An adjuvanted herpes simplex virus 2 subunit vaccine elicits a T cell response in mice and is an effective therapeutic vaccine in Guinea pigs.
Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4(+) and CD8(+) T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease.


Optimization of specificity in a cellular protein interaction network by negative selection.
Most proteins that participate in cellular signalling networks contain modular protein-interaction domains. Multiple versions of such domains are present within a given organism: the yeast proteome, for example, contains 27 different Src homology 3 (SH3) domains. This raises the potential problem of cross-reaction. It is generally thought that isolated domain-ligand pairs lack sufficient information to encode biologically unique interactions, and that specificity is instead encoded by the context in which the interaction pairs are presented. Here we show that an isolated peptide ligand from the yeast protein Pbs2 recognizes its biological partner, the SH3 domain from Sho1, with near-absolute specificity--no other SH3 domain present in the yeast genome cross-reacts with the Pbs2 peptide, in vivo or in vitro. Such high specificity, however, is not observed in a set of non-yeast SH3 domains, and Pbs2 motif variants that cross-react with other SH3 domains confer a fitness defect, indicating that the Pbs2 motif might have been optimized to minimize interaction with competing domains specifically found in yeast. System-wide negative selection is a subtle but powerful evolutionary mechanism to optimize specificity within an interaction network composed of overlapping recognition elements.


Foot infections due to Hendersonula toruloidea and Scytalidium hyalinum in coal miners.
A total of 250 coal miners were screened for mycotic skin infections. Sixty-six (34.8%) miners had clinical lesions on their feet which proved to be of mycotic etiology by direct microscopy and culture. Hendersonula toruloidea, the commonest etiological agent, was the sole agent recovered from 23 (34.8%) of the positive cases and was also isolated from three (4.5%) cases of mixed infection with dermatophytes (two cases with Trichophyton rubrum and one with Trichophyton mentagrophytes var. mentagrophytes). Scytalidium hyalinum was recovered as the sole causal agent in four (6.1%) patients and from one case of mixed infection with T. mentagrophytes var. mentagrophytes. The dermatophytes isolated as sole etiological agents included T. mentagrophytes var. mentagrophytes (13 isolates) T. rubrum (10), Trichophyton tonsurans (5), Epidermophyton floccosum (4) and Microsporum gypseum (3). The toe web was invariably involved in all cases of H. toruloidea and S. hyalinum infection and was also the commonest site of infection by dermatophytes. Occasionally the sole, toe and finger nails were also involved. Other body sites were infrequently involved and then only in infections caused by dermatophytes. The epidemiology of H. toruloidea and S. hyalinum infections is reviewed.


Optimal management strategies to control local population growth or population spread may not be the same.
The objective of most pest management programs is to "control" the pest species. However, optimal control of local abundance and population growth may require different management strategies than optimal control of spatial spread. We use coupled demographic-dispersal models to address the relative importance of different management approaches to these two main control objectives for the invasive thistle Carduus nutans. The models are parameterized with data from thistle populations in the native (France) and invaded ranges (Australia and New Zealand). We assess a wide range of commonly used management strategies for their absolute and relative impacts on population growth and spread in both invaded-range scenarios. The projected population growth rate in New Zealand is more than twice that in Australia, while the spread rate is more than four times the Australian value. In general, spread and growth are both most strongly affected by the same life cycle transitions; however, in a few cases certain vital rates disproportionately affect either spread or growth. The transition that represents the contribution of large rosettes in one year to the number of large rosettes in the following year (the large rosette-large rosette transition) in Australia is dominated by reproduction (rather than survival) and hence is relatively more important to spread than to population growth. In New Zealand, the small rosette-small rosette transition is also predominantly dispersal-related. However, establishment of small plants from the seed bank contributes more to population growth than spread, as no dispersal is involved. The fine-resolution vital-rate-based modeling approach allows us to identify potentially novel optimal management strategies: approaches that reduce microsite availability show promise for reducing both population growth and spread, while strategies that affect dispersal parameters will affect spread. Additionally, the relative ranking of some biocontrol agents shifts depending on whether control of population growth or population spread is the desired outcome and therefore could alter which of the agents are preferred for release in a new area. The possibility of differences in ranked agent effectiveness has been predicted theoretically, but never before demonstrated using field data.


Distributed relaxation processes in sensory adaptation.
Dynamic description of most receptors, even in their near-linear ranges, has not led to understanding of the underlying physical events-in many instances because their curious transfer functions are not found in the usual repertoire of integral-order control-system analysis. We have described some methods, borrowed from other fields, which allow one to map any linear frequency response onto a putative weighting over an ensemble of simpler relaxation processes. One can then ask whether the resultant weighting of such processes suggests a corresponding plausible distribution of values for an appropriate physical variable within the sensory transducer. To illustrate this approach, we have chosen the fractional-order low-frequency response of Limulus lateral-eye photoreceptors. We show first that the current "adapting-bump" hypothesis for the generator potential can be formulated in terms of local first-order relaxation processes in which local light flux, the cross section of rhodopsin for photon capture, and restoration rate of local conductance-changing capability play specific roles. A representative spatial distribution for one of these parameters, which just accounts for the low-frequency response of the receptor, is then derived and its relation to cellular properties and recent experiments is examined. Finally, we show that for such a system, nonintegral-order dynamics are equivalent to nonhyperbolic statics, and that the efficacy distribution derived to account for the small-signal dynamics in fact predicts several decades of near-logarithmic response in the steady state. Encouraged by the result that one plausible proposal can account approximately for both the low-frequency dynamics (the transfer function s(k)) and the range-compressing statics (the Weber-Fechner relationship) measured in this photoreceptor, we have described some formally similar applications of these distributed effects to the vertebrate retina and to analogous properties of mechanoreceptors and chemoreceptors.


SNARE-mediated lipid mixing depends on the physical state of the vesicles.
Reconstitution experiments have suggested that N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins constitute a minimal membrane fusion machinery but have yielded contradictory results, and it is unclear whether the mechanism of membrane merger is related to the stalk mechanism that underlies physiological membrane fusion. Here we show that reconstitution of solubilized neuronal SNAREs into preformed 100 nm liposomes (direct method) yields proteoliposomes with more homogeneous sizes and protein densities than the standard reconstitution method involving detergent cosolubilization of proteins and lipids. Standard reconstitutions yield slow but efficient lipid mixing at high protein densities and variable amounts of lipid mixing at moderate protein densities. However, the larger, more homogenous proteoliposomes prepared by the direct method yield almost no lipid mixing at moderate protein densities. These results suggest that the lipid mixing observed for standard reconstitutions is dominated by the physical state of the membrane, perhaps due to populations of small vesicles (or micelles) with high protein densities and curvature stress created upon reconstitution. Accordingly, changing membrane spontaneous curvature by adding lysophospholipids inhibits the lipid mixing observed for standard reconstitutions. Our data indicate that the lipid mixing caused by high SNARE densities and/or curvature stress occurs by a stalk mechanism resembling the mechanism of fusion between biological membranes, but the neuronal SNAREs are largely unable to induce lipid mixing at physiological protein densities and limited curvature stress.


Development of an exercise intervention to improve cognition in people with mild to moderate dementia: Dementia And Physical Activity (DAPA) Trial, registration ISRCTN32612072.
More than 800000 people in the UK have dementia, and it is a government priority to improve dementia care. Drug treatment options are relatively limited. The Dementia And Physical Activity (DAPA) study is a randomised trial which targets cognition in people with dementia, using an exercise programme. There is evidence to suggest that both aerobic and resistance exercise may be useful in improving cognition. Hence the intervention comprises a supervised part of twice-weekly exercise classes of one hour duration for 4 months, including aerobic exercise at moderate intensity on static bicycles, and resistance (weight training) exercise using weight vests, weight belts and dumbbells. Thereafter participants progress to unsupervised, independent exercise. Aids to behaviour modification have been incorporated into the intervention. The DAPA intervention has been designed to maximise likelihood of effectiveness and cost-effectiveness, and for delivery in the UK National Health Service.


Agonist-induced sequestration, recycling, and resensitization of platelet-activating factor receptor. Role of cytoplasmic tail phosphorylation in each process.
Agonist-induced sequestration, recycling, and resensitization of platelet-activating factor (PAF) receptor were characterized in transfected Chinese hamster ovary cells. Exposure of the cells to PAF led to rapid sequestration of the receptors into the intracellular compartment and desensitization of the response to PAF. The sequestration was inhibited by pretreatments that perturbed the clathrin-mediated pathway. Subsequent removal of PAF by washing with receptor antagonists led to rapid recycling of the sequestered receptors to the cell surface accompanied by resensitization to PAF. To evaluate the potential role of phosphorylation in the receptor cytoplasmic tail during these processes, mutant receptors in which the tails were truncated or substituted, so as to lack serine/threonine residues, were created. PAF phosphorylated the wild-type receptor rapidly and strongly, but the mutants did not. The maximal extent of sequestration of each mutant was lower than that of the wild-type, and one of the substituted mutants showed no sequestration. Furthermore, the sequestration-defective mutant showed evidence of desensitization after agonist stimulation but not resensitization after agonist removal. Thus, agonist-induced phosphorylation of the cytoplasmic tail facilitates but is not essential for receptor sequestration, and sequestration/recycling appears important in receptor resensitization.


