and domestic birds (25 different species, 40 g-7.7 kg body mass) without and with diverse pathologic indications (e.g., body or head trauma). Animals were generally and ophthalmologically examined, and the diagnostic findings of direct ophthalmoscopy and OCT were compared. The OCT examination revealed an increased number of animals with clinical findings and allowed a detailed assessment of structural changes in retinal and choroidal tissue compared to simple direct ophthalmoscopy. Common findings were retinal and choroidal degeneration, retinal detachment, choroidal schisis, drusen, and drusenoid changes. Histologic and immunohistochemical analysis of retinal tissue confirmed the findings of the OCT examination. Spectral domain OCT of eyes in living birds is applicable and useful as a diagnostic tool in veterinary clinical practices and for vision research in general. Optical coherence tomography improves the quality of the common assessment methods in avian ophthalmology, and expands the diagnostic possibilities with respect to identification and prognosis of diseases. This will be particularly important for hereditary retinal defects, especially of precious breeding individuals, or estimation of treatment success in traumatized wild birds with the aim of release back into the wild.


Sex Work Is Associated With Increased Vaginal Microbiome Diversity in Young Women From Mombasa, Kenya.
Although nonoptimal vaginal bacteria and inflammation have been associated with increased HIV risk, the upstream drivers of these phenotypes are poorly defined in young African women. Mombasa, Kenya. We characterized vaginal microbiome and cytokine profiles of sexually active young women aged 14-24 years (n = 168) in 3 study groups: those engaging in formal sex work, in transactional sex, and nonsex workers. Vaginal secretions were collected using self-inserted SoftCup, and assayed for cytokines and vaginal microbiome through multiplex ELISA and 16S rRNA sequencing, respectively. Epidemiological data were captured using a validated questionnaire. The median age of participants was 20 years (interquartile range: 18-22 years). Approximately two-thirds of young women (105/168) had vaginal microbial communities characterized by Gardnerella and/or Prevotella spp. dominance; a further 29% (49/168) were predominantly Lactobacillus iners. Microbiome clustering explained a large proportion of cytokine variation (>50% by the first 2 principal components). Age was not associated with vaginal microbial profiles in bivariable or multivariable analyses. Women self-identifying as sex workers had increased alpha (intraindividual) diversity, independent of age, recent sexual activity, HIV, and other sexually transmitted infections (beta = 0.47, 95% confidence interval: 0.05 to 0.90, P = 0.03). Recent sex (number of partners or sex acts last week, time since last vaginal sex) correlated with increased alpha diversity, particularly in participants who were not involved in sex work. Nonoptimal vaginal microbiomes were common in young Kenyan women and associated with sex work and recent sexual activity, but independent of age. Restoring optimal vaginal microflora may represent a useful HIV prevention strategy.


Neurodevelopmental origins of abnormal cortical morphology in dissociative identity disorder.
To examine the two constitutes of cortical volume (CV), that is, cortical thickness (CT) and surface area (SA), in individuals with dissociative identity disorder (DID) with the view of gaining important novel insights into the underlying neurobiological mechanisms mediating DID. This study included 32 female patients with DID and 43 matched healthy controls. Between-group differences in CV, thickness, and SA, the degree of spatial overlap between differences in CT and SA, and their relative contribution to differences in regional CV were assessed using a novel spatially unbiased vertex-wise approach. Whole-brain correlation analyses were performed between measures of cortical anatomy and dissociative symptoms and traumatization. Individuals with DID differed from controls in CV, CT, and SA, with significantly decreased CT in the insula, anterior cingulate, and parietal regions and reduced cortical SA in temporal and orbitofrontal cortices. Abnormalities in CT and SA shared only about 3% of all significantly different cerebral surface locations and involved distinct contributions to the abnormality of CV in DID. Significant negative associations between abnormal brain morphology (SA and CV) and dissociative symptoms and early childhood traumatization (0 and 3 years of age) were found. In DID, neuroanatomical areas with decreased CT and SA are in different locations in the brain. As CT and SA have distinct genetic and developmental origins, our findings may indicate that different neurobiological mechanisms and environmental factors impact on cortical morphology in DID, such as early childhood traumatization.


Differentiation in vitro of T3+ large granular lymphocytes with characteristic cytotoxic activity from an isolated hematopoietic progenitor colony.
Blast colonies were developed by rIL-3 from the spleen cells of mice pretreated with 5-fluorouracil (5-FU) in the methylcellulose cultures. When such IL-3-induced blast colonies were individually lifted up and recultured in the presence of rIL-3 and recombinant erythropoietin (rEpo), a variety of hematopoietic colonies developed from every single colony, including neutrophils, macrophages, eosinophils, megakaryocytes, mast cells, and erythroblasts. The results indicated that IL-3-induced blast colonies consisted of multipotential hematopoietic progenitor cells. By culturing individual IL-3-induced blast colonies in the presence of rIL-2 and irradiated peritoneal macrophages, on the other hand, the proliferation of homogeneous lymphoid cells was observed in 5 of 24 wells, each of which received a single blast colony. Morphologically, they were typical large granular lymphocytes (LGL), and thus it was indicated that LGL could be differentiated directly from the hematopoietic progenitor cells utterly in vitro by rIL-2 and accessory macrophages. From one of these culture wells, a continuous LGL line, IL3B1, was successfully obtained. The proliferation of IL3B1 was dependent on IL-2 in the presence of accessory macrophages, but they no longer responded to IL-3, nor to another T cell growth factor, IL-4. Flow cytometric analysis indicated that the phenotype of IL3B1 was Thy-1+,T3+,L3T4-,Lyt-2-,T200+ Asialo GM1+, whereas that of original IL-3-induced blast cells was Thy-1+,T3-,L3T4-,Lyt-2-,B220-. The results suggested that the expression of T3 molecules was induced in the process of LGL differentiation from the hematopoietic progenitor cells in vitro. Conforming to this, it was revealed that both gamma and beta chain genes of the TCR were rearranged in IL3B1. Northern blot analysis indicated that IL3B1 had abundant mRNA for gamma chain, while mRNA for beta chain was rather faint. Functionally, IL3B1 exhibited typical NK-patterned cytotoxic activity against a panel of tumor cell targets. In addition, they showed significant cytotoxic activity against normal bone marrow cells, as well as various factor-dependent myelogenous progenitor cell lines, all of which were resistant to endogenous NK activity of the fresh spleen cells. These results indicated that at least a set of T3+ LGL with rearranged TCR genes could be directly differentiated from isolated hematopoietic progenitor cells in vitro. Results also suggested that such a prethymically differentiated subset of T-lineage lymphocytes, namely T3+ double-negative LGL, had particular cytotoxic activity in addition to conventional NK activity, which might well contribute to feedback regulation of hematopoiesis.


Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.
We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.


Synthesis and molecular structure of the dihydrobis(thioxotriazolinyl)borato complexes of zinc(II), bismuth(III), and nickel(II). M...H-B interaction studied by Ab initio calculations.
Reacting the heterocycle 5-thioxo-1,4-dihydro-4-ethyl-3-methyl-1,2,4-triazole (thioxotriazoline) with sodium tetrahydroborate in the molar ratio of approximately 2:1 at 130 degrees C provides the new ligand dihydrobis(thioxotriazolinyl)borato, [Bt(Et,Me)](-), as its sodium salt. The neutral complexes of this anionic ligand with zinc(II), bismuth(III), and nickel(II) have been synthesized and characterized by X-ray crystallography. In every complex, the ligand is coordinated to the metal in the S(2) mode, generating eight-membered chelate rings. The bismuth and nickel complexes exhibit two M.H-B interactions responsible for the dodecahedral and octahedral geometries, respectively. For the zinc complex, the trigonal-bipyramidal coordination is achieved with an apical Zn.H-B interaction. The crystal structures for the three complexes are described, and ab initio calculations on Bi(III), Ni(II), and Zn(II) compounds have been performed in order to assess the nature of the M.H-B interaction and its role for the definition of the molecular geometries.


Cognitive function and social abilities in patients with schizophrenia: relationship with atypical antipsychotics.
Although atypical antipsychotics have been associated with improvements in cognitive function in schizophrenia, the neurochemical basis for such effects is not well understood. Candidate neurotransmitter systems primarily involve dopamine and serotonin. The current study explored this issue by examining the cognitive abilities, social function and quality of life in patients with schizophrenia who were medicated with atypical antipsychotics. Comparisons were done for matched schizophrenia patients who were on antipsychotics with (i) an affinity for multiple receptors (olanzapine, clozapine, quetiapine) versus those that have preferential affinity for dopamine receptors (risperidone, amisulpride); and patients on medication with (ii) a high affinity for serotonin (5HT-2A) receptors (risperidone, olanzapine, clozapine) versus those with a low (or no) affinity for 5HT-2A receptors (quetiapine, amisulpride). No differences emerged between groups on any cognitive or social variable when the groups were compared for the dopaminergic properties of antipsychotic medication. By contrast, differences did emerge when patients were compared on the 5HT-2A affinity of their antipsychotic medications. Patients on low 5HT-2A-affinity antipsychotics exhibited a better performance on a measure of selective attention and adjustment to living. These findings accord with the notion that serotonergic mechanisms are important determinants of both the cognitive and the social effects of the atypical antipsychotics.


Microparticle association and heterogeneity of tumor-derived tissue factor in plasma: is it important for coagulation activation?
Tumor-derived tissue factor (TF) activates coagulation in vitro and in vivo in an orthotopic model of human pancreatic cancer. Here, we further characterized tumor-derived TF in this model. Conditioned medium (CM) of L3.6pl human pancreatic tumor cells and plasma from nude mice bearing L3.6pl tumors were ultracentrifuged, and the pellets were filtered through membranes with different pore sizes. The size distribution of particles was analyzed in CM or plasma fractions with nanoparticle tracking and dynamic light scattering. Human TF antigen and activity were measured in pellets and supernatants with ELISA and clotting or thrombin generation assays, respectively. Human alternatively spliced TF (asTF) was measured with ELISA. Human TF and thrombin-antithrombin complex (TAT) concentrations were assessed in plasma of mice injected with filtered fractions of CM. Particles in both CM and plasma were < 0.4 μm. TF antigen and activity in the CM were mainly associated with microparticles (MP). Approximately 50% of antigen and 20% of activity were associated with particles of < 0.1 μm. Injection of < 0.1 μm particles into mice caused a 30% drop in platelet counts and an increase in TAT levels. In contrast, ~ 90% of TF antigen in tumor-bearing mice plasmas was non-sedimentable, whereas TF activity was exclusively associated with MP. Particles of < 0.1 μm and the supernatants of both CM and plasma gained TF activity after addition of exogenous phospholipids. Although asTF was found in MP-free CM supernatants, it was also present in CM and plasma pellets. Tumor-derived particles of < 0.1 μm and non-sedimentable TF are or can become procoagulant in the presence of phospholipids, and may contribute to the procoagulant potential of circulating TF.


Effect of ketanserin administration on intraocular pressure.
We evaluated the effect of oral single-dose (20 mg) ketanserin on intraocular pressure (IOP) in normotensive and hypertensive eyes. This study included 15 healthy volunteers and 16 patients with ocular hypertension. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, IOP and pupil diameter were recorded at baseline and at 1-hour intervals for 6 h, in addition, tonographic outflow facility was studied at the third hour after the administration of placebo or an oral single dose of 20 mg ketanserin given in a randomized double-blind crossover fashion. The alternative treatment was applied a week later. In both groups, oral single-dose (20 mg) ketanserin significantly lowered IOP and SBP (p < 0.01). No variation was observed in DBP, heart rate and pupil diameter (p >0.01). Moreover, after drug administration, the total outflow facility measured by conventional tonography increased in a statistically significant way (p < 0.01). Placebo did not induce any significant reduction in IOP and SBP in either group. The results showed that systemic ketanserin can be used in the treatment of glaucoma patients to reduce IOP.


Spinal tuberculosis: CT and MRI feature.
Spinal tuberculosis (TB) is perhaps the most clinically important extrapulmonary form of the disease. Early recognition is therefore necessary to minimize residual spinal deformity and/or permanent neurological deficit. We defined the CT and MRI image morphology of spinal TB and correlated the imaging features of these two modalities. CT (29 patients) and MRI (11 patients) images were retrospectively analyzed in 30 patients with proved spinal TB. CT and MRI findings were compared in cases with both imaging tests (10 cases). The parameters assessed were the type and extent of bone and soft tissue involvement. The majority of the 30 patients were males (n=18) in the 30-49 year age group (43%). The most common clinical presentation was backache (73.3%) followed by fever (63.3%) and malaise (36.6%). The lumbar spine was the commonest site of the disease (43.3%) followed by the thoracic region (36.6%). A fragmentary type of bone destruction was the most frequent CT feature of the disease (48.2%) followed by the lytic type (24.1%). Intervertebral disc destruction (72%) and paravertebral mass/abscess (65.5%) were other features. Of the 11 patients who had an MRI, contiguous vertebral disease with disc destruction was seen in 10 cases. In 4 patients, there was distant vertebral disease in addition to the disease at the symptomatic site. MRI offers excellent visualization of the bone and soft tissue components of spinal tuberculosis and helps to identify disease at distant asymptomatic sites. CT is useful in assessing bone destruction, but is less accurate in defining the epidural extension of the disease and therefore its effect on neural structures. MR imaging clearly demonstrated the extent of soft tissue disease and its effect on the theca/cord and foramen in cases with doubtful CT findings.


