Factors involved in Schistosoma mansoni infection in rural areas of northeast Brazil.
Two contiguous villages in Tracunhaém county (State of Pernambuco), endemic for schistosomiasis, were studied: Itapinassu (138 inhabitants) and São Joaquim (91 inhabitants). Agriculture predominates in the former region while ceramics is the main activity in the latter. Although no statistical difference was found regarding prevalence, severe infection (> 400 epg) predominated in Itapinassu, probably related to the kind of occupation. No association was found between parasite burden and severity of disease, in spite of the high infection rates for Schistosoma mansoni in both communities (approx. 60%). Typical epidemiological features of schistosomiasis such as age-related prevalences and intensities of infection (high in children, low in adults) were also mutual characteristics. Nutritional status determined through anthropometric evaluation was carried out by measuring specific anthropometric indicators. A deficit of energy intake, as well as vitamin A and riboflavin deficiencies were detected. The prevalence of moderate or severe undernutrition in patients under 18 years old was 21.9% in Itapinassu and 24.1% in São Joaquim. In this group an association was found between prevalence of schistosomiasis and chronic undernutrition. Similarly, for patients over 18 year old the prevalence of undernutrition was higher than 20%. However, in this case no association between nutritional status and either prevalence of schistosomiasis or parasite burden could be detected. The two communities had not been treated for eight years.


Developing quality indicators for general practice care for vulnerable elders; transfer from US to The Netherlands.
Measurement of the quality of healthcare is a first step for quality improvement. To measure quality of healthcare, a set of quality indicators is needed. We describe the adaptation of a set of systematically developed US quality indicators for healthcare for vulnerable elders in The Netherlands. We also compare the US and the Dutch set to see if quality indicators can be transferred between countries, as has been done in two studies in the UK, with mixed results. 108 US quality indicators on GP care for vulnerable elders, covering eight conditions, were assessed by a panel of nine clinical experts in The Netherlands. A modified version of the RAND/UCLA appropriateness method was used. The panel members received US literature reviews, extended with more recent and Dutch literature, summarising the evidence for each quality indicator. 72 indicators (67% of US set) were (nearly) identical in the Dutch and US sets. For some conditions, this percentage was much lower. For undernutrition, only half of the US indicators were included in the Dutch set. For depression, many indicators were discarded or changed in a significant way, with the result that only five of the original 17 indicators (29%) are the same in the Dutch and the US set. Quality indicators can be transferred between countries, but with caution, because in two of the three studies on transferring indicators between the US and Europe, 33-44% of the indicators were discarded. For some conditions in the current study, this percentage is much higher. For undernutrition, there is hardly any evidence, and differences between the indicator sets can be attributed to differences in expert opinion between the countries. For depression, it seems that different evidence is considered important in the US and in The Netherlands, of which the Dutch body of knowledge is not known in the US.


Why don't healthcare professionals talk about sex? A systematic review of recent qualitative studies conducted in the United kingdom.
Sexuality is considered to be an important aspect of holistic care, yet research has demonstrated that it is not routinely addressed in healthcare services. A greater understanding of this can be achieved through synthesizing qualitative studies investigating healthcare professionals' experiences of talking about sex. In doing so, policy makers and healthcare providers may be able to better address the sexual issues of service users. To gain an in-depth understanding of healthcare professionals' subjective experience of discussing sexuality with service users by identifying the factors that impede and facilitate such discussions. Review of healthcare professionals' experience of discussing sexuality with service users. Electronic databases and reference lists of published articles were searched in July 2011. Primary research studies were included in the review if they explored health professionals' experiences of discussing sexuality with adult service users, used qualitative methods, and were conducted in the United Kingdom over the last 10 years. Each study was reviewed and assessed. A secondary thematic analysis method was used where key themes were extracted and grouped and key concepts were explored. Nineteen interconnected themes emerged relating to healthcare professionals' experience of discussing sexuality with service users, including fear about "opening up a can of worms," lack of time, resources, and training, concern about knowledge and abilities, worry about causing offense, personal discomfort, and a lack of awareness about sexual issues. Some themes were particularly marked relating to the sexuality of the opposite-gender, black and ethnic minority groups, older and nonheterosexual service users, and those with intellectual disabilities. The majority of healthcare professionals do not proactively discuss sexuality issues with service users, and this warrants further attention. An understanding of the perceived barriers and facilitators indicates that interventions to improve the extent to which sexuality issues are addressed need to take organizational, structural, and personal factors into consideration.