Modelling the action potential propagation in a heart with structural heterogeneities: From high-resolution MRI to numerical simulations.
Mathematical modelling and numerical simulation in cardiac electrophysiology have already been studied extensively. However, there is a clear lack of techniques and methodologies for studying the propagation of action potential in a heart with structural defects. In this article, we present a modified version of the bidomain model, derived using homogenisation techniques with the assumption of existence of diffusive inclusions in the cardiac tissue. The diffusive inclusions represent regions without electrically active myocytes, for example, fat, fibrosis, and so forth. We present an application of this model to a rat heart. Starting from high-resolution MRI, the geometry of the heart is built and meshed using image processing techniques. We perform a study of the effects of tissue heterogeneities induced by diffusive inclusions on the velocity and shape of the depolarisation wavefront. We present several test cases with different geometries of diffusive inclusions. We reach the conclusion that the conduction velocity is not affected in the best cases, while it is affected by up to 76% in the worst case scenario. Additionally, the shape of the wavefront was affected in some cases.


Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study.
Emergence of variants with specific mutations in key epitopes in the spike protein of SARS-CoV-2 raises concerns pertinent to mass vaccination campaigns and use of monoclonal antibodies. We aimed to describe the emergence of the B.1.1.7 variant of concern (VOC), including virological characteristics and clinical severity in contemporaneous patients with and without the variant. In this cohort study, samples positive for SARS-CoV-2 on PCR that were collected from Nov 9, 2020, for patients acutely admitted to one of two hospitals on or before Dec 20, 2020, in London, UK, were sequenced and analysed for the presence of VOC-defining mutations. We fitted Poisson regression models to investigate the association between B.1.1.7 infection and severe disease (defined as point 6 or higher on the WHO ordinal scale within 14 days of symptoms or positive test) and death within 28 days of a positive test and did supplementary genomic analyses in a cohort of chronically shedding patients and in a cohort of remdesivir-treated patients. Viral load was compared by proxy, using PCR cycle threshold values and sequencing read depths. Of 496 patients with samples positive for SARS-CoV-2 on PCR and who met inclusion criteria, 341 had samples that could be sequenced. 198 (58%) of 341 had B.1.1.7 infection and 143 (42%) had non-B.1.1.7 infection. We found no evidence of an association between severe disease and death and lineage (B.1.1.7 vs non-B.1.1.7) in unadjusted analyses (prevalence ratio [PR] 0·97 [95% CI 0·72-1·31]), or in analyses adjusted for hospital, sex, age, comorbidities, and ethnicity (adjusted PR 1·02 [0·76-1·38]). We detected no B.1.1.7 VOC-defining mutations in 123 chronically shedding immunocompromised patients or in 32 remdesivir-treated patients. Viral load by proxy was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold value (mean 28·8 [SD 4·7] vs 32·0 [4·8]; p=0·0085) and genomic read depth (1280 [1004] vs 831 [682]; p=0·0011). Emerging evidence exists of increased transmissibility of B.1.1.7, and we found increased virus load by proxy for B.1.1.7 in our data. We did not identify an association of the variant with severe disease in this hospitalised cohort. University College London Hospitals NHS Trust, University College London/University College London Hospitals NIHR Biomedical Research Centre, Engineering and Physical Sciences Research Council.


Neonatal cerebral morphometry and later risk of persistent inattention/hyperactivity in children born very preterm.
Attention problems are among the most prevalent neurobehavioral morbidities affecting very preterm (VPT) born children. The first study aim was to document rates of persistent attention/hyperactivity problems from ages 4 to 9 years in a regional cohort of VPT born children. The second aim was to examine the extent to which persistent problems were related to cerebral white matter abnormality and structural development on neonatal MRI. Data were drawn from a prospective longitudinal study of 110 VPT (≤32 weeks gestation) and 113 full-term (FT) children born from 1998 to 2000. At term equivalent, all VPT and 10 FT children underwent cerebral structural MRI, with scans analyzed qualitatively for white matter abnormalities and quantitatively for cortical and subcortical gray matter, myelinated and unmyelinated white matter, and cerebrospinal fluid volumes. At ages 4, 6, and 9 years, each child's parent and teacher completed the Inattention/Hyperactivity subscale of the Strengths and Difficulties Questionnaire. VPT born children had a fivefold increased risk of persistent attention/hyperactivity problems compared with FT children (13.1% vs. 2.8%; p = .002). No association was found between neonatal white matter abnormalities and later persistent inattention/hyperactivity risk (p ≥ .24). In contrast, measures of cerebral structural development including volumetric estimates of total cerebral tissue and cerebrospinal fluid relative to intracranial volume were associated with an increased risk of persistent attention/hyperactivity problems in VPT born children (p = .001). The dorsal prefrontal region showed the largest volumetric reduction (↓3.2-8.2 mL). These brain-behavior associations persisted and in some cases, strengthened after covariate adjustment for postmenstrual age at MRI, gender, and family socioeconomic status. Just over one in 10 VPT born children are subject to early onset and persistent attention/hyperactivity problems during childhood. These problems appear to reflect, at least in part, neonatal disturbances in cerebral growth and development rather than the effects of white matter injury.


Evolution and impact of eye and vision terms in written English.
With this article, we aimed to trace the evolution and impact of eye-related terms common in written English during the past 2 centuries by studying digital resources. Eye-related words and phrases (n-grams) occurring in English books at a frequency of 0.00001% for at least 25 years between 1790 and 2008 were identified from the Google n-gram database by searching for 254 strings such as eye or ophth. The first known English use of these n-grams was identified from historical articles and from multiple digital resources. Eye color was not commonly described as brown or green before 1840. Many common bigrams, such as bright eyes, suggested light emanating from the eyes, consistent with the extramission theory of vision. Based on word frequency, the impact of the revolutionary 1850 ophthalmoscope exceeded that of the stethoscope for 60 years. Glaucoma was not commonly written until the ophthalmoscope permitted visualization of the characteristic optic neuropathy. Green spectacles gave way during the early 1900s to dark glasses, subsequently renamed sunglasses. Until the mid-1900s, an eye surgeon was more often described as an oculist than an ophthalmologist, and inflamed eyes were said to experience ophthalmia more often than uveitis. Macular degeneration was rarely written about for more than a century after 1850 because it was labeled choroiditis. Of the 135 n-grams in the dictionary, an earlier written instance was identified in 92 cases (68%). Online databases of the written word reveal the origin and impact of many important vision concepts.


Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks.
To investigate the cellular mechanisms for altered Ca2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ currents (ICa,L), whole-cell Ca2+ transients ([Ca2+]i), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca2+]i amplitude (at 0 mV, 1330+/-62 nmol/L [SHRs] versus 836+/-48 nmol/L [controls], P<0.05) that was not associated with changes in ICa,L density or kinetics, resting [Ca2+]i, or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger average amplitudes (173+/-192 nmol/L [SHRs] versus 109+/-64 nmol/L [control]; P<0.05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca2+]i amplitude, time to relaxation, and average Ca2+ spark amplitude ("big sparks"). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release (ICa,L), SR Ca2+ content, or the expression of several SR Ca2+-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca2+ entry through L-type Ca2+ channels and the release of Ca2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca2+ channels and SR Ca2+ release channels may underlie the changes in Ca2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.


Psychological characteristics and perceptions of stuttering of adults who stutter with and without support group experience.
To compare adults who stutter with and without support group experience on measures of self-esteem, self-efficacy, life satisfaction, self-stigma, perceived stuttering severity, perceived origin and future course of stuttering, and importance of fluency. Participants were 279 adults who stutter recruited from the National Stuttering Association and Board Recognized Specialists in Fluency Disorders. Participants completed a Web-based survey comprised of various measures of well-being including the Rosenberg Self-Esteem Scale, Generalized Self-Efficacy Scale, Satisfaction with Life Scale, a measure of perceived stuttering severity, the Self-Stigma of Stuttering Scale, and other stuttering-related questions. Participants with support group experience as a whole demonstrated lower internalized stigma, were more likely to believe that they would stutter for the rest of their lives, and less likely to perceive production of fluent speech as being highly or moderately important when talking to other people, compared to participants with no support group experience. Individuals who joined support groups to help others feel better about themselves reported higher self-esteem, self-efficacy, and life satisfaction, and lower internalized stigma and perceived stuttering severity, compared to participants with no support group experience. Participants who stutter as an overall group demonstrated similar levels of self-esteem, higher self-efficacy, and lower life satisfaction compared to averages from normative data for adults who do not stutter. Findings support the notion that self-help support groups limit internalization of negative attitudes about the self, and that focusing on helping others feel better in a support group context is linked to higher levels of psychological well-being. At the end of this activity the reader will be able to: (a) describe the potential psychological benefits of stuttering self-help support groups for people who stutter, (b) contrast between important aspects of well-being including self-esteem self-efficacy, and life satisfaction, (c) summarize differences in self-esteem, self-efficacy, life satisfaction, self-stigma, perceived stuttering severity, and perceptions of stuttering between adults who stutter with and without support group experience, (d) summarize differences in self-esteem, self-efficacy, and life satisfaction between adults who stutter and normative data for adults who do not stutter.