Learning of a novel visuo-postural co-ordination task in adults with multiple sclerosis.
A behavioural study was conducted to investigate how cerebellar dysfunction associated with multiple sclerosis affects the ability to learn a novel visuo-postural co-ordination task. A prospective design, 2 group by 1 treatment (4 practice blocks). Ten patients with multiple sclerosis diagnosed with cerebellar ataxia and 10 age-matched healthy controls. Participants stood over a dual force platform (ERBE Balance System) and performed visually guided lateral weight-shifting movements. The task required subjects to gradually transfer weight between sides while maintaining each foot's force vector within visually specified force constraints ranging from 0% to 100% of bodyweight with maximum allowed variation set to +/-20%. The time required to complete the task and the number of spatial errors (noted each time the foot's vector exceeded the +/-20% force constraint) were recorded. Training consisted of 3 blocks of 5 trials separated by 1-minute intervals and followed by 5 retention trials. Statistics revealed a significant decrease in movement time and spatial errors across trial blocks in both groups; however, the group with multiple sclerosis showed a limited and slower rate of performance improvement characterized by increased within- and between-subject variability. These findings may have important implications in the design of rehabilitation protocols for improving motor skill performance in adults with multiple sclerosis.


Positional plagiocephaly following ventriculoperitoneal shunting in neonates and infancy-how serious is it?
We test the hypothesis that ventriculoperitoneal (VP) shunt insertion significantly increases contralateral positional plagiocephaly. We reviewed 339 children who had a VP shunt inserted at Birmingham Children's Hospital between 2006 and 2013, noting laterality of shunt insertion and frontal or occipital position. We ascertained the presence of post-operative positional plagiocephaly using the cranial vault asymmetry index. Multinomial logistic regression modelling was used to examine relationships between plagiocephaly, shunt position, gender and age. Adjusted odds and risk ratios for effect of variables on plagiocephaly were calculated. Children with occipital VP shunts are at significant risk of developing contralateral positional plagiocephaly, particularly in the first 12 months of life. We recommend careful follow-up and advice regarding head positioning following surgery. There should be consideration for active monitoring to avoid plagiocephaly, including physiotherapy and health visitor interventions. Endoscopic third ventriculostomy in selected cases or anterior shunt placement could be considered. A larger national study would be of interest to evaluate the extent of an otherwise correctable problem.


Antibacterial drug discovery in the resistance era.
The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.


Optimising paediatric afferent component early warning systems: a hermeneutic systematic literature review and model development.
To identify the core components of successful early warning systems for detecting and initiating action in response to clinical deterioration in paediatric inpatients. A hermeneutic systematic literature review informed by translational mobilisation theory and normalisation process theory was used to synthesise 82 studies of paediatric and adult early warning systems and interventions to support the detection of clinical deterioration and escalation of care. This method, which is designed to develop understanding, enabled the development of a propositional model of an optimal afferent component early warning system. Detecting deterioration and initiating action in response to clinical deterioration in paediatric inpatients involves several challenges, and the potential failure points in early warning systems are well documented. Track and trigger tools (TTT) are commonly used and have value in supporting key mechanisms of action but depend on certain preconditions for successful integration into practice. Several supplementary interventions have been proposed to improve the effectiveness of early warning systems but there is limited evidence to recommend their wider use, due to the weight and quality of the evidence; the extent to which systems are conditioned by the local clinical context; and the need to attend to system component relationships, which do not work in isolation. While it was not possible to make empirical recommendations for practice, the review methodology generated theoretical inferences about the core components of an optimal system for early warning systems. These are presented as a propositional model conceptualised as three subsystems: detection, planning and action. There is a growing consensus of the need to think beyond TTTs in improving action to detect and respond to clinical deterioration. Clinical teams wishing to improve early warning systems can use the model to consider systematically the constellation of factors necessary to support detection, planning and action and consider how these arrangements can be implemented in their local context. CRD42015015326.


Stimulation of collagen synthesis in fibroblast cultures by a triterpene extracted from Centella asiatica.
The drug "Titrated Extract from Centella asiatica" (TECA), used for its stimulating properties on the healing of wounds, is a mixture of 3 terpenes extracted from a tropical plant: asiatic acid (30%, w/w), madecassic acid (30%, w/w) and asiaticoside (40%, w/w). The effects of TECA and its individual components were checked on human foreskin fibroblast monolayer cultures. TECA increased the collagen synthesis in a dose-dependent fashion whereas a simultaneous decrease in the specific activity of neosynthesized collagen was observed. Asiatic acid was found to be the only component responsible for collagen synthesis stimulation. TECA and all three terpenes increased the intracellular free proline pool. This effect was independent of the stimulation of collagen synthesis.


Expression of Runx1, -2 and -3 during tooth, palate and craniofacial bone development.
We describe the expression of three Runt-related RUNX genes (previously termed AML, Cbfa, or Pebp2alpha) Runx1 and Runx3 during the development of teeth and other craniofacial tissues and compare them to Runx2 expression reported earlier. All three genes were expressed in mesenchymal condensates. Runx1 was expressed in several cartilage primordia earlier than Runx3, and Runx2 was intense in all mesenchymal condensations of bones and teeth. Only Runx1 was expressed in epithelia, and in tooth germs transcripts were detected in outer dental epithelium. Runx1 was also intensely expressed in the midline epithelium of palatal shelves. In early tooth morphogenesis Runx3 was coexpressed with Runx2 in a thin layer of mesenchymal cells underlying dental epithelium. Unlike Runx2, Runx3 was expressed in odontoblasts. However, Runx3 mutant mice did not show obvious tooth phenotype or deviations of Runx1 and Runx2 expression patterns in the tooth.