Sub-harmonic periodic pulse train recovery from aperiodic optical pulse sequences through dispersion-induced temporal self-imaging.
Temporal self-imaging effects (TSIs) are observed when a periodic pulse train propagates through a first-order dispersive medium. Under specific dispersion conditions, either an exact, rate multiplied or rate divided image of the input signal is reproduced at the output. TSI possesses an interesting self-restoration capability even when acting over an aperiodic train of pulses. In this work, we investigate and demonstrate, for the first time to our knowledge, the capability of TSI to produce periodic sub-harmonic (rate-divided) pulse trains from aperiodic sequences. We use this inherent property of the TSI to implement a novel, simple and reconfigurable sub-harmonic optical clock recovery technique from RZ-OOK data signals. The proposed technique features a very simple realization, involving only temporal phase modulation and first-order dispersion and it allows one to set the repetition rate of the reconstructed clock signal in integer fractions (sub-harmonics) of the input bit rate. Proof-of-concept experiments are reported to validate the proposed technique and guidelines for optimization of the clock-recovery process are also outlined.


The role of IL-6 in host defence against infections: immunobiology and clinical implications.
IL-6 is a pleiotropic cytokine with broad-ranging effects within the integrated immune response. One of the roles of IL-6 is to support immunocompetence, defined as the ability of a host to respond to infections. Understanding the precise role of this cytokine in immunocompetence requires a critical appraisal of data derived from both preclinical and clinical studies. Primary immunodeficiency diseases involving IL-6 or its signalling pathways reveal that IL-6 is critical in the defence against numerous types of pathogens. Studies of IL-6 signalling in preclinical models reveal that selective inhibition of either classic IL-6 signalling or IL-6 trans-signalling has differential effects on the host response to different types of infections. Knowledge of such variation might inform bioengineering of new IL-6-targeting molecules and potentially enable modulation of their toxicity. Clinical studies of IL-6 inhibitors, mainly tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies. Targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases.


Insights into the structure and nanomechanics of a quatsome membrane by force spectroscopy measurements and molecular simulations.
Quatsomes (QS) are unilamellar nanovesicles constituted by quaternary ammonium surfactants and sterols in defined molar ratios. Unlike conventional liposomes, QS are stable upon long storage such as for several years, they show outstanding vesicle-to-vesicle homogeneity regarding size and lamellarity, and they have the structural and physicochemical requirements to be a potential platform for site-specific delivery of hydrophilic and lipophilic molecules. Knowing in detail the structure and mechanical properties of the QS membrane is of great importance for the design of deformable and flexible nanovesicle alternatives, highly pursued in nanomedicine applications such as the transdermal administration route. In this work, we report the first study on the detailed structure of the cholesterol : CTAB QS membrane at the nanoscale, using atomic force microscopy (AFM) and spectroscopy (AFM-FS) in a controlled liquid environment (ionic medium and temperature) to assess the topography of supported QS membranes (SQMs) and to evaluate the local membrane mechanics. We further perform molecular dynamics (MD) simulations to provide an atomistic interpretation of the obtained results. Our results are direct evidence of the bilayer nature of the QS membrane, with characteristics of a fluid-like membrane, compact and homogeneous in composition, and with structural and mechanical properties that depend on the surrounding environment. We show how ions alter the lateral packing, modifying the membrane mechanics. We observe that according to the ionic environment and temperature, different domains may coexist in the QS membranes, ascribed to variations in molecular tilt angles. Our results indicate that QS membrane properties may be easily tuned by altering the lateral interactions with either different environmental ions or counterions.


The influence of scopolamine and extreme temperatures on the lipid level in some mouse organs.
The effect of scopolamine administration at dose 0,5 g/kg b.w. and high (+40 degrees C) and low (+4 degrees C) temperature on the level of triacyloglycerides, total lipids and cholesterol in the mouse liver, kidney and muscle of males and females. The homogenates of the liver, kidney and muscle were taken for examination. The concentrations of triacyloglycerides, total lipids and cholesterol was estimated according to the Bio-La-Tests (Poland). The concentration of triacyloglycerides and total lipids in the liver, kidney and muscle increased of males and females after scopolamine injections and after exposure to high and low temperatures. Scopolamine may effect an increase in the rate of the lipid metabolism.