An elite controller of picornavirus infection targets an epitope that is resistant to immune escape.
The emergence of novel viral pathogens can lead to devastating consequences in the infected population. However, on occasion, rare hyper-responsive elite controllers are able to mount a protective primary response to infection and clear the new pathogen. Factors distinguishing elite controllers from other members of the population are not completely understood. We have been using Theiler's murine encephalomyelitis as a model of primary infection in mice and clearance of the virus is limited to one MHC genotype capable of generating a protective response to a single viral peptide VP2121-130. The genetics of host susceptibility to TMEV, a natural mouse pathogen, has been studied extensively and non-protective CD8 responses to other peptides have been documented, however, little is known why the protective response to infection focuses on the VP2121-130 peptide. To study this question, we have generated TMEV mutants that encode for mutations within the VP2121-130 peptide. We find that very few of mutants are able to assemble and infect in vitro. These mutations are not related to virus RNA structure since non-coding mutations do not interfere with assembly. In the rare event when functional VP2121-130 mutant viruses did emerge, they were attenuated to some level or retained the ability to develop an immune response to the wild-type VP2121-130 sequence, demonstrating that the virus is incapable of escaping the protective response. These findings advance our understanding of how characteristics of the host immune response and an infectious agent can interact to lead to the appearance of rare super controllers in a population. Furthermore, the immutable nature of the viral antigen highlights the importance of choosing appropriate vaccine antigens and has implications for the development of agents that are able to generate protective CD8 T-cell responses.


Theoretical and experimental aspects of the production of aerosols for use in atomic absorption spectroscopy.
The role of the aerosol in atomic absorption spectroscopy is considered and theories of the production of aerosols by pneumatic and ultrasonic devices are outlined. The predicted droplet size is related to sensitivity and interference by Al and Si in the estimation of Mg. Experiments using pneumatic and ultrasonic (70-kHz and 115-kHz) nebulizers at sample flow rates from 0.05 ml/min to 3.5 ml/min and with spray chambers of 100-cm(3) to 500-cm(3) capacity are reported. The results obtained indicate that ultrasonic nebulizers must be operated at high frequency (>500 kHz) and high power to generate fine aerosols (~5-micro diam) at sample flow rates of 1-5 ml/min if they are to be an improvement in sensitivity and interference on the pneumatic nebulizer.


An effort to use human-based exome capture methods to analyze chimpanzee and macaque exomes.
Non-human primates have emerged as an important resource for the study of human disease and evolution. The characterization of genomic variation between and within non-human primate species could advance the development of genetically defined non-human primate disease models. However, non-human primate specific reagents that would expedite such research, such as exon-capture tools, are lacking. We evaluated the efficiency of using a human exome capture design for the selective enrichment of exonic regions of non-human primates. We compared the exon sequence recovery in nine chimpanzees, two crab-eating macaques and eight Japanese macaques. Over 91% of the target regions were captured in the non-human primate samples, although the specificity of the capture decreased as evolutionary divergence from humans increased. Both intra-specific and inter-specific DNA variants were identified; Sanger-based resequencing validated 85.4% of 41 randomly selected SNPs. Among the short indels identified, a majority (54.6%-77.3%) of the variants resulted in a change of 3 base pairs, consistent with expectations for a selection against frame shift mutations. Taken together, these findings indicate that use of a human design exon-capture array can provide efficient enrichment of non-human primate gene regions. Accordingly, use of the human exon-capture methods provides an attractive, cost-effective approach for the comparative analysis of non-human primate genomes, including gene-based DNA variant discovery.


Cyst germination proteins of the potato pathogen Phytophthora infestans share homology with human mucins.
We have cloned genes of Phytophthora infestans, the causal agent of potato late blight, that are activated shortly before the onset of invasion of the host tissue. The three genes isolated appear to be arranged in a genomic cluster and belong to a small polymorphic gene family. A conspicuous feature of the deduced proteins is an internal octapeptide repeat with the consensus sequence TTYAP TEE. Because of this structural motif, these novel P. infestans proteins were named Car (Cyst-germination-specific acidic repeat) proteins. One of the genes, car90, codes for 1,489 amino acids including 120 octapeptide tandem repeats. Car proteins are transiently expressed during germination of cysts and formation of appressoria and are localized at the surface of germlings. The structural motif of tandemly repeated oligopeptides also occurs in a prominent class of proteins, the mucins, from mammals. The P. infestans Car proteins share 51% sequence homology with the tandem repeat region of a subfamily of human mucins. According to the physiological functions ascribed to mucins, we suggest that Car proteins may serve as a mucous cover protecting the germling from desiccation, physical damage, and adverse effects of the plant defense response and may assist in adhesion to the leaf surface.


Extra-gynoecial pollen-tube growth in apocarpous angiosperms is phylogenetically widespread and probably adaptive.
• Fusion of floral carpels (syncarpy) in angiosperms is thought to have allowed for significant improvements in offspring quantity and quality in syncarpous species over gymnosperms and apocarpous (free-carpelled) angiosperms. Given the disadvantages of apocarpy, it remains an evolutionary puzzle why many angiosperm lineages with free carpels (apocarpy) have been so successful and why some lineages show reversals to apocarpy. • To investigate whether some advantages of syncarpy may accrue in other ways to apocarpous species, we reviewed previous studies of pollen-tube growth in apocarpous species and also documented pollen-tube growth in nine additional apocarpous species in six families. • Anatomical studies of a scattering of apocarpous paleodicots, monocots, and eudicots show that, after transiting the style, 'extra' pollen tubes exit fully fertilized carpels and grow to other carpels with unfertilized ovules. In many species this occurs via openings in the simple carpels, as we report here for Sagittaria potamogetifolia, Sagittaria pygmaea, Sedum lineare, and Schisandra sphenanthera. • The finding that extra-gynoecial pollen-tube growth is widespread in apocarpous species eliminates the possibility of a major fitness cost of apocarpy relative to syncarpy and may help to explain the persistence of, and multiple reversals to, apocarpy in the evolutionary history of angiosperms.


Complete genome sequence of the drought resistance-promoting endophyte Klebsiella sp. LTGPAF-6F.
Bacterial endophytes with capacity to promote plant growth and improve plant tolerance against biotic and abiotic stresses have importance in agricultural practice and phytoremediation. A plant growth-promoting endophyte named Klebsiella sp. LTGPAF-6F, which was isolated from the roots of the desert plant Alhagi sparsifolia in north-west China, exhibits the ability to enhance the growth of wheat under drought stress. The complete genome sequence of this strain consists of one circular chromosome and two circular plasmids. From the genome, we identified genes related to the plant growth promotion and stress tolerance, such as nitrogen fixation, production of indole-3-acetic acid, acetoin, 2,3-butanediol, spermidine and trehalose. This genome sequence provides a basis for understanding the beneficial interactions between LTGPAF-6F and host plants, and will facilitate its applications as biotechnological agents in agriculture.


Dietary intake of seaweed and minerals and prevalence of allergic rhinitis in Japanese pregnant females: baseline data from the Osaka Maternal and Child Health Study.
It may be worthwhile to assess the possible protective effect of the traditional Japanese diet on allergic disorders. This cross-sectional study investigated the relationship between dietary intake of seaweed, vegetables, fruit, antioxidants, fiber, and minerals and the prevalence of allergic rhinitis. Study subjects were 1002 Japanese pregnant women. Allergic rhinitis (including cedar pollinosis) was defined as present if subjects had received drug treatment at some point during the previous 12 months. Information on dietary factors was collected by using a self-administered diet history questionnaire. Seaweed intake was associated independently with a decreased prevalence of allergic rhinitis. Significant inverse dose-response relationships were found between calcium and phosphorus intake and allergic rhinitis prevalence. There also was a tendency for an inverse association between magnesium consumption and allergic rhinitis. Additional adjustment for calcium or magnesium intake apparently did not influence the inverse association with seaweed consumption. Consumption of vegetables, fruit, vitamins C and E, fiber, and zinc showed no association with allergic rhinitis, whereas a significant positive relationship was observed between beta-carotene intake and allergic rhinitis. High dietary intake of seaweed, calcium, magnesium, and phosphorus may be associated with a decreased prevalence of allergic rhinitis.


Microcatheter-assisted trabeculotomy versus rigid probe trabeculotomy in childhood glaucoma.
To compare microcatheter-assisted trabeculotomy with standard rigid probe trabeculotomy for the treatment of childhood glaucoma. The early postoperative (12 months) results of microcatheter-assisted trabeculotomy (group 1) performed by single surgeon were retrospectively compared with those of rigid probe trabeculotomy (group 2) performed by the same surgeon in patients treated for childhood glaucoma. Success was defined as an intraocular pressure (IOP) <21 mm Hg with at least a 30% reduction from preoperative IOP with (qualified success) or without (complete success) the use of anti-glaucoma medication. A total of 43 eyes of 36 patients were included. Mean IOP in group 1 was significantly lower than that in group 2 at 6 months (17.0±5.1 vs 22.5±9.8; p=0.042), 9 months (16.3±5.0 vs 21.6±9.6; p=0.009) and 12 months (14.8±2.5 vs 19.0±7.1; p=0.049) postoperatively. The mean percentage reduction in IOP from preoperative to the last postoperative follow-up was greater in group 1 (47.3±17.7%) than in group 2 (34.2±21.9%) (p=0.036). group 1 demonstrated an 81.0% complete and 86.4% qualified success rate, exceeding the 51.6% complete (p=0.060) and 61.9% qualified (p=0.037) success rate of group 2. There were no long-term complications in either group, but choroidal detachment occurred in one eye in group 2. Microcatheter-assisted circumferential trabeculotomy is a more effective treatment and is as safe as traditional trabeculotomy with a rigid probe for primary congenital glaucoma in the early postoperative course. ChiCTR-OCC-15005789, Results.