A multigene family of glycosyltransferases in a model plant, Arabidopsis thaliana.
Glycosyltransferases transfer sugars from NDP-sugar donors to acceptors. The multigene family of transferases described in this paper typically transfer glucose from UDP-glucose to low-molecular-mass acceptors in the cytosol of plant cells. There are 107 sequences in the genome of Arabidopsis thaliana that contain a consensus, suggesting they belong to this Group 1 multigene family. The family has been analysed phylogenetically, and a functional genomics approach has been applied to explore the relatedness of sequence similarity to catalytic specificity and stereoselectivity. Enzymes belonging to this class of transferases glycosylate a vast array of acceptors, including natural products such as secondary metabolites and hormones, as well as xenobiotics absorbed by the plant, such as herbicides and pesticides. Conjugation to glucose potentially changes the activity of the acceptor molecule and invariably changes its location within the plant cell. Using the genomics approach described, a platform of knowledge has been constructed that will enable an understanding to be gained on the role of these enzymes in cellular homoeostasis, as well as their activity in biotransformations in vitro that require strict regioselectivity of glycosylation.


Magnetic microchip traps and single-atom detection.
Microchip traps provide a promising approach to quantum information processing and communication (QIPC) with neutral atoms: strong and complex potentials can be produced for acting on the qubit atoms, and the potentials can be scaled to higher qubit numbers by virtue of the microfabrication process. We describe experimental results that are relevant to use in QIPC, such as the transport of Bose-Einstein-condensed atomic ensembles along the chip surface with the help of a magnetic conveyor belt. The second part of the paper is devoted to single-atom detection on the chip.


Small for gestational age and adulthood risk of disability pension: the contribution of childhood and adulthood conditions.
Early exiting from the labor force and into disability pension (DP) represents a major social problem in Sweden and elsewhere. We examined how being asymmetric (A-SGA) or symmetric (S-SGA) small for gestational age predicts transitioning into DP. We analyzed a longitudinal sample of 8125 men and women from the Stockholm Birth Cohort (SBC), born in 1953 and not on DP in 1990. The SBC consists of data from various sources, including self-reported information and data from administrative registers. The follow-up period was from 1991 to 2009. Yearly information on the receipt of DP benefits from register data was operationalized as a dichotomous variable. 13 percent of the sample moved into DP during follow-up. Cox proportional hazards regression was used to examine whether disadvantageous fetal growth--A-SGA and S-SGA--predicted DP. Men and women born A-SGA had a substantially increased hazard of DP. The full model suggested a hazard ratio of 1.68 (CI: 1.11-2.54), only being affected slightly by adulthood conditions. Several childhood conditions were also associated with DP. Such factors, however, mainly affected DP risk through adulthood conditions. The effect of SGA on DP appeared particularly strong among individuals from socioeconomically disadvantaged backgrounds. The evidence presented suggests that being A-SGA influences the risk of DP, independent of childhood and adulthood conditions, and similarly for men and women. Due to A-SGA being rather infrequent, reducing the occurrence of A-SGA would, however, only have a marginal impact on the stock of DP pensioners. For the individual affected, the elevation in the risk of DP was nevertheless substantial. Other childhood conditions exercised a larger influence on the stock of DP recipients, but they mostly operated through adulthood attainment. The importance of socioeconomic resources in childhood for the long term health consequences of SGA is interesting from a policy perspective and warrants further research.


ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors.
Extracellular nucleotides are pleiotropic regulators of mammalian cell function. Adenosine triphosphate (ATP) released from CD4(+) helper T cells upon stimulation of the T cell receptor (TCR) contributes in an autocrine manner to the activation of mitogen-activated protein kinase (MAPK) signaling through purinergic P2X receptors. Increased expression of p2rx7, which encodes the purinergic receptor P2X7, is part of the transcriptional signature of immunosuppressive CD4(+)CD25(+) regulatory T cells (T(regs)). Here, we show that the activation of P2X7 by ATP inhibits the suppressive potential and stability of T(regs). The inflammatory cytokine interleukin-6 (IL-6) increased ATP synthesis and P2X7-mediated signaling in T(regs), which induced their conversion to IL-17-secreting T helper 17 (T(H)17) effector cells in vivo. Moreover, pharmacological antagonism of P2X receptors promoted the cell-autonomous conversion of naïve CD4(+) T cells into T(regs) after TCR stimulation. Thus, ATP acts as an autocrine factor that integrates stimuli from the microenvironment and cellular energetics to tune the developmental and immunosuppressive program of the T cell in adaptive immune responses.


Evidence-Based Clinical Practice Guidelines for Microcystic Adnexal Carcinoma: Informed by a Systematic Review.
Microcystic adnexal carcinoma (MAC) occurs primarily in older adults of white race/ethnicity on sun-exposed skin of the head and neck. There are no formal guiding principles based on expert review of the evidence to assist clinicians in providing the highest-quality care for patients. To develop recommendations for the care of adults with MAC. A systematic review of the literature (1990 to June 2018) was performed using MEDLINE, Embase, Web of Science, and the Cochrane Library. The keywords searched were microcystic adnexal carcinoma, sclerosing sweat gland carcinoma, sclerosing sweat duct carcinoma, syringomatous carcinoma, malignant syringoma, sweat gland carcinoma with syringomatous features, locally aggressive adnexal carcinoma, and combined adnexal tumor. A multidisciplinary expert committee critically evaluated the literature to create recommendations for clinical practice. Statistical analysis was used to estimate optimal surgical margins. In total, 55 studies met our inclusion criteria. The mean age of 1968 patients across the studies was 61.8 years; 54.1% were women. Recommendations were generated for diagnosis, treatment, and follow-up of MAC. There are 5 key findings of the expert committee based on the available evidence: (1) A suspect skin lesion requires a deep biopsy that includes subcutis. (2) MAC confined to the skin is best treated by surgery that examines the surrounding and deep edges of the tissue removed (Mohs micrographic surgery or complete circumferential peripheral and deep margin assessment). (3) Radiotherapy can be considered as an adjuvant for MAC at high risk for recurrence, surgically unresectable tumors, or patients who cannot have surgery for medical reasons. (4) Patients should be seen by a physician familiar with MAC every 6 to 12 months for the first 5 years after treatment. Patient education on photoprotection, periodic skin self-examination, postoperative healing, and the possible normal changes in local sensation (eg, initial hyperalgesia) should be considered. (5) There is limited evidence to guide the treatment of metastasis in MAC due to its rarity. Limitations of our findings are that the medical literature on MAC comprises only retrospective reviews and descriptions of individual patients and there are no controlled studies to guide management. The presented clinical practice guidelines provide an outline for the diagnosis and management of MAC. Future efforts using multi-institutional registries may improve our understanding of the natural history of the disease in patients with lymph node or nerve involvement, the role of radiotherapy, and the treatment of metastatic MAC with drug therapy.