Dissociation of DNA polymerase alpha-primase complex during meiosis in Coprinus cinereus.
Previously, the activity of DNA polymerase alpha was found in the meiotic prophase I including non-S phase stages, in the basidiomycetes, Coprinus cinereus. To study DNA polymerase alpha during meiosis, we cloned cDNAs for the C. cinereus DNA polymerase alpha catalytic subunit (p140) and C. cinereus primase small subunit (p48). Northern analysis indicated that both p140 and p48 are expressed not only at S phase but also during the leptotene/zygotene stages of meiotic prophase I. In situ immuno-staining of cells at meiotic prophase I revealed a sub population of p48 that does not colocalize with p140 in nuclei. We also purified the pol alpha-primase complex from meiotic cells by column chromatography and characterized its biochemical properties. We found a subpopulation of primase that was separated from the pol alpha-primase complex by phosphocellulose column chromatography. Glycerol gradient density sedimentation results indicated that the amount of intact pol alpha-primase complex in crude extract is reduced, and that a smaller complex appears upon meiotic development. These results suggest that the form of the DNA polymerase alpha-primase complex is altered during meiotic development.


A PCR-Based Method for Distinguishing between Two Common Beehive Bacteria, Paenibacillus larvae and Brevibacillus laterosporus.
Paenibacillus larvae and Brevibacillus laterosporus are two bacteria that are members of the Paenibacillaceae family. Both are commonly found in beehives and have historically been difficult to distinguish from each other due to related genetic and phenotypic characteristics and a shared ecological niche. Here, we discuss the likely mischaracterization of three 16S rRNA sequences previously published as P. larvae and provide the phylogenetic evidence that supported the GenBank reassignment of the sequences as B. laterosporus We explore the issues that arise by using only 16S rRNA or other single-gene analyses to distinguish between these bacteria. We also present three sets of molecular markers, two sets that distinguish P. larvae from B. laterosporus and other closely related species within the Paenibacillus genus and a third set that distinguishes B. laterosporus from P. larvae and other closely related species within the Brevibacillus genus. These molecular markers provide a tool for proper identification of these oft-mistaken species.IMPORTANCE 16S rRNA gene sequencing in bacteria has long been held as the gold standard for typing bacteria and, for the most part, is an excellent method of taxonomically identifying different bacterial species. However, the high level of 16S rRNA sequence similarity of some published strains of P. larvae and B. laterosporus, as well as possible horizontal gene transfer events within their shared ecological niche, complicates the use of 16S rRNA sequence as an effective molecular marker for differentiating these two species. Additionally, shared characteristics of these bacteria limit the effectiveness of using traditional phenotypic identification assays, such as the catalase test. The results from this study provide PCR methods to quickly differentiate between these two genera and will be useful when studying Brevibacillus, Paenibacillus, and other disease-relevant bacteria commonly found in beehives.


Maternal Literacy, Facility Birth, and Education Are Positively Associated with Better Infant and Young Child Feeding Practices and Nutritional Status among Ugandan Children.
Understanding maternal factors that influence child feeding is necessary to inform intervention planning in settings in which mothers experience substantial social vulnerabilities. The purpose of this study was to assess maternal sociodemographic factors that may constrain women's caring capabilities and subsequent child nutrition in Uganda. We analyzed data from the 2006 and 2011 Uganda Demographic and Health Surveys to model the associations between maternal sociodemographic factors, child feeding practices, and anthropometry with multivariate logistic regression models. The proportion of children fed according to recommended guidelines declined in Uganda from 2006 to 2011. Mothers who lacked literacy skills were less likely to achieve recommended complementary feeding indicators; however, literacy was not associated with breastfeeding practices. Mothers in the upper 60% wealth percentile were more likely to meet minimum meal frequency, diversity, and adequacy indicators. Mothers who gave birth at health facilities (2006 OR: 0.49; 95% CI: 0.26, 0.91; P < 0.05) and who were in the upper 60% wealth percentile (2011 OR: 0.43; 95% CI: 0.21, 0.69) were less likely to exclusively breastfeed until 6 mo. There were no significant associations between age at first pregnancy, maternal education, and infant and young child feeding practices. Women with a formal education had children with lower stunting and underweight probabilities in both time periods (OR range: 0.43-0.74). Women who delivered in childbirth facilities were less likely to have a child with low weight-for-age, length-for-age, or weight-for-length z scores (OR range: 0.59-0.82). Marital status, the age at first child birth, not accepting domestic violence, freedom to travel away from home, and involvement in household and reproductive decisions were not associated with child anthropometry in either time period. Mothers with low literacy skills, who deliver their children at home, and who lack formal education are particularly at risk of poor child feeding and represent a group that may benefit from enhanced interventions that address their particular vulnerabilities. Factors that contribute to improved maternal feeding capabilities but may impair breastfeeding practices need to be better understood.