Infusing developmental neuroscience into school-based preventive interventions: implications and future directions.
Recent advances in developmental neuroscience have the potential to significantly impact the behavioral and academic outcomes of adolescents. By adopting a translational approach, we aim to promote the transfer of knowledge related to neurological, cognitive, and emotion regulatory factors that underlie youth's ability to respond to educational and prevention programming. This article synthesizes basic and applied research from the field of developmental neuroscience to highlight the significance of this work for the creation, evaluation, and tailoring of school-based preventive interventions designed to address aggressive behavior problems. We draw on research related to stress, social-cognitive factors, emotional perception and regulation, and executive functioning to identify potential neurodevelopmental mediators and moderators of prevention program impacts. Findings suggest that a high level of brain plasticity characterizes early childhood and adolescent stages of development, providing optimal windows of opportunity for intervention. The available research emphasizes the importance of executive functioning and related emotional regulatory factors as potential mechanisms for change in educational and risk prevention models. Neuroscience research provides insights into underlying mechanisms that, when appropriately targeted, can help optimize the impact of social-emotional learning curricula. Recommendations are made for how to apply relevant findings from neuroscience and related disciplines to improve behavioral and academic outcomes for school-aged youth. Additional research areas are identified to inform the creation of neurodevelopmentally sensitive preventive interventions targeting aggressive behavior problems which, in turn, are expected to affect academic outcomes.


Defining publication bias: protocol for a systematic review of highly cited articles and proposal for a new framework.
Selective publication of studies, which is commonly called publication bias, is widely recognized. Over the years a new nomenclature for other types of bias related to non-publication or distortion related to the dissemination of research findings has been developed. However, several of these different biases are often still summarized by the term 'publication bias'. As part of the OPEN Project (To Overcome failure to Publish nEgative fiNdings) we will conduct a systematic review with the following objectives:- To systematically review highly cited articles that focus on non-publication of studies and to present the various definitions of biases related to the dissemination of research findings contained in the articles identified.- To develop and discuss a new framework on nomenclature of various aspects of distortion in the dissemination process that leads to public availability of research findings in an international group of experts in the context of the OPEN Project.We will systematically search Web of Knowledge for highly cited articles that provide a definition of biases related to the dissemination of research findings. A specifically designed data extraction form will be developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article.For the development of a new framework we will construct an initial table listing different levels and different hazards en route to making research findings public. An international group of experts will iteratively review the table and reflect on its content until no new insights emerge and consensus has been reached. Results are expected to be publicly available in mid-2013. This systematic review together with the results of other systematic reviews of the OPEN project will serve as a basis for the development of future policies and guidelines regarding the assessment and prevention of publication bias.


Nutritional supplements for the treatment of ADHD.
Polyunsaturated fatty acid supplementation appears to have modest benefit for improving ADHD symptoms. Melatonin appears to be effective in treating chronic insomnia in children with ADHD but appears to have minimal effects in reducing core ADHD symptoms. Many other natural supplements are widely used in the United States despite minimal evidence of efficacy and possible side effects. This review synthesizes and evaluates the scientific evidence regarding the potential efficacy and side effects of natural supplements and herbal remedies for ADHD. We provide clinicians with recommendations regarding their potential use and role in overall ADHD treatment.


Automatic large-scale classification of bird sounds is strongly improved by unsupervised feature learning.
Automatic species classification of birds from their sound is a computational tool of increasing importance in ecology, conservation monitoring and vocal communication studies. To make classification useful in practice, it is crucial to improve its accuracy while ensuring that it can run at big data scales. Many approaches use acoustic measures based on spectrogram-type data, such as the Mel-frequency cepstral coefficient (MFCC) features which represent a manually-designed summary of spectral information. However, recent work in machine learning has demonstrated that features learnt automatically from data can often outperform manually-designed feature transforms. Feature learning can be performed at large scale and "unsupervised", meaning it requires no manual data labelling, yet it can improve performance on "supervised" tasks such as classification. In this work we introduce a technique for feature learning from large volumes of bird sound recordings, inspired by techniques that have proven useful in other domains. We experimentally compare twelve different feature representations derived from the Mel spectrum (of which six use this technique), using four large and diverse databases of bird vocalisations, classified using a random forest classifier. We demonstrate that in our classification tasks, MFCCs can often lead to worse performance than the raw Mel spectral data from which they are derived. Conversely, we demonstrate that unsupervised feature learning provides a substantial boost over MFCCs and Mel spectra without adding computational complexity after the model has been trained. The boost is particularly notable for single-label classification tasks at large scale. The spectro-temporal activations learned through our procedure resemble spectro-temporal receptive fields calculated from avian primary auditory forebrain. However, for one of our datasets, which contains substantial audio data but few annotations, increased performance is not discernible. We study the interaction between dataset characteristics and choice of feature representation through further empirical analysis.


In vivo imaging of malaria parasites--recent advances and future directions.
A new view into the life of malaria parasites is now possible owing to recent advances in imaging techniques and to the generation of tagged parasites. Insights into how parasites interact with their insect vectors and mammalian hosts have been gained by the study of various parasitic forms in their natural environment. Quantitative analysis of Plasmodium ookinete motility has revealed different modes of motility in parasite invasion of the mosquito gut and the extrusion of invaded gut cells from the epithelium. Similar analysis with Plasmodium sporozoites has revealed the importance of parasite motility in transmission from the mosquito vector to the mammalian host.


Repair-mediated duplication by capture of proximal chromosomal DNA has shaped vertebrate genome evolution.
DNA double-strand breaks (DSBs) are a common form of cellular damage that can lead to cell death if not repaired promptly. Experimental systems have shown that DSB repair in eukaryotic cells is often imperfect and may result in the insertion of extra chromosomal DNA or the duplication of existing DNA at the breakpoint. These events are thought to be a source of genomic instability and human diseases, but it is unclear whether they have contributed significantly to genome evolution. Here we developed an innovative computational pipeline that takes advantage of the repetitive structure of genomes to detect repair-mediated duplication events (RDs) that occurred in the germline and created insertions of at least 50 bp of genomic DNA. Using this pipeline we identified over 1,000 probable RDs in the human genome. Of these, 824 were intra-chromosomal, closely linked duplications of up to 619 bp bearing the hallmarks of the synthesis-dependent strand-annealing repair pathway. This mechanism has duplicated hundreds of sequences predicted to be functional in the human genome, including exons, UTRs, intron splice sites and transcription factor binding sites. Dating of the duplication events using comparative genomics and experimental validation revealed that the mechanism has operated continuously but with decreasing intensity throughout primate evolution. The mechanism has produced species-specific duplications in all primate species surveyed and is contributing to genomic variation among humans. Finally, we show that RDs have also occurred, albeit at a lower frequency, in non-primate mammals and other vertebrates, indicating that this mechanism has been an important force shaping vertebrate genome evolution.


Are prostaglandins involved in the antihypertensive effect of dihydralazine?
1. Two female and two male patients with essential hypertension were given dihydralazine plus saline or dihydralazine plus diclofenac intravenously on two separate occasions. The dihydralazine dose (range: 16.2--32.4 mg/2 h) was chosen individually to reduce systolic blood pressure by 20 mmHg from the control value before the investigation; the intravenous diclofenac dose was 75 mg/20 ml of saline for all patients. 2. Dihydralazine decreased diastolic blood pressure more than systolic blood pressure and increased heart rate; diclofenac reduced both of these effects. 3. Dihydralazine increased urinary volume and sodium clearance; both these effects were antagonized by concomitant treatment with diclofenac. 4. Whereas dihydralazine did not influence creatinine clearance appreciably, concomitant administration of diclofenac reduced creatinine clearance. 5. Urinary prostaglandin E2 was reduced by diclofenac. 6. We suggest that dihydralazine-mediated vasodilation is reduced by cyclo-oxygenase inhibition.


Role of the GABA(A)beta2, GABA(A)alpha6, GABA(A)alpha1 and GABA(A)gamma2 receptor subunit genes cluster in drug responses and the development of alcohol dependence.
gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA(A) and GABA(B) receptors. A possible role for the GABA(A) receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA(A) subunit mRNA expression in cell models has suggested that the long form of the gamma2 subunit is essential for ethanol enhanced potentiation of GABA(A) receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)alpha6 and GABA(A)gamma2 subunits. An Arg(100)/Glu(100) change at the GABA(A)alpha6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA(A) subunit (beta2, alpha6, alpha1 and gamma2) genes on human chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)alpha6 and GABA(A)gamma2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA(A) subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA(A)gamma2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA(A)beta2, alpha6, alpha1 and gamma2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA(A)beta2, alpha6, alpha1 and gamma2 subunit genes have an important role in alcohol related phenotypes (300 words).


Rural veterans and access to high-quality care for high-risk surgeries.
To determine whether older Veterans Health Administration (VA) health care enrollees obtain most high-risk surgeries in non-VA hospitals under Medicare, whether residence in less populous areas increases this reliance on non-VA care or the likelihood of obtaining it in hospitals with higher mortality rates, and whether directing VA enrollees to better hospitals would add a substantial travel burden. VA and Medicare hospital discharge data from 2000 and 2001 for VA enrollees 65 years or older who received any of 14 high-risk elective procedures, including heart, vascular, and cancer surgeries. STUDY DESIGN/DATA EXTRACTION: We compared urban, suburban, and rural patients on use of VA versus non-VA hospitals, use of non-VA hospitals of higher versus lower mortality rates, travel times to get to these hospitals, and the additional travel burden if they had gone to lower mortality hospitals. Regardless of residence, VA enrollees obtained most high-risk surgeries in non-VA hospitals. Urban veterans were most likely to get heart or cancer surgeries in lower mortality hospitals, but rural veterans were most likely to get vascular surgeries in lower mortality hospitals. Average travel times to lower or higher mortality hospitals did not differ greatly. Accessing better hospitals need not add a great travel burden for rural veterans.