Racial Composition Over the Life Course: Examining Separate and Unequal Environments and the Risk for Heart Disease for African American Men.
Studies have demonstrated the effects of segregated social and physical environments on the development of chronic diseases for African Americans. Studies have not delineated the effects of segregated environments specifically on the health of African American men over their lifetime. This study examines the relationship between life course measures of racial composition of social environments and diagnosis of hypertension among African American men. We analyzed cross-sectional data from a convenience sample of African American men seeking health care services in an outpatient primary care clinic serving a medically underserved patient population (N=118). Multivariable logistic regression analyses were used to examine associations between racial composition of multiple environments across the life course (eg, junior high school, high school, neighborhood growing up, current neighborhood, place of employment, place of worship) and hypertension diagnosis. The majority (86%) of participants were not currently in the workforce (retired, unemployed, or disabled) and more than half (54%) reported an annual household income of <$9,999; median age was 53. Results suggest that African American men who grew up in mostly Black neighborhoods (OR=4.3; P=.008), and worked in mostly Black environments (OR=3.1; P=.041) were more likely to be diagnosed with hypertension than those who did not. We found associations between mostly Black residential and workplace settings and hypertension diagnoses among African American men. Findings suggest exposure to segregated environments during childhood and later adulthood may impact hypertension risk among African American men over the life course.


Misuse of prescription and illicit drugs among high-risk young adults in Los Angeles and New York.
BACKGROUND: Prescription drug misuse among young adults is increasingly viewed as a public health concern, yet most research has focused on student populations and excluded high-risk groups. Furthermore, research on populations who report recent prescription drug misuse is limited. This study examined patterns of prescription drug misuse among high-risk young adults in Los Angeles (LA) and New York (NY), which represent different local markets for illicit and prescription drugs. DESIGN AND METHODS: Between 2009 and 2011, 596 young adults (16 to 25 years old) who had misused prescription drugs within the past 90 days were interviewed in Los Angeles and New York. Sampling was stratified to enroll three groups of high-risk young adults: injection drug users (IDUs); homeless persons; and polydrug users. RESULTS: In both sites, lifetime history of receiving a prescription for an opioid, tranquilizer, or stimulant was high and commonly preceded misuse. Moreover, initiation of opioids occurred before heroin and initiation of prescription stimulants happened prior to illicit stimulants. NY participants more frequently misused oxycodone, heroin, and cocaine, and LA participants more frequently misused codeine, marijuana, and methamphetamine. Combining prescription and illicit drugs during drug using events was commonly reported in both sites. Opioids and tranquilizers were used as substitutes for other drugs, e.g., heroin, when these drugs were not available. CONCLUSION: Patterns of drug use among high-risk young adults in Los Angeles and New York appear to be linked to differences in local markets in each city for illicit drugs and diverted prescription drugs.


Bullous skin reaction seen after extravasation of calcium gluconate.
Intravenous (IV) calcium is usually given to temporarily treat the effects of hyperkalaemia on muscle and heart. When extravasation of a calcium gluconate infusion occurs, there may be rapid and marked swelling and erythema, with signs of soft-tissue necrosis or infection, and ensuing extensive local calcification, called calcinosis cutis. We report a 26-year-old woman who was hospitalized for exacerbation of acute intermittent porphyria. She had a history of hypertension and chronic renal failure. On the second day of her hospitalization, she developed hyperpotassaemia (6.7 mEq/L potassium; normal range 3.5-5 mEq/L). She was given an IV infusion of 10 mL calcium gluconate into the left dorsal pedal vein. Bullous skin reactions occurred in the infusion area nearly 2 h after administration. The patient's leg was elevated and the lesions cleaned with 0.9% saline. By day 9 of hospitalization, the lesions had markedly regressed. Several drugs have been associated with dermoepidermal blistering as an adverse drug reaction, but there is only one existing report in the literature about this side-effect associated with calcium gluconate. Clinicians should be alert to the possibility of bullous skin reactions, which may be a predictor of extravasation and necrosis, when treating patients with IV calcium gluconate.


Purification and biochemical heterogeneity of the mammalian SWI-SNF complex.
We have purified distinct complexes of nine to 12 proteins [referred to as BRG1-associated factors (BAFs)] from several mammalian cell lines using an antibody to the SWI2-SNF2 homolog BRG1. Microsequencing revealed that the 47 kDa BAF is identical to INI1. Previously INI1 has been shown to interact with and activate human immunodeficiency virus integrase and to be homologous to the yeast SNF5 gene. A group of BAF47-associated proteins were affinity purified with antibodies against INI1/BAF47 and were found to be identical to those co-purified with BRG1, strongly indicating that this group of proteins associates tightly and is likely to be the mammalian equivalent of the yeast SWI-SNF complex. Complexes containing BRG1 can disrupt nucleosomes and facilitate the binding of GAL4-VP16 to a nucleosomal template similar to the yeast SWI-SNF complex. Purification of the complex from several cell lines demonstrates that it is heterogeneous with respect to subunit composition. The two SWI-SNF2 homologs, BRG1 and hbrm, were found in separate complexes. Certain cell lines completely lack BRG1 and hbrm, indicating that they are not essential for cell viability and that the mammalian SWI-SNF complex may be tailored to the needs of a differentiated cell type.