DNA methyltransferase 3b regulates articular cartilage homeostasis by altering metabolism.
Osteoarthritis (OA) is the most common form of arthritis worldwide. It is a complex disease affecting the whole joint but is generally characterized by progressive degradation of articular cartilage. Recent genome-wide association screens have implicated distinct DNA methylation signatures in OA patients. We show that the de novo DNA methyltransferase (Dnmt) 3b, but not Dnmt3a, is present in healthy murine and human articular chondrocytes and its expression decreases in OA mouse models and in chondrocytes from human OA patients. Targeted deletion of Dnmt3b in murine articular chondrocytes results in an early-onset and progressive postnatal OA-like pathology. RNA-Seq and methylC-Seq analyses of Dnmt3b loss-of-function chondrocytes show that cellular metabolic processes are affected. Specifically, TCA metabolites and mitochondrial respiration are elevated. Importantly, a chondroprotective effect was found following Dnmt3b gain of function in murine articular chondrocytes in vitro and in vivo. This study shows that Dnmt3b plays a significant role in regulating postnatal articular cartilage homeostasis. Cellular pathways regulated by Dnmt3b in chondrocytes may provide novel targets for therapeutic approaches to treat OA.


Corelease of dopamine and GABA by a retinal dopaminergic neuron.
Numerous neurons release two transmitters of low molecular mass, but it is controversial whether they are localized within the same synaptic vesicle, with the single exception of GABA and glycine because they are ferried into the vesicle by the same transporter. Retinal dopaminergic (DAergic) amacrine cells synthesize both dopamine (DA) and GABA. Both transmitters are released over the entire cell surface and act on neighboring and distant neurons by volume transmission, but, in addition, DAergic cells establish GABAergic synapses onto AII amacrine cells, the neurons that transfer rod signals to cone bipolars. By combining recordings of DA and GABA release from isolated, genetically identified perikarya of DAergic cells from the mouse retina, we observed that a proportion of the events of DA and GABA exocytosis were simultaneous, suggesting corelease. Furthermore, a proportion of the secretory organelles in the perikaryon and synaptic endings of DAergic cells contained both vesicular transporters for DA [vesicular monoamine transporter 2 (VMAT2)] and GABA [vesicular GABA transporter (VGAT)]. Because the majority of the DA release events concerned a single transmitter and organelles were present that contained a single transporter, either VMAT2 or VGAT, we conclude that the secretory organelles of DAergic cells contain variable concentrations of the two transmitters, which are in turn determined by a variable mixture of the two transporter molecules in their limiting membrane. This variability can be explained if the relative numbers of transporter molecules is determined stochastically during the budding of the somatic organelles from the trans-Golgi network or the retrieval of the vesicular membrane from the plasmalemma after exocytosis.


Biosynthesis and therapeutic properties of Lavandula essential oil constituents.
Lavenders and their essential oils have been used in alternative medicine for several centuries. The volatile compounds that comprise lavender essential oils, including linalool and linalyl acetate, have demonstrative therapeutic properties, and the relative abundance of these metabolites is greatly influenced by the genetics and environment of the developing plants. With the rapid progress of molecular biology and the genomic sciences, our understanding of essential oil biosynthesis has greatly improved over the past few decades. At the same time, there is a recent surge of interest in the use of natural remedies, including lavender essential oils, in alternative medicine and aromatherapy. This article provides a review of recent developments related to the biosynthesis and medicinal properties of lavender essential oils.