Understanding and using the brief Implicit Association Test: recommended scoring procedures.
A brief version of the Implicit Association Test (BIAT) has been introduced. The present research identified analytical best practices for overall psychometric performance of the BIAT. In 7 studies and multiple replications, we investigated analytic practices with several evaluation criteria: sensitivity to detecting known effects and group differences, internal consistency, relations with implicit measures of the same topic, relations with explicit measures of the same topic and other criterion variables, and resistance to an extraneous influence of average response time. The data transformation algorithms D outperformed other approaches. This replicates and extends the strong prior performance of D compared to conventional analytic techniques. We conclude with recommended analytic practices for standard use of the BIAT.


Transient drug supersaturation kinetics of beclomethasone dipropionate in rapidly drying films.
Supersaturation is an effective method to enhance the delivery of active compounds into the skin, however the long-term instability of the drug in these formulations that exceed thermodynamic unity prevents clinical use. The creation of supersaturation in situ by volatile solvent evaporation after application may overcome this. The aim of this study was to determine how altering the kinetics of transient supersaturation and recrystallisation would effect the rate of beclomethasone dipropionate (BDP) release from metered dose aerosols (MDA) that also consisted of hydrofluoroalkane 134a, ethanol (EtOH), and poly(vinyl pyrrolidone) (PVP) K90. An MDA containing 10% EtOH generated a sub-saturated concentration of BDP immediately after dose actuation and did not become supersaturated until 30 min post-actuation. Increasing the EtOH to 20% (w/w) and thus the BDP to 1.76% created supersaturation upon dose actuation but the drug recyrstallised within minutes of application. It was shown that the formulations with higher DS had accelerated rates of release despite rapid recrystallisation (444.9+/-79.3 microg/(cm2 h) for the fastest compared to 206.5+/-23.0 microg/(cm2 h) for the slowest). In highly volatile sprays maintaining BDP supersaturation for extended periods of time was less important than generating instantaneous, high levels of supersaturation to enhance drug release.


Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia.
The purpose of this study was to investigate the effects of sildenafil on retinal injury following neonatal hypoxia-ischemia (HI) at term-equivalent age in rat pups. Hypoxia-ischemia was induced in male Long-Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-hour exposure to 8% oxygen. Sham-operated rats served as the control group. Both groups were administered vehicle or 2, 10, or 50 mg/kg sildenafil, twice daily for 7 consecutive days. Retinal function was assessed by flash electroretinograms (ERGs) at P29, and retinal structure was assessed by retinal histology at P30. Hypoxia-ischemia caused significant functional (i.e., attenuation of the ERG a-wave and b-wave amplitudes and photopic negative response) and structural (i.e., thinning of the total retina, especially the inner retinal layers) retinal damage in the left eyes (i.e., ipsilateral to the carotid ligation). Treatment with the different doses of sildenafil led to a dose-dependent increase in the amplitudes of the ERG a- and b-waves and of the photopic negative response in HI animals, with higher doses associated with greater effect sizes. Similarly, a dose response was observed in terms of improvements in the retinal layer thicknesses. Hypoxia-ischemia at term-equivalent age induced functional and structural damage mainly to the inner retina. Treatment with sildenafil provided a dose-dependent recovery of retinal function and structure.


Clinical effectiveness of percutaneous adhesiolysis using Navicath for the management of chronic pain due to lumbosacral disc herniation.
Epidural steroid injection has been frequently performed to treat chronic pain due to lumbosacral disc herniation (L-HIVD). However, a considerable number of patients do not achieve pain relief using this method because perineural or epidural adhesions prevent the spread of injectate into the epidural space. Percutaneous adhesiolysis (PA) is thought to be a useful method because it can eliminate the deleterious effects of adhesion. This study aimed to evaluate the effectiveness of PA in managing chronic pain due to L-HIVD and the clinical and radiological predictive factors for the effectiveness of PA using NaviCath®. Retrospective study Spine hospital From a group of patients diagnosed with L-HIVD, we selected the 86 patients who underwent PA with NaviCath® who had experienced chronic lower back or leg pain for at least 3 months and had failed to respond to anti-inflammatory medications or physical therapy of at least 1 month's duration and fluoroscopy guided transforaminal epidural injection. We recorded the Numeric Rating Scale for back pain (NRS back) and leg pain (NRS leg) and the Oswestry Disability Index (ODI) at pretreatment, 2 weeks, and 3 months after treatment. Clinical data and magnetic resonance imaging (MRI) findings were obtained to assess the possible predictive factors for PA efficacy. Retrospective chart review without a control group. At 2 weeks after PA, significant improvement was observed in NRS back, NRS leg, and ODI compared with pretreatment. This improvement was maintained until 3 months after treatment. Among 86 patients, 61 (70.9%), 53 (61.6%) and 61 patients (70.9%) showed successful outcomes in NRS back, NRS leg, and ODI at 2 weeks, respectively. Among 74 patients who were followed up at 3 months, 47 (63.5%), 44 patients (59.5%), and 50 patients (67.6%) showed successful results in NRS back, NRS leg, and ODI at 3 months, respectively. A significantly higher proportion of patients with a history of previous lumbar surgery showed unsuccessful results on NRS back, NRS leg, and ODI scores at 2 weeks and 3 months. Co-existence of spinal stenosis was associated with a significantly higher proportion of unsuccessful results in NRS back and ODI at 2 weeks and 3 months, as well as NRS leg at 3 months. Patients with spondylolisthesis also showed a significantly higher proportion of unsuccessful results in NRS and ODI at 2 weeks. PA with NaviCath® showed clinical effectiveness in the treatment of chronic pain due to L-HIVD that was not responsive to transforaminal epidural injection. Previous surgery and the presence of spinal stenosis or spondylolisthesis were poor prognostic predictors. This procedure may enable the physician to place the catheter tip and deliver medicine more precisely.


Initiatives to reduce overcrowding and access block in Australian emergency departments: a literature review.
Australian emergency departments are experiencing an increasing demand for their services. Patient throughput continues to expand resulting in overcrowding and access block where patients cannot gain entry to appropriate hospital beds. This is despite both state and federal governments implementing numerous schemes to address the complex causes of stress on emergency departments. This paper explores the current literature and highlights the key strategies adopted by different emergency departments to reduce delays and streamline patient flow, including: waiting room nurses; streaming; rapid assessment teams; short stay units and care coordination programmes. Many of these initiatives have proven successful at reducing the number of people re-presenting to the emergency department, addressing time delays and improving the management of existing resources and patient flow. More recent changes include increasing the scope of practice and workload for triage nurses. With the recent introduction of the National Emergency Access Target, which requires that most patients presenting to Australian emergency departments are reviewed and transferred or discharged from the department within 4h, traditional roles of nurses in the emergency department are changing and expanding to meet the needs of modern healthcare systems.


Psychotic-Like Experiences and Nonsuicidal Self-Injury in England: Results from a National Survey [corrected].
Little is known about the association between psychotic-like experiences (PLEs) and nonsuicidal self-injury (NSSI) in the general adult population. Thus, the aim of this study was to examine the association using nationally-representative data from England. Data from the 2007 Adult Psychiatric Morbidity Survey was analyzed. The sample consisted of 7403 adults aged ≥ 16 years. Five forms of PLEs (mania/hypomania, thought control, paranoia, strange experience, auditory hallucination) were assessed with the Psychosis Screening Questionnaire. The association between PLEs and NSSI was assessed by multivariable logistic regression. Hierarchical models were constructed to evaluate the influence of alcohol and drug dependence, common mental disorders, and borderline personality disorder symptoms on this association. The prevalence of NSSI was 4.7% (female 5.2% and male 4.2%), while the figures among those with and without any PLEs were 19.2% and 3.9% respectively. In a regression model adjusted for sociodemographic factors and stressful life events, most types of PLE were significantly associated with NSSI: paranoia (OR 3.57; 95%CI 1.96-6.52), thought control (OR 2.45; 95%CI 1.05-5.74), strange experience (OR 3.13; 95%CI 1.99-4.93), auditory hallucination (OR 4.03; 95%CI 1.56-10.42), and any PLE (OR 2.78; 95%CI 1.88-4.11). The inclusion of borderline personality disorder symptoms in the models had a strong influence on the association between PLEs and NSSI as evidenced by a large attenuation in the ORs for PLEs, with only paranoia continuing to be significantly associated with NSSI. Substance dependence and common mental disorders had little influence on the association between PLEs and NSSI. Borderline personality disorder symptoms may be an important factor in the link between PLEs and NSSI. Future studies on PLEs and NSSI should take these symptoms into account.