Discovery of novel immunopharmacological ligands targeting the IL-17 inflammatory pathway.
Interleukin 17 (IL-17) is a proinflammatory cytokine that acts as an immune checkpoint for several autoimmune diseases. Therapeutic neutralizing antibodies that target this cytokine have demonstrated clinical efficacy in psoriasis. However, biologics have limitations such as their high cost and their lack of oral bioavailability. Thus, it is necessary to expand the therapeutic options for this IL-17A/IL-17RA pathway, applying novel drug discovery methods to find effective small molecules. In this work, we combined biophysical and cell-based assays with structure-based docking to find novel ligands that target this pathway. First, a virtual screening of our chemical library of 60000 compounds was used to identify 67 potential ligands of IL-17A and IL-17RA. We developed a biophysical label-free binding assay to determine interactions with the extracellular domain of IL-17RA. Two molecules (CBG040591 and CBG060392) with quinazolinone and pyrrolidinedione chemical scaffolds, respectively, were confirmed as ligands of IL-17RA with micromolar affinity. The anti-inflammatory activity of these ligands as cytokine-release inhibitors was evaluated in human keratinocytes. Both ligands inhibited the release of chemokines mediated by IL-17A, with an IC50 of 20.9 ± 12.6 μM and 23.6 ± 11.8 μM for CCL20 and an IC50 of 26.7 ± 13.1 μM and 45.3 ± 13.0 μM for CXCL8. Hence, they blocked IL-17A proinflammatory activity, which is consistent with the inhibition of the signalling of the IL-17A receptor by ligand CBG060392. Therefore, we identified two novel immunopharmacological ligands targeting the IL-17A/IL-17RA pathway with antiinflammatory efficacy that can be promising tools for a drug discovery program for psoriasis.


Effects of Donning and Wearing Personal Protective Equipment on Tourniquet Use and Conversion.
We sought to gather data about the effects of personal protective equipment (PPE) use on tourniquet interventions by preliminarily developing a way to simulate delay effects, particularly on time and blood loss. Such knowledge might aid readiness. Field calls to emergency departments may indicate donning of PPE before patient arrival. The purpose of this study was to investigate (1) delay effects of donning the PPE studied on field-tourniquet control of hemorrhage and (2) delay effects of wearing the PPE on application of a field tourniquet and its conversion to a pneumatic tourniquet. The experiment simulated 30 tests of nonpneumatic field tourniquet use (http://www.combattourniquet.com/wp -content). The research intervention was the use of PPE. Data were grouped. The control group had no PPE (PPE0). PPE1 and PPE2 groups had mostly improvised and off-the-shelf equipment, respectively. PPE1 included donning a coat, goggles, face covering, cap, booties, and gloves. PPE2 had analogous items. The group order was randomized. A test included paired trials: field tourniquet, followed by conversion. An investigator simulated the caregiver. A task trainer simulated a thigh amputation. Donning delays were evaluated as differences in mean times to stop bleeding compared with PPE0. Blood loss results from donning PPE were calculated as the delay multiplied by its bleeding rate, 500mL/min. PPE0 had no delay: its mean blood loss was 392mL. PPE1 had 805mL more blood loss than PPE0 did. PPE2 exceeded PPE0 by 1004mL. Donning time (blood loss) for PPE1 and PPE2 were 1.4 minutes (712mL) and 1.7 minutes (863mL), respectively. The wearing of PPE did not slow down field tourniquet application or its conversion. How long it took to don PPE delayed the time to stop bleeding and increased blood loss, but wearing PPE slowed down neither field tourniquet application nor its conversion.


Assembly, postsynthetic modification and hepatocyte targeting by multiantennary, galactosylated soft structures.
Enzyme modifiable, hollow self-assembled structures offer an excellent scope for multiantennary delivery vectors. Herein, we report synthesis and applications of bis-galactose lysine based supramolecular ensembles, which possess surface galactose moieties amenable to enzymatic modifications. This post-synthetic modification generates reactive aldehyde groups, which could possibly serve as dynamic anchors for crosslinking and cell adhesion.


Supraorbital keyhole surgery for optic nerve decompression and dura repair.
Supraorbital keyhole surgery is a limited surgical procedure with reduced traumatic manipulation of tissue and entailing little time in the opening and closing of wounds. We utilized the approach to treat head injury patients complicated with optic nerve compression and cerebrospinal fluid leakage (CSF). Eleven cases of basal skull fracture complicated with either optic nerve compression and/or CSF leakage were surgically treated at our department from February 1995 to June 1999. Six cases had primary optic nerve compression, four had CSF leakage and one case involved both injuries. Supraorbital craniotomy was carried out using a keyhole-sized burr hole plus a small craniotomy. The size of craniotomy approximated 2 x 3 cm2. The optic nerve was decompressed via removal of the optic canal roof and anterior clinoid process with high-speed drills. The defect of dura was repaired with two pieces of tensa fascia lata that were attached on both sides of the torn dural defect with tissue glue. Seven cases with optic nerve injury included five cases of total blindness and two cases of light perception before operation. Vision improved in four cases. The CSF leakage was stopped successfully in all four cases without complication. As optic nerve compression and CSF leakage are skull base lesions, the supraorbital keyhole surgery constitutes a suitable approach. The supraorbital keyhole surgery allows for an anterior approach to the skull base. This approach also allows the treatment of both CSF leakage and optic nerve compression. Our results indicate that supraorbital keyhole operation is a safe and effective method for preserving or improving vision and attenuating CSF leakage following injury.


Patient information and participation still in need of improvement: evaluation of patients' perceptions of quality of care.
To identify areas in need of quality improvement by investigating inpatients' perceptions of quality of care, and to identify differences in perceptions of care related to patient gender, age and type of admission. Nursing managers play an important role in the development of high-quality care. Quality of care was assessed using the Quality from the Patients' Perspective (QPP). In all, 2734 inpatients at a Swedish university hospital completed the QPP. Inadequate quality was identified for 15 out of 24 items, e.g. information given on treatment and examination results, opportunities to participate in decisions related to care and information on self-care. Patients with emergency admissions reported lower scores for quality of information and doctors' care than did patients with planned admissions. Results from the present survey identified areas in need of quality improvement and differences in perceived care quality between patients. Quality of care must be developed in close collaboration with other healthcare professionals; in this respect, nursing managers could play an important role. Nursing managers could play a more active part in measuring quality of care, and in using results from such measurements to develop and improve quality of care.