SARS-CoV-2 infection and vaccine effectiveness in England (REACT-1): a series of cross-sectional random community surveys.
England has experienced a third wave of the COVID-19 epidemic since the end of May, 2021, coinciding with the rapid spread of the delta (B.1.617.2) variant, despite high levels of vaccination among adults. Vaccination rates (single dose) in England are lower among children aged 16-17 years and 12-15 years, whose vaccination in England commenced in August and September, 2021, respectively. We aimed to analyse the underlying dynamics driving patterns in SARS-CoV-2 prevalence during September, 2021, in England. The REal-time Assessment of Community Transmission-1 (REACT-1) study, which commenced data collection in May, 2020, involves a series of random cross-sectional surveys in the general population of England aged 5 years and older. Using RT-PCR swab positivity data from 100 527 participants with valid throat and nose swabs in round 14 of REACT-1 (Sept 9-27, 2021), we estimated community-based prevalence of SARS-CoV-2 and vaccine effectiveness against infection by combining round 14 data with data from round 13 (June 24 to July 12, 2021; n=172 862). During September, 2021, we estimated a mean RT-PCR positivity rate of 0·83% (95% CrI 0·76-0·89), with a reproduction number (R) overall of 1·03 (95% CrI 0·94-1·14). Among the 475 (62·2%) of 764 sequenced positive swabs, all were of the delta variant; 22 (4·63%; 95% CI 3·07-6·91) included the Tyr145His mutation in the spike protein associated with the AY.4 sublineage, and there was one Glu484Lys mutation. Age, region, key worker status, and household size jointly contributed to the risk of swab positivity. The highest weighted prevalence was observed among children aged 5-12 years, at 2·32% (95% CrI 1·96-2·73) and those aged 13-17 years, at 2·55% (2·11-3·08). The SARS-CoV-2 epidemic grew in those aged 5-11 years, with an R of 1·42 (95% CrI 1·18-1·68), but declined in those aged 18-54 years, with an R of 0·81 (0·68-0·97). At ages 18-64 years, the adjusted vaccine effectiveness against infection was 62·8% (95% CI 49·3-72·7) after two doses compared to unvaccinated people, for all vaccines combined, 44·8% (22·5-60·7) for the ChAdOx1 nCov-19 (Oxford-AstraZeneca) vaccine, and 71·3% (56·6-81·0) for the BNT162b2 (Pfizer-BioNTech) vaccine. In individuals aged 18 years and older, the weighted prevalence of swab positivity was 0·35% (95% CrI 0·31-0·40) if the second dose was administered up to 3 months before their swab but 0·55% (0·50-0·61) for those who received their second dose 3-6 months before their swab, compared to 1·76% (1·60-1·95) among unvaccinated individuals. In September, 2021, at the start of the autumn school term in England, infections were increasing exponentially in children aged 5-17 years, at a time when vaccination rates were low in this age group. In adults, compared to those who received their second dose less than 3 months ago, the higher prevalence of swab positivity at 3-6 months following two doses of the COVID-19 vaccine suggests an increased risk of breakthrough infections during this period. The vaccination programme needs to reach children as well as unvaccinated and partially vaccinated adults to reduce SARS-CoV-2 transmission and associated disruptions to work and education. Department of Health and Social Care, England.


Multiple-trait structured antedependence model to study the relationship between litter size and birth weight in pigs and rabbits.
Some genetic studies need to take into account correlations between traits that are repeatedly measured over time. Multiple-trait random regression models are commonly used to analyze repeated traits but suffer from several major drawbacks. In the present study, we developed a multiple-trait extension of the structured antedependence model (SAD) to overcome this issue and validated its usefulness by modeling the association between litter size (LS) and average birth weight (ABW) over parities in pigs and rabbits. The single-trait SAD model assumes that a random effect at time [Formula: see text] can be explained by the previous values of the random effect (i.e. at previous times). The proposed multiple-trait extension of the SAD model consists in adding a cross-antedependence parameter to the single-trait SAD model. This model can be easily fitted using ASReml and the OWN Fortran program that we have developed. In comparison with the random regression model, we used our multiple-trait SAD model to analyze the LS and ABW of 4345 litters from 1817 Large White sows and 8706 litters from 2286 L-1777 does over a maximum of five successive parities. For both species, the multiple-trait SAD fitted the data better than the random regression model. The difference between AIC of the two models (AIC_random regression-AIC_SAD) were equal to 7 and 227 for pigs and rabbits, respectively. A similar pattern of heritability and correlation estimates was obtained for both species. Heritabilities were lower for LS (ranging from 0.09 to 0.29) than for ABW (ranging from 0.23 to 0.39). The general trend was a decrease of the genetic correlation for a given trait between more distant parities. Estimates of genetic correlations between LS and ABW were negative and ranged from -0.03 to -0.52 across parities. No correlation was observed between the permanent environmental effects, except between the permanent environmental effects of LS and ABW of the same parity, for which the estimate of the correlation was strongly negative (ranging from -0.57 to -0.67). We demonstrated that application of our multiple-trait SAD model is feasible for studying several traits with repeated measurements and showed that it provided a better fit to the data than the random regression model.