CXC and CC chemokine receptors on coronary and brain endothelia.
Chemokine receptors on leukocytes play a key role in inflammation and HIV-1 infection. Chemokine receptors on endothelia may serve an important role in HIV-1 tissue invasion and angiogenesis. The expression of chemokine receptors in human brain microvascular endothelial cells (BMVEC) and coronary artery endothelial cells (CAEC) in vitro and cryostat sections of the heart tissue was determined by light and confocal microscopy and flow cytometry with monoclonal antibodies. Chemotaxis of endothelia by CC chemokines was evaluated in a transmigration assay. In BMVEC, the chemokine receptors CCR3 and CXCR4 showed the strongest expression. CXCR4 was localized by confocal microscopy to both the cytoplasm and the plasma membrane of BMVEC. In CAEC, CXCR4 demonstrated a strong expression with predominantly periplasmic localization. CCR5 expression was detected both in BMVEC and CAEC but at a lower level. Human umbilical cord endothelial cells (HUVEC) expressed strongly CXCR4 but only weakly CCR3 and CCR5. Two additional CC chemokines, CCR2A and CCR4, were detected in BMVEC and CAEC by immunostaining. Immunocytochemistry of the heart tissues with monoclonal antibodies revealed a high expression of CXCR4 and CCR2A and a low expression of CCR3 and CCR5 on coronary vessel endothelia. Coronary endothelia showed in vitro a strong chemotactic response to the CC chemokines RANTES, MIP-1alpha, and MIP-1beta. The endothelia isolated from the brain display strongly both the CCR3 and CXCR4 HIV-1 coreceptors, whereas the coronary endothelia express strongly only the CXCR4 coreceptor. CCR5 is expressed at a lower level in both endothelia. The differential display of CCR3 on the brain and coronary endothelia could be significant with respect to the differential susceptibility of the heart and the brain to HIV-1 invasion. In addition, CCR2A is strongly expressed in the heart endothelium. All of the above chemokine receptors could play a role in endothelial migration and repair.


Microsomal nucleoprotein particles from pea seedlings.
Ultracentrifugal analysis of an extract of pea epicotyls, previously freed of debris and larger particles by centrifugation at 40,000 g for 10 minutes, has revealed the presence of a major component which possesses a sedimentation coefficient of 74 S. This component constitutes about 25 per cent of the TCA-precipitable material in the clarified epicotyl extract and is estimated to make up 1 to 2 per cent of the dry weight of the original tissue. In size, chemical composition, and morphology, the 74 S component resembles the nucleoproteins of the microsomes from animal tissues. The 74 S component of pea epicotyl extracts has been purified by repeated cycles of differential centrifugation to yield a preparation which is 80 per cent homogeneous in the analytical ultracentrifuge. It has been found to contain 30 to 37 per cent RNA as judged by a variety of analytical techniques. Approximately 55 per cent of the weight of the material is protein and a further 4.5 per cent phospholipide. Electron micrographs of air-dried specimens of the purified preparation show the 74 S constituent to be flattened spheres with an average height of 180 A and an average diameter of approximately 280 A. The molecular weight of the 74 S particles is computed from sedimentation, viscosity, and partial specific volume data to be 4.5 million +/- 10 per cent in agreement with the value estimated from electron micrographs. The 74 S or microsomal component of pea epicotyls is rapidly aggregated in the presence of low concentrations of Mg ions or by somewhat higher concentrations of Ca or K salts. ATP on the contrary causes resolution of electrolyte-induced microsomal aggregates with simultaneous degradation of the particles to an ultracentrifugally inhomogeneous mixture of lower molecular weight materials.


A suggested procedure for testing large cassegrainian optical systems.
The optical elements of a cassegrainian telescope are commonly tested individually, with their axes in a horizontal position. When these optical elements are inserted in the telescope, the resulting imagery is often disappointing. The quality of the imagery in the telescope may be predicted more accurately if the primary and secondary mirrors, with their axes in the vertical position, are tested against each other with the aid of null compensating reimaging optics. An example is given to illustrate the application of the technique.


Immunogenicity and immunization costs of adjuvanted versus non-adjuvanted hepatitis B vaccine in chronic kidney disease patients.
Hepatitis B virus (HBV) vaccination is recommended for all susceptible chronic pre-hemodialysis and hemodialysis patients. This study assessed the immunogenicity of HBV vaccines (adjuvanted and non-adjuvanted) in chronic kidney disease patients vaccinated at the Hospital Clinic of Barcelona (Spain) between January 2007 and July 2012. In addition, the costs for the health system were evaluated accor-ding to the proportion of vaccine responders after receiving either vaccine. Patients receiving 3 doses of hepatitis B adjuvanted vaccine were 3 times more likely to seroconvert than patients immunized with non-adjuvanted vaccines, OR 3.56 (95% CI 1.84-6.85). This resulted in fewer patients requiring a second course of HBV vaccination and fewer outpatient visits, saving more than €9,500 per 100 patients. The higher immunogenicity of the adjuvanted HBV vaccine would counterbalance the lower costs associated with the non-adjuvanted vaccine.


Preserved metabolic reserve capacity in skeletal muscle of post-infarction heart failure patients.
It has been proposed that exercise capacity during whole body exercise in post-infarction congestive heart failure (CHF) patients is limited by skeletal muscle function. We therefore investigated the balance between cardiopulmonary and muscular metabolic capacity. CHF patients (n=8) and healthy subjects (HS, n=12) were included. Patients with coronary artery disease (CAD, n=8) were included as a control for medication. All subjects performed a stepwise incremental load test during bicycling (∼24 kg muscle mass), two-legged knee extensor (2-KE) exercise (∼4 kg muscle mass) and one-legged knee extensor (1-KE) exercise (∼2 kg muscle mass). Peak power and peak pulmonary oxygen uptake (VO(2peak) ) increased and muscle-specific VO(2peak) decreased with an increasing muscle mass involved in the exercise. Peak power and VO(2peak) were lower for CHF patients than HS, with values for CAD patients falling between CHF patients and HS. During bicycling, all groups utilized 24-29% of the muscle-specific VO(2peak) as measured during 1-KE exercise, with no difference between the groups. Hence, the muscle metabolic reserve capacity during whole body exercise is not different between CHF patients and HS, indicating that appropriately medicated and stable post-infarction CHF patients are not more limited by intrinsic skeletal muscle properties during whole body exercise than HS.


Impact of Percent Body Fat on All-Cause Mortality among Adequate Dialysis Patients with and without Insulin Resistance: A Multi-Center Prospective Cohort Study.
The association between body fat and mortality in hemodialysis patients remains controversial. We examined the effect of percent body fat (PBF) on all-cause mortality among adequate hemodialysis patients with and without insulin resistance (IR). A prospective cohort study was conducted on 365 adequate hemodialysis patients (equilibrated Kt/V ≥ 1.2) from seven hospitals. Patients' characteristics and clinical and biochemical parameters were assessed at baseline between September 2013 and April 2017. Patients were followed up for all-cause mortality until April 2018. The median value of homeostatic model assessment (HOMA-IR) was used to classify IR. Cox proportional hazard models were utilized to examine predictors of all-cause mortality. During 1.4 (1.0-3.2) years of follow-up, 46 patients died. In patients with IR (HOMA-IR ≥ 5.18), PBF was significantly higher in the survival group than in the death group (31.3 ± 9.0 vs. 25.4 ± 8.2, p = 0.005). After controlling for confounding factors, PBF was significantly associated with lower risk for all-cause mortality in patients with IR (hazard ratio, 0.94; 95% confidence interval, 0.89-1.00; p = 0.033). The association was not observed in patients without IR. In conclusion, percent body fat shows a protective effect on survival in hemodialysis patients with IR.


The prevalence of neovascularity in patients clinically diagnosed with rotator cuff tendinopathy.
Shoulder dysfunction is common and pathology of the rotator cuff tendons and subacromial bursa are considered to be a major cause of pain and morbidity. Although many hypotheses exist there is no definitive understanding as to the origin of the pain arising from these structures. Research investigations from other tendons have placed intra-tendinous neovascularity as a potential mechanism of pain production. The prevalence of neovascularity in patients with a clinical diagnosis of rotator cuff tendinopathy is unknown. As such the primary aim of this pilot study was to investigate if neovascularity could be identified and to determine the prevalence of neovascularity in the rotator cuff tendons and subacromial bursa in subjects with unilateral shoulder pain clinically assessed to be rotator cuff tendinopathy. The secondary aims were to investigate the association between the presence of neovascularity and pain, duration of symptoms, and, neovascularity and shoulder function. Patients with a clinical diagnosis of unilateral rotator cuff tendinopathy referred for a routine diagnostic ultrasound (US) scan in a major London teaching hospital formed the study population. At referral patients were provided with an information document. On the day of the scan (on average, at least one week later) the patients agreeing to participate were taken through the consent process and underwent an additional clinical examination prior to undergoing a bilateral grey scale and colour Doppler US examination (symptomatic and asymptomatic shoulder) using a Philips HDI 5000 Sono CT US machine. The ultrasound scans were performed by one of two radiologists who recorded their findings and the final assessment was made by a third radiologist blinded both to the clinical examination and the ultrasound examination. The findings of the radiologists who performed the scans and the blinded radiologist were compared and any disagreements were resolved by consensus. Twenty-six patients agreed to participate and formed the study population. Of these, 6 subjects were not included in the final assessment following the pre-scan clinical investigation. This is because one subject had complete cessation of symptoms between the time of the referral and entry into the trial. Another five had developed bilateral shoulder pain during the same period. The mean age of the 20 subjects forming the study population was 50.2 (range 32-69) years (SD = 10.9) and the mean duration of symptoms was 22.6 (range .75 to 132) months (SD = 40.1). Of the 20 subjects included in the formal analysis, 13 subjects (65%) demonstrated neovascularity in the symptomatic shoulder and 5 subjects (25%) demonstrated neovascularity in the asymptomatic shoulder. The subject withdrawn due to complete cessation of symptoms was not found to have neovascularity in either shoulder and of the 5 withdrawn due to bilateral symptoms; two subjects were found to have signs of bilateral neovascularity, one subject demonstrated neovascularity in one shoulder and two subjects in neither shoulder. This study demonstrated that neovascularity does occur in subjects with a clinical diagnosis of rotator cuff tendinopathy and to a lesser extent in asymptomatic shoulders. In addition, the findings of this investigation did not identify an association between the presence of neovascularity; and pain, duration of symptoms or shoulder function. Future research is required to determine the relevance of these findings.