An assessment of strategies to control dental caries in Aboriginal children living in rural and remote communities in New South Wales, Australia.
A community-led oral health service for Aboriginal people in Central Northern NSW identified the need for oral health promotion, as well as dental treatment; in three remote communities with limited access to dental services. A three-stage plan based on the Precede-Proceed model was used to develop a school-based preventive oral health program. The program will be piloted in three schools over 12 months aimed at improving the oral health of local Aboriginal children. The proposed program includes four components: daily in-school toothbrushing; distribution of free fluoride toothpaste and toothbrushes; in-school and community dental health education and the installation of refrigerated and chilled water fountains to supply a school water bottle program. Primary school children will be issued toothbrushing kits to be kept at school to facilitate daily brushing using a fluoride toothpaste under the supervision of trained teachers and/or Oral Health Aides. School children, parents and guardians will be issued free fluoride toothpaste and toothbrushes for home use at three-monthly intervals. Four dental health education sessions will be delivered to children at each school and parents/guardians at local community health centres over the 12 month pilot. Dental education will be delivered by an Oral Health Therapist and local Aboriginal Dental Assistant. The program will also facilitate the installation of refrigerated and filtered water fountain to ensure cold and filtered water is available at schools. A structured school water bottle program will encourage the consumption of water. A process evaluation will be undertaken to assess the efficiency, feasibility and effectiveness of the pilot program. The proposed program includes four core evidence-based components which can be implemented in rural and remote schools with a high Aboriginal population. Based on the Precede-Proceed model, this program seeks to empower the local Aboriginal community to achieve improved oral health outcomes. TRN: ISRCTN16110292 Date of Registration: 20 June 2018.


Development and Validation of Stability-indicating High Performance Liquid Chromatographic Method for the Estimation of Everolimus in Tablets.
The present study depicts the development of a validated reversed-phase high performance liquid chromatographic method for the determination of the everolimus in presence of degradation products or pharmaceutical excipients. Stress study was performed on everolimus and it was found that it degrade sufficiently in oxidizing and acidic conditions but less degradation was found in alkaline, neutral, thermal and photolytic conditions. The separation was carried out on Hypersil BDS C18 column (100×4.6 mm, 5 μ) column having particle size 5 μ using acetate buffer:acetonitrile (50:50 v/v) with pH 6.5 adjusted with orthophosphoric acid as mobile phase at flow rate of 1 ml/min. The wavelength of the detection was 280 nm. A retention time (Rt) nearly 3.110 min was observed. The calibration curve for everolimus was linear (r(2)=0.999) from range of 25-150 μg/ml with limit of detection and limit of quantification of 0.036 μg/ml and 0.109 μg/ml, respectively. Analytical validation parameters such as selectivity, specificity, linearity, accuracy and precision were evaluated and relative standard deviation value for all the key parameters were less than 2.0%. The recovery of the drug after standard addition was found to be 100.55%. Thus, the developed RP-HPLC method was found to be suitable for the determination of everolimus in tablets containing various excipients.


Intervendor consistency and reproducibility of left ventricular 2D global and regional strain with two different high-end ultrasound systems.
We aimed to assess intervendor agreement of global (GLS) and regional longitudinal strain by vendor-specific software after EACVI/ASE Industry Task Force Standardization Initiatives for Deformation Imaging. Fifty-five patients underwent prospective dataset acquisitions on the same day by the same operator using two commercially available cardiac ultrasound systems (GE Vivid E9 and Philips iE33). GLS and regional peak longitudinal strain were analyzed offline using corresponding vendor-specific software (EchoPAC BT13 and QLAB version 10.3). Absolute mean GLS measurements were similar between the two vendors (GE -17.5 ± 5.2% vs. Philips -18.9 ± 5.1%, P = 0.15). There was excellent intervendor correlation of GLS by the same observer [r = 0.94, P < 0.0001; bias -1.3%, 95% CI limits of agreement (LOA) -4.8 to 2.2%). Intervendor comparison for regional longitudinal strain by coronary artery territories distribution were: LAD: r = 0.85, P < 0.0001; bias 0.5%, LOA -5.3 to 6.4%; RCA: r = 0.88, P < 0.0001; bias -2.4%, LOA -8.6 to 3.7%; LCX: r = 0.76, P < 0.0001; bias -5.3%, LOA -10.6 to 2.0%. Intervendor comparison for regional longitudinal strain by LV levels were: basal: r = 0.86, P < 0.0001; bias -3.6%, LOA -9.9 to 2.0%; mid: r = 0.90, P < 0.0001; bias -2.6%, LOA -7.8 to 2.6%; apical: r = 0.74; P < 0.0001; bias -1.3%, LOA -9.4 to 6.8%. Intervendor agreement in GLS and regional strain measurements have significantly improved after the EACVI/ASE Task Force Strain Standardization Initiatives. However, significant wide LOA still exist, especially for regional strain measurements, which remains relevant when considering vendor-specific software for serial measurements.


Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
(a) To determine the excess mortality from all causes and from coronary heart disease in patients with familial hypercholesterolaemia; (b) to examine how useful various criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes are in identifying these patients. Prospective cohort study. Eleven hospital outpatient lipid clinics in the United Kingdom. 282 men and 244 women aged 20-74 with heterozygous familial hypercholesterolaemia. Standardised mortality ratio, all adults in England and Wales being taken as standard (standardised mortality ratio = 100 for standard population). The cohort was followed up for 2234 person years during 1980-9. Fifteen of the 24 deaths were due to coronary heart disease, giving a standardised mortality ratio of 386 (95% confidence interval 210 to 639). The excess mortality from this cause was highest at age 20-39 (standardised mortality ratio 9686; 3670 to 21,800) and decreased significantly with age. The standardised mortality ratio for all causes was 183 (117 to 273) and also was highest at age 20-39 (standardised mortality ratio 902; 329 to 1950). There was no significant difference between men and women. Criteria for measurement of cholesterol concentration in cardiovascular screening programmes (family history, presence of myocardial infarction, angina, stroke, corneal arcus, xanthelasma, obesity, hypertension, diabetes, or any of these) were present in 78% of patients. Familial hypercholesterolaemia is associated with a substantial excess mortality from coronary heart disease in young adults but may not be associated with a substantial excess mortality in older patients. Criteria for selective measurement of cholesterol concentration in cardiovascular screening programmes identify about three quarters of patients with the clinically overt condition.


Paying lip service to publication ethics: scientific publishing practices and the Foundation for a Smoke-Free World.
Litigation forced the dissolution of three major tobacco industry-funded organisations because of their egregious role in spreading scientific misinformation. Yet in 2017, a new scientific organisation-the Foundation for a Smoke-Free World (FSFW)-was launched, funded entirely by tobacco corporation Philip Morris International (PMI). Experts fear FSFW similarly serves to benefit its funder's scientific and political agenda. We present three case studies of FSFW's publishing practices to explore: whether FSFW and its affiliates are acting with scientific integrity in their attempts to publish research; how conflicts of interest (COI) are governed in the journals FSFW targets; whether scientific publishing needs to be better protected from the tobacco industry in light of this, and if so, how. FSFW and its grantees have resorted to repeated obfuscation when publishing their science. FSFW staff have failed to act transparently and arguably have sought control over editorial processes (at times facilitated by PR firm, Ruder Finn). FSFW-funded organisations (including its Italian 'Centre of Excellence') and researchers affiliated with FSFW (including those working as editors and peer-reviewers) have failed to disclose their links to FSFW and PMI. While journals also failed to apply their COI policies, including on tobacco industry-funded research, the findings highlight that such policies are almost entirely dependent on researchers fully declaring all potential COIs. The paper explores ways to address these problems, including via standardised reporting of COI and funding in journals; journal policies prohibiting publication of tobacco industry-funded science; development of an author-centric database of financial interests; and legally mandated tobacco industry financial contributions to fund science on new tobacco and nicotine products.