Selective mobility and sensitivity to SNAREs is exhibited by the Arabidopsis KAT1 K+ channel at the plasma membrane.
Recent findings indicate that proteins in the SNARE superfamily are essential for cell signaling, in addition to facilitating vesicle traffic in plant cell homeostasis, growth, and development. We previously identified SNAREs SYP121/Syr1 from tobacco (Nicotiana tabacum) and the Arabidopsis thaliana homolog SYP121 associated with abscisic acid and drought stress. Disrupting tobacco SYP121 function by expressing a dominant-negative Sp2 fragment had severe effects on growth, development, and traffic to the plasma membrane, and it blocked K(+) and Cl(-) channel responses to abscisic acid in guard cells. These observations raise questions about SNARE control in exocytosis and endocytosis of ion channel proteins and their organization within the plane of the membrane. We have used a dual, in vivo tagging strategy with a photoactivatable green fluorescent protein and externally exposed hemagglutinin epitopes to monitor the distribution and trafficking dynamics of the KAT1 K(+) channel transiently expressed in tobacco leaves. KAT1 is localized to the plasma membrane within positionally stable microdomains of approximately 0.5 microm in diameter; delivery of the K(+) channel, but not of the PMA2 H(+)-ATPase, to the plasma membrane is suppressed by Sp2 fragments of tobacco and Arabidopsis SYP121, and Sp2 expression leads to profound changes in KAT1 distribution and mobility within the plane of the plasma membrane. These results offer direct evidence for SNARE-mediated traffic of the K(+) channel and a role in its distribution within subdomains of the plasma membrane, and they implicate a role for SNAREs in positional anchoring of the K(+) channel protein.


DNA topoisomerase I and DNA gyrase as targets for TB therapy.
Tuberculosis (TB) is the deadliest bacterial disease in the world. New therapeutic agents are urgently needed to replace existing drugs for which resistance is a significant problem. DNA topoisomerases are well-validated targets for antimicrobial and anticancer chemotherapies. Although bacterial topoisomerase I has yet to be exploited as a target for clinical antibiotics, DNA gyrase has been extensively targeted, including the highly clinically successful fluoroquinolones, which have been utilized in TB therapy. Here, we review the exploitation of topoisomerases as antibacterial targets and summarize progress in developing new agents to target DNA topoisomerase I and DNA gyrase from Mycobacterium tuberculosis.


The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis.
S100A4 has been implicated in cancer and several inflammatory diseases, including RA. The aim of the present study was to determine whether S100A4 can stimulate proinflammatory cytokine production in mononuclear cells. Peripheral blood mononuclear cells (PBMCs) isolated from patients with RA were stimulated with S100A4, S100A8, S100A9 and S100A12. The production of IL-1β, IL-6 and TNF-α was measured by ELISA. Receptor for advanced glycation end products (RAGEs) and Toll-like receptor 4 (TLR4) signalling were examined. For signalling pathway blocking studies, inhibitors of myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa B (NF-κB) and the mitogen activated protein (MAP) kinases p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) were used. MAP kinase activation was evaluated by western blotting. Stimulation of PBMCs with S100A4 significantly up-regulated IL-1β, IL-6 and TNF-α production compared with unstimulated cells (P < 0.001). Importantly, the production of these cytokines was markedly enhanced in response to S100A4 compared with S100A8 and S100A12; however, it was less pronounced compared with S100A9. Furthermore, enhanced production of proinflammatory cytokines in S100A4-stimulated PMBCs was at least partly mediated via TLR4, but not RAGEs, and by activation of the transcription factor NF-κB and the MAP kinases p38 and ERK1/2. This is the first study to demonstrate that S100A4 can induce an inflammatory response mediated by TLR4 and by the activation of NF-κB and the kinases p38 and ERK1/2 in mononuclear cells from patients with RA. Therefore S100A4 may be a potential therapeutic target for immune-mediated diseases.


Evaluation of two methods of estimating larval habitat productivity in western Kenya highlands.
Malaria vector intervention and control programs require reliable and accurate information about vector abundance and their seasonal distribution. The availability of reliable information on the spatial and temporal productivity of larval vector habitats can improve targeting of larval control interventions and our understanding of local malaria transmission and epidemics. The main objective of this study was to evaluate two methods of estimating larval habitat productivity in the western Kenyan highlands, the aerial sampler and the emergence trap. The study was conducted during the dry and rainy seasons in 2008, 2009 and 2010. Aerial samplers and emergence traps were set up for sixty days in each season in three habitat types: drainage ditches, natural swamps, and abandoned goldmines. Aerial samplers and emergence traps were set up in eleven places in each habitat type. The success of each in estimating habitat productivity was assessed according to method, habitat type, and season. The effect of other factors including algae cover, grass cover, habitat depth and width, and habitat water volume on species productivity was analysed using stepwise logistic regression Habitat productivity estimates obtained by the two sampling methods differed significantly for all species except for An. implexus. For for An. gambiae s.l. and An. funestus, aerial samplers performed better, 21.5 and 14.6 folds, than emergence trap respectively, while the emergence trap was shown to be more efficient for culicine species. Seasonality had a significant influence on the productivity of all species monitored. Dry season was most productive season. Overall, drainage ditches had significantly higher productivity in all seasons compared to other habitat types. Algae cover, debris, chlorophyll-a, and habitat depth and size had significant influence with respect to species. These findings suggest that the aerial sampler is the better of the two methods for estimating the productivity of An. gambiae s.l. and An. funestus in the western Kenya highlands and possibly other malaria endemic parts of Africa. This method has proven to be a useful tool for monitoring malaria vector populations and for control program design, and provides useful means for determining the most suitable sites for targeted interventions.