Male-sterilizing interactions between duplications and deficiencies for proximal X-chromosome material in Drosophila melanogaster.
The genetic limits of sixty-four deficiencies in the vicinity of the euchromatic-heterochromatic junction of the X chromosome were mapped with respect to a number of proximal recessive lethal mutations. They were also tested for male fertility in combination with three Y chromosomes carrying different amounts of proximal X-chromosome-derived material (BSYy+, y+Ymal126 and y+Ymal+). All deficiencies that did not include the locus of bb and a few that did were male-fertile in all male-viable Df(1)/Dp(1;Y) combinations. Nineteen bb deficiencies fell into six different classes by virtue of their male-fertility phenotypes when combined with the duplicated Y chromosomes. The six categories of deficiencies are consistent with a formalism that invokes three factors or regions at the base of the X, one distal and two proximal to bb, which bind a substance critical for precocious inactivation of the X chromosome in the primary spermatocyte. Free duplications carrying these regions or factors compete for the substance in such a way that, in the presence of such duplications, proximally deficient X chromosomes are unable to command sufficient substance for proper control of X-chromosome gene activity preparatory to spermatogenesis. We conclude that there is no single factor at the base of the X that is required for the fertility of males whose genotype is otherwise normal.


Biomechanical Responses of Lamina Cribrosa to Intraocular Pressure Change Assessed by Optical Coherence Tomography in Glaucoma Eyes.
The purpose of this study was to measure change in anterior lamina cribrosa depth (ALD) globally and regionally in glaucoma eyes at different intraocular pressures (IOP). Twenty-seven glaucoma patients were imaged before and after IOP-lowering procedures using optical coherence tomography. The anterior lamina was marked in approximately 25 locations in each of six radial scans to obtain global and regional estimates of ALD. ALD and its change with IOP were compared with optic disc damage, nerve fiber layer thickness, and visual field loss. Variables associated with deeper baseline ALD included larger cup/disc ratio, thinner rim area, larger cup volume, thinner central corneal thickness, and male sex (all P ≤ 0.02). When IOP was lowered, ALD position became more anterior, more posterior, or was unchanged. The mean ALD change after lowering was 27 ± 142 μm (P = 0.3). The mean absolute value of ALD change was 112 ± 90 μm (P = 0.002). Change in ALD was greater in eyes with lower IOP in paired comparisons (P = 0.006) but was not associated with the magnitude of IOP lowering between imaging sessions (P = 0.94). Eyes with no significant change in ALD tended to have more visual field loss than those with significant anterior ALD displacement (P = 0.07). Areas within each optic nerve head that corresponded to zones with thicker nerve fiber layer had greater ALD positional change (P = 0.0007). The lamina can move either anteriorly or posteriorly with IOP decrease, with greater displacement at lower IOP. Glaucoma eyes and regions within glaucoma eyes associated with greater glaucoma damage exhibited smaller responses.


Communicating about expected course and re-consultation for respiratory tract infections in children: an exploratory study.
Acute respiratory tract infection is the commonest reason for children consulting, and about one-fifth re-consult for the same illness episode. Fifty-nine audiotape recordings from nine general practitioners (GPs) consulting with children with acute respiratory tract infections were examined. Prognosis was mentioned in only 22 consultations, with GPs predicting a brief course in 11, a possibly longer than expected course in six, and with predicted duration not made explicit in five. Carers were invited to re-consult if they were 'unhappy' with the child's condition in 11 consultations, and specific triggers to re-consult were provided in 15. A patient information leaflet was given out only once. Providing carers with an evidence-based account of the likely clinical course and communicating specific triggers to re-consult may help them manage more of these illness episodes without re-consulting.


Genome profiling (GP) method based classification of insects: congruence with that of classical phenotype-based one.
Ribosomal RNAs have been widely used for identification and classification of species, and have produced data giving new insights into phylogenetic relationships. Recently, multilocus genotyping and even whole genome sequencing-based technologies have been adopted in ambitious comparative biology studies. However, such technologies are still far from routine-use in species classification studies due to their high costs in terms of labor, equipment and consumables. Here, we describe a simple and powerful approach for species classification called genome profiling (GP). The GP method composed of random PCR, temperature gradient gel electrophoresis (TGGE) and computer-aided gel image processing is highly informative and less laborious. For demonstration, we classified 26 species of insects using GP and 18S rDNA-sequencing approaches. The GP method was found to give a better correspondence to the classical phenotype-based approach than did 18S rDNA sequencing employing a congruence value. To our surprise, use of a single probe in GP was sufficient to identify the relationships between the insect species, making this approach more straightforward. The data gathered here, together with those of previous studies show that GP is a simple and powerful method that can be applied for actually universally identifying and classifying species. The current success supported our previous proposal that GP-based web database can be constructible and effective for the global identification/classification of species.


Imagery and hypnosis in the treatment of cancer patients.
Many patients with cancer often seek some means of connecting their mental activity with the unwelcome events occurring in their bodies, via techniques such as imagery and hypnosis. Hypnosis has been shown to be an effective method for controlling cancer pain. The techniques most often employed involve physical relaxation coupled with imagery that provides a substitute focus of attention for the painful sensation. Other related imagery techniques, such as guided imagery, involve attention to internally generated mental images without the formal use of hypnosis. The most well-known of these techniques involves the use of "positive mental images" of a strong army of white blood cells killing cancer cells. Despite claims to the contrary, no reliable evidence has shown that this technique affects disease progression or survival. Studies evaluating more broadly defined forms psychosocial support have come to conflicting conclusions about whether or not these interventions affect survival of cancer patients. However, 10-year follow-up of a randomized trial involving 86 women with cancer showed that a year of weekly "supportive/expressive" group therapy significantly increased survival duration and time from recurrence to death. This intervention encourages patients to express and deal with strong emotions and also focuses on clarifying doctor-patient communication. Numerous other studies suggest that suppression of negative affect, excessive conformity, severe stress, and lack of social support predict a poorer medical outcome from cancer. Thus, further investigation into the interaction between body and mind in coping with cancer is warranted.


Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.
Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial. The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.


Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin.
During division of metazoan cells, the nucleus disassembles to allow chromosome segregation, and then reforms in each daughter cell. Reformation of the nucleus involves chromatin decondensation and assembly of the double-membrane nuclear envelope around the chromatin; however, regulation of the process is still poorly understood. In vitro, nucleus formation requires p97 (ref. 3), a hexameric ATPase implicated in membrane fusion and ubiquitin-dependent processes. However, the role and relevance of p97 in nucleus formation have remained controversial. Here we show that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B. During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. These data reveal an essential pathway that regulates reformation of the nucleus after mitosis and defines ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation.


The flexibility of cognitive control: Age equivalence with experience guiding the way.
Prior research has shown that aging is accompanied by changes in cognitive control. Older adults are less effective in maintaining an attentional bias in favor of goal-relevant information and are less flexible in shifting control relative to younger adults. Using a novel variant of the Stroop color-naming task, we tested the hypothesis that age-related differences in the flexible shifting of control may be small or absent when control is guided by experience (i.e., environmental input guiding attention). Younger and older adults named the color of color words in abbreviated lists of trials. In Experiment 1, experience within the early segment of the list was manipulated to encourage adoption of more (mostly congruent condition) or less (mostly incongruent condition) attention toward the word. More important, the middle and late portions were 50% congruent in both conditions. Older adults, like younger adults, demonstrated flexible acquisition and shifting of control settings (i.e., relative attention to word vs. color information). In Experiment 2 we replicated this finding. Additionally, we found that both age groups flexibly acquired and shifted control settings for "transfer" items (i.e., items that were 50% congruent in all lists and list segments), pointing to a generalizable (i.e., global) form of control rather than an item-specific mechanism. Discussion focuses on the role of experience-guided control in enabling flexible performance in older adults. (PsycINFO Database Record


Impaired NF-kappaB activation in T cells permits tolerance to primary heart allografts and to secondary donor skin grafts.
T-cell activation is essential for acute allograft rejection. However, the biochemical signaling pathways used by T cells mediating rejection have not been extensively investigated. In vitro, T-cell activation is associated with nuclear translocation of specific transcription factors that regulate expression of genes critical for T-cell function. Given the central role of NF-kappaB in T-cell activation In vitro, we examined its role in the acute rejection of skin and cardiac allografts using mice with defective NF-kappaB translocation in T cells due to the presence of a super repressor IkappaBalpha transgene. T-cell-intrinsic NF-kappaB activation was required for cardiac but not skin allograft rejection, suggesting differential T-cell priming by the two tissues. Strikingly, priming with heart allografts induced complete acceptance of subsequently transplanted donor skin grafts, indicating that impaired NF-kappaB activation in T cells facilitates the induction of donor-specific tolerance to highly immunogenic tissues. These data suggest the biochemical pathways necessary for allograft rejection vary, based on the antigen and the context in which it is presented, and that inhibition of T-cell-intrinsic NF-kappaB activation during allogeneic priming may represent a novel strategy whereby tolerance to transplanted organs can be achieved.