Correlation among clock gene expression rhythms, sleep quality, and meal conditions in delayed sleep-wake phase disorder and night eating syndrome.
Clock genes that comprise the circadian clock system control various physiological functions. Delayed sleep-wake phase disorder (DSWPD) and night eating syndrome (NES) are characterized by delayed sleep and meal timing, respectively. We estimated that clock gene expression rhythms in DSWPD patients may be delayed in comparison with the healthy subjects due to delayed melatonin secretion rhythms, producing eveningness chronotype in these individuals. However, it was difficult to estimate which clock gene expression rhythms were delayed or not in NES patients, because previous studies revealed that melatonin secretion rhythm was a little delayed compared with healthy individuals and that chronotype of NES patients depended on the individuals. Therefore, we examined expression rhythms of clock genes such as Period3 (Per3), nuclear receptor subfamily 1, group D, member 1 (Nr1d1) and Nr1d2 in these patients. Further, we expected sleep and meal patterns in DSWPD and NES patients may be more diverse than patterns observed in healthy subjects, and thus analyzed relationships among clock gene expression rhythms, sleep quality, sleep midpoint time, and meal times. We enrolled healthy male participants along with DSWPD and NES male patients, and asked all participants to answer questionnaires and to keep diaries to record information on their sleep and meals. Further, we asked them to collect 5-10 beard follicle samples, 6 times every 4 h. We measured clock gene expression rhythms using total RNA extracted from beard follicle cells. Peak time of clock gene expression in the NES group showed more diversity than the other groups, and that in the DSWPD group was delayed compared with the control group. In addition, the peak time of clock gene expression was negatively correlated with sleep quality and positively correlated with meal time after a long fast. Amplitudes of clock gene expression, especially Per3, positively responded to better mental and physical conditions as well as with better sleep quality. Results of this study suggest that peak times of clock gene expression in NES patients depended on the individuals; some patients with NES showed similar clock gene expression rhythm to healthy subjects, and other patients with NES showed similar to DSWPD patients. Moreover, this study suggests that meal time after a long fast may influence more determination in clock gene expression rhythms than the time of breakfast. Therefore, this study also indicates that Per3 clock gene may be one of the parameters that will help us understand sleep and meal rhythm disturbances.


Development and Implementation of the World Health Organization Emergency Medical Teams: Minimum Technical Standards and Recommendations for Rehabilitation.
Emergency medical teams provide urgent medical and surgical care in emergencies characterized by a surge in trauma or disease. Rehabilitation has historically not been included in the acute phase of care, as teams have either not perceived it as their responsibility or have relied on external providers, including local services and international organizations, to provide services. Low- and middle-income countries, which often have limited rehabilitation capacity within their health system, are particularly vulnerable to disaster and are usually ill-equipped to address the increased burden of rehabilitation needs that arise. The resulting unmet needs for rehabilitation culminate in unnecessary complications for patients, delayed recovery, reduced functional outcomes, and often impede return to daily activities and life roles. Recognizing the systemic neglect of rehabilitation in global emergency medical response, the World Health Organization, in collaboration with key operational partners and experts, developed technical standards and recommendations for rehabilitation which are integrated into the WHO verification process for EMTs. This protocol report presents: 1) the rationale for the development of the standards and accompanying recommendations; 2) the methodology of the development process; 3) the minimum standards and other significant content included in the document; 4) challenges encountered during development and implementation; and 5) current and next steps to continue strengthening the inclusion of rehabilitation in emergency medical response.


L-arginine metabolism inhibits arthritis and inflammatory bone loss.
To investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss. L-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by μCT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients. L-arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients. Our study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.


Influence of vitamin D receptor genotype on bone mineral density in postmenopausal women: a twin study in Britain.
To investigate the possible association between vitamin D receptor genotype and bone mineral density in a large group of postmenopausal twins. Cross sectional twin study. Twin population based in Britain. 95 dizygotic (non-identical) pairs of twins and 87 monozygotic (identical) pairs of twins aged 50-69 years, postmenopausal, and free of diseases affecting bone, recruited from a national register of twins and with a media campaign. Bone mineral density measured at the hip, lumbar spine, forearm, and for the whole body by dual energy x ray absorptiometry in relation to differences in the vitamin D receptor genotype. At all sites the values of bone density among dizygotic twins were more similar in those of the same vitamin D receptor genotype than in those of differing genotype, and the values in the former were closer to the correlations seen in monozygotic twins. Women with the genotype that made them at risk of osteoporotic fracture had an adjusted bone mineral density that was significantly lower by SD 0.5 to 0.6 at the hip, lumbar spine, and for the whole body. The results could not be explained by differences in age, weight, years since menopause, or use of hormone replacement therapy. The findings that in postmenopausal women in Britain bone density-particularly at the hip and spine-is genetically linked and specifically associated with the vitamin D receptor genotypes should lead to novel approaches to the prevention and treatment of osteoporosis.


Multimessenger observations of a flaring blazar coincident with high-energy neutrino IceCube-170922A.
Previous detections of individual astrophysical sources of neutrinos are limited to the Sun and the supernova 1987A, whereas the origins of the diffuse flux of high-energy cosmic neutrinos remain unidentified. On 22 September 2017, we detected a high-energy neutrino, IceCube-170922A, with an energy of ~290 tera-electron volts. Its arrival direction was consistent with the location of a known γ-ray blazar, TXS 0506+056, observed to be in a flaring state. An extensive multiwavelength campaign followed, ranging from radio frequencies to γ-rays. These observations characterize the variability and energetics of the blazar and include the detection of TXS 0506+056 in very-high-energy γ-rays. This observation of a neutrino in spatial coincidence with a γ-ray-emitting blazar during an active phase suggests that blazars may be a source of high-energy neutrinos.