Roslingifier: Semi-Automated Storytelling for Animated Scatterplots.
We present Roslingifier, a data-driven storytelling method for animated scatterplots. Like its namesake, Hans Rosling (1948-2017), a professor of public health and a spellbinding public speaker, Roslingifier turns a sequence of entities changing over time-such as countries and continents with their demographic data-into an engaging narrative elling the story of the data. This data-driven storytelling method with an in-person presenter is a new genre of storytelling technique and has never been studied before. In this article, we aim to define a design space for this new genre-data presentation-and provide a semi-automated authoring tool for helping presenters create quality presentations. From an in-depth analysis of video clips of presentations using interactive visualizations, we derive three specific techniques to achieve this: natural language narratives, visual effects that highlight events, and temporal branching that changes playback time of the animation. Our implementation of the Roslingifier method is capable of identifying and clustering significant movements, automatically generating visual highlighting and a narrative for playback, and enabling the user to customize. From two user studies, we show that Roslingifier allows users to effectively create engaging data stories and the system features help both presenters and viewers find diverse insights.


Pakistan's health policy: appropriateness and relevance to women's health needs.
The interface between national health policy and women's health needs is complex in developing countries like Pakistan. This paper aims to assess if Pakistan's national health policy 2001 is relevant and appropriate to women's health needs. Through review of existing data on women, a profile of women's health needs was developed which was transformed into framework of analysis. This framework indicates that Pakistani women's health needs are determined by gender disparities in health and health-related sectors. Comparison of national health policy with women's health needs framework reveals that although policy focuses on women's health through prioritization of gender equity, it is however addressed as an isolated theme without acknowledging the vital role gender inequalities in health and health-related sectors play in defining women's health needs. Moreover, gender equity is translated as provision of reproductive health services to married mothers, ignoring various critical overarching issues of women's life such as sexual abuse, violence, induced abortion, etc. Health systems strengthening strategies are though suggested but these fails to recognize main obstacles of utilization of healthcare services by women including non-availability of female healthcare providers and gender-based obstacles to healthcare utilization such as illiteracy, lack of empowerment to make decisions related to health, etc. In order to be relevant and appropriate to women's health needs the policy should: (1) use gender equity in health and health-related sectors as an approach to develop a healthy policy (2) expand the focus from reproductive health to life cycle approach to address all issues around women's life (3) strengthen health systems through creation of gender equity among all cadres of health providers (4) tailoring health interventions to counter gender-based obstacles to utilization of healthcare services and (5) dissemination interventions for behavior change.


Freud, Darwin, and the holding environment.
Freud's hypothesis of the neonate, derived from the data of adult psychoneurotic patients, was of a supremely narcissistic being who lived in a dreamlike state of hallucinatory satisfaction. A corollary hypothesis was that the neonate's drive to attach was learned and emerged only after the failure of wish fulfillment. These hypotheses provided the ground for Freud's theories of regression, dream, primary process, and pleasure principle. Darwin's data of the neonate, collected from his observations of a variety of mammals, led him to the conclusion that attachment in mammals is innate. Until 1969 and the work of John Bowlby, psychoanalytic thinking faithfully followed Freud. If psychoanalysis is to survive, then it must attach itself to data and discard any theories that are based on unproveable hypotheses, even if those hypotheses are Freud's.