Surgical Stabilization Improves Survival of Spinal Fractures Related to Ankylosing Spondylitis.
National registry cohort study. The aim of this study was to investigate the effect of surgical stabilization on survival of spinal fractures related to ankylosing spondylitis (AS). Spinal fractures related to AS are associated with considerable morbidity and mortality. Multiple studies suggest a beneficial effect of surgical stabilization in these patients. In the Swedish patient registry, all patients treated in an inpatient facility are registered with diagnosis and treatment codes. The Swedish mortality registry collects date and cause of death for all fatalities. Registry extracts of all patients with AS and spinal fractures including date of death and treatment were prepared and analyzed for epidemiological purposes. Seventeen thousand two hundred ninety-seven individual patients with AS were admitted to treatment facilities in Sweden between 1987 and 2011. Nine hundred ninety patients with AS (age 66 ± 14 years) had 1131 spinal fractures, of which 534 affected cervical, 352 thoracic, and 245 lumbar vertebrae. Thirteen percent had multiple levels of injuries during the observed period. Surgically treated patients had a greater survival than those treated nonsurgically [hazard ratio (HR) 0.79, P = 0.029]. Spinal cord injury was the major factor contributing to mortality in this cohort (HR 1.55, P < 0.001). The proportion of surgically treated spinal fractures increased linearly during the last decades (r = 0.92, P < 0.001) and was 64% throughout the observed years. Spinal cord injury threatened the survival of patients with spinal fractures related to AS. Even though surgical treatment is associated with a considerable complication rate, it improved the survival of spinal fractures related to AS. 3.


Inequities in access to biologic and synthetic DMARDs across 46 European countries.
We investigated access to biologic and synthetic disease modifying drugs (bDMARDs and sDMARDs) in patients with rheumatoid arthritis (RA) across Europe. A cross-sectional study at national level was performed in 49 European countries. A questionnaire was sent to one expert, addressing the number of approved and reimbursed bDMARDs and sDMARDs, prices and co-payments, as well as acceptability of bDMARDs (barriers). Data on socio-economic welfare (gross domestic product per capita (GDP), health expenditure, income) were retrieved from web-based sources. Data on health status of RA patients were retrieved from an observational study. Dimensions of access (availability, affordability and acceptability) were correlated with the country's welfare and RA health status. In total, 46 countries (94%) participated. Six countries did not reimburse any of the five sDMARDs surveyed, and in ten countries no bDMARDs were reimbursed. While the price of annual treatment with an average sDMARD was never higher than GPD, the price of one year treatment with a bDMARD exceeded GPD in 26 countries. Perceived barriers for access to bDMARDs were mainly found among financial and administrative restrictions. All dimensions of access were positively correlated with the country's economic welfare (coefficients 0.69 to 0.86 for overall access scores). Patients with RA in lower income European countries have less access to bDMARDs and sDMARDs, with particularly striking unaffordability of bDMARDs in some of these countries. When accepting that sDMARDs and bDMARDs are equally needed across countries to treat RA, our data point to inequities in access to pharmacological treatment for RA in Europe.


Microbial and bioconversion production of D-xylitol and its detection and application.
D-Xylitol is found in low content as a natural constituent of many fruits and vegetables. It is a five-carbon sugar polyol and has been used as a food additive and sweetening agent to replace sucrose, especially for non-insulin dependent diabetics. It has multiple beneficial health effects, such as the prevention of dental caries, and acute otitis media. In industry, it has been produced by chemical reduction of D-xylose mainly from photosynthetic biomass hydrolysates. As an alternative method of chemical reduction, biosynthesis of D-xylitol has been focused on the metabolically engineered Saccharomyces cerevisiae and Candida strains. In order to detect D-xylitol in the production processes, several detection methods have been established, such as gas chromatography (GC)-based methods, high performance liquid chromatography (HPLC)-based methods, LC-MS methods, and capillary electrophoresis methods (CE). The advantages and disadvantages of these methods are compared in this review.


Evaluation of the Evidence Base for the Alcohol Industry's Actions to Reduce Drink Driving Globally.
To evaluate the evidence base for the content of initiatives that the alcohol industry implemented to reduce drink driving from 1982 to May 2015. We systematically analyzed the content of 266 global initiatives that the alcohol industry has categorized as actions to reduce drink driving. Social aspects public relations organizations (i.e., organizations funded by the alcohol industry to handle issues that may be damaging to the business) sponsored the greatest proportion of the actions. Only 0.8% (n = 2) of the sampled industry actions were consistent with public health evidence of effectiveness for reducing drink driving. The vast majority of the alcohol industry's actions to reduce drink driving does not reflect public health evidenced-based recommendations, even though effective drink-driving countermeasures exist, such as a maximum blood alcohol concentration limit of 0.05 grams per deciliter for drivers and widespread use of sobriety checkpoints.


Coronary artery disease performance measures and statin use in patients with recent percutaneous coronary intervention or recent coronary artery bypass grafting (from the NCDR PINNACLE registry).
The association between coronary revascularization strategy (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) and compliance with coronary artery disease (CAD) performance measures is not well studied. Our analysis studied patients enrolled in the Practice Innovation and Clinical Excellence registry, who underwent coronary revascularization using PCI or CABG in the 12 months before their most recent outpatient visit in 2011. We compared the attainment of CAD performance measures and statin use in eligible patients with PCI and CABG using hierarchical logistic regression models. Our study cohort consisted of 112,969 patients (80,753 with PCI and 32,216 with CABG). After adjustment for site and patient characteristics, performance measure compliance for tobacco use query (odds ratio [OR] 0.80; 95% confidence interval [CI] 0.76 to 0.86), antiplatelet therapy (OR 0.9; 95% CI 0.86 to 0.94) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy (OR 0.89; 95% CI 0.84 to 0.94) was lower in CABG compared with patients with PCI. Patients who underwent recent CABG had higher rates of β-blocker (OR 1.25; 95% CI 1.16 to 1.33) and statin treatment (OR 1.37; 95% CI 1.31 to 1.43) compared with patients with PCI. Of the 79 practice sites, 15 (19%) had ≥75% of their patients with CAD (CABG or PCI) meeting 75% to 100% of all eligible CAD performance measures. In conclusion, gaps persist in compliance with specific CAD performance measures in patients with recent PCI or CABG, and 1 in 5 practices had ≥75% compliance of eligible CAD performance measures in the most of their patients.


EXPERIMENTAL OBSERVATIONS ON THE PATHOGENESIS OF GALL-BLADDER INFECTIONS IN TYPHOID, CHOLERA, AND DYSENTERY.
1. The theory of the production of gall-bladder lesions in typhoid, by descending infection of the bile from the liver receives support from investigations with the common duct fistula method in the rabbit. More bacilli appear in the bile with increased doses and more gall-bladder infections are obtained by increased doses. More bacilli appear in the bile after mesenteric vein injection than after ear vein injection and more lesions result under the first condition. More bacilli appear in the bile after injection of the same dose in immunized animals than in normal animals and more lesions also result in immunized animals. In cholera and dysentery the same mechanism is suggested with the additional factor of a portal system septicemia. 2. After the appearance of microorganisms in rabbit bile, their fate is apparently largely determined by the antiseptic properties of the bile. 100 per cent infections cannot be secured by intravenous doses large enough to insure the presence of microorganisms in the bile. Rabbit bile in vitro may be antiseptic to the microorganisms considered. The antiseptic action is largely due to its alkalinity. It is apparently possible to protect the rabbit to some degree against gall-bladder infection by a previous injection of sodium bicarbonate. 3. Alkaline therapy is suggested in the prevention and cure of gall-bladder carriers.


Polyurethane/poly(hydroxyethyl methacrylate) semi-interpenetrating polymer networks for biomedical applications.
The thermodynamic miscibility, morphology, phase distribution, mechanical properties, surface properties, water sorption, bacterial adhesion and cytotoxicity of semi-interpenetrating polymer networks (semi-IPNs) based on crosslinked polyurethane (PU) and poly(hydroxyethylmethacrylate) (PHEMA) were studied to give an insight into their structure and properties. The free energies of mixing of the two polymers in semi-IPNs have been determined and it was shown that the values are positive and depend on the amount of PHEMA. This demonstrates that the components are immiscible, the extent of which is dependent upon variations in composition. The morphology of the semi-IPNs was analyzed with scanning electron microscopy and tapping mode atomic force microscopy (TMAFM). The micrographs of the semi-IPNs and TMAFM phase images indicated that distinct phase separation at the nanometer scale is observed. The mechanical properties reflect the changes in structure of semi-IPNs with composition. The stress at break increases from 3.4 MPa to 23.9 MPa, and the Young's modulus from 12.7 MPa up to 658.5 MPa with increasing amounts of PHEMA, but strain at break has a maximum at 40.4% PHEMA. The bacterial adhesion and cytotoxicity data suggest that semi-IPNs with PHEMA content above 22% may be used for biomedical material applications.