Ethnicity and long-term vascular outcomes in Type 2 diabetes: a prospective observational study (UKPDS 83).
Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long-term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes. In a prospective observational study of 4273 UK Prospective Diabetes Study participants followed for a median of 18 years, 3543 (83%) were White Caucasian, 312 (7%) Afro-Caribbean and 418 (10%) Asian Indian. Relative risks for predefined outcomes were assessed comparing Afro-Caribbean and Asian Indian with White Caucasian using accelerated failure time models, with adjustment for cardiovascular risk factors and other potentially confounding variables. During follow-up, 2468 (58%) participants had any diabetes-related end point, 1037 (24%) a myocardial infarction and 401 (9%) a stroke, and 1782 (42%) died. Asian Indian were at greater risk (relative risk, 95% confidence interval) for any diabetes-related end point (1.18, 1.07-1.29), but at lower risk of all-cause mortality (0.89, 0.80-0.97) and peripheral vascular disease (0.43, 0.23-0.82), vs. White Caucasian. Afro-Caribbean participants were at lower risk for all-cause mortality (0.84, 0.76-0.93), diabetes-related death (0.75, 0.64-0.88), myocardial infarction (0.55, 0.43-0.71) and peripheral vascular disease (0.55, 0.33-0.93) vs. White Caucasian. No ethnicity-related associations were found for stroke or microangiopathy. Asian Indian ethnicity is associated with the greatest burden of disease, but not with an increased risk of major vascular complications or death. Afro-Caribbean ethnicity is associated with reduced risk of all-cause and diabetes-related death, myocardial infarction and peripheral vascular disease, suggesting an ethnicity-specific protective mechanism.


Hematobiochemical and histopathological alterations of kidney and testis due to exposure of 4G cell phone radiation in mice.
The radiofrequency electromagnetic radiation emitted by smart phones on biological systems has wide media coverage and public concern in recent years. The aim of this study was to explore the effects of fourth-generation cell phone radiation exposure on hematological (Total leukocyte count, Total erythrocyte count, and hemoglobin %), biochemical (Serum creatinine) parameters, and histopathological changes in the kidney and testis of Swiss albino mice. A total of 30 male Swiss albino mice weighing 45-65 g was randomly divided into three groups (n = 10). The first group A was the control group, the second group B, was exposed to 40 minutes of mobile phone radiation daily, the third group C was exposed to 60 minutes of radiation daily from two 2400 Megahertz fourth-generation connected mobile phones for 60 days, respectively. The electromagnetic radiation frequency radiometer measured the frequency of electromagnetic radiation emitted from cell phones. The specific absorption rate was calculated as 0.087 W/kg. The control group was kept under similar conditions, but the electromagnetic field was not given for the same period. All the mice were sacrificed at the end of the experiment. The blood samples were collected for hematobiochemical study, and then kidney and testis tissues were collected for histopathological study. Results of the study showed that the body weight and total erythrocyte count values were significantly (p < 0.05) decreased while total leukocyte count, hemoglobin %, and serum creatinine values were significantly (p < 0.05) increased in both the radiation exposure groups relative to the control group. Histopathological observation showed the kidney of 60 minutes exposed mice interstitial inflammation that causes marked mononuclear cellular infiltration compared to the 40 minutes and control mice. Compared to control mice, histopathological examinations of testicular tissue from the exposed mice, showed irregular in shapes and non-uniform sizes and fewer spermatogenic cells layer that leads to the larger lumen in the seminiferous tubules. It is concluded that fourth-generation cell phone radiation exposure may affect blood hemostasis and inflammation of mice's kidney and testis tissue. Based on these studies, it is important to increase public consciousness of potential adverse effects of mobile phone radiofrequency electromagnetic radiation exposure.


Tracking of peptide-specific CD4+ T-cell responses after an acute resolving viral infection: a study of parvovirus B19.
The evolution of peptide-specific CD4(+) T-cell responses to acute viral infections of humans is poorly understood. We analyzed the response to parvovirus B19 (B19), a ubiquitous and clinically significant pathogen with a compact and conserved genome. The magnitude and breadth of the CD4(+) T-cell response to the two B19 capsid proteins were investigated using a set of overlapping peptides and gamma interferon-specific enzyme-linked immunospot assays of peripheral blood mononuclear cells (PBMCs) from a cohort of acutely infected individuals who presented with acute arthropathy. These were compared to those for a cohort of B19-specific immunoglobulin M-negative (IgM(-)), IgG(+) remotely infected individuals. Both cohorts of individuals were found to make broad CD4(+) responses. However, while the responses following acute infection were detectable ex vivo, responses in remotely infected individuals were only detected after culture. One epitope (LASEESAFYVLEHSSFQLLG) was consistently targeted by both acutely (10/12) and remotely (6/7) infected individuals. This epitope was DRB1*1501 restricted, and a major histocompatibility complex peptide tetramer stained PBMCs from acutely infected individuals in the range of 0.003 to 0.042% of CD4(+) T cells. Tetramer-positive populations were initially CD62L(lo); unlike the case for B19-specific CD8(+) T-cell responses, however, CD62L was reexpressed at later times, as responses remained stable or declined slowly. This first identification of B19 CD4(+) T-cell epitopes, including a key immunodominant peptide, provides the tools to investigate the breadth, frequency, and functions of cellular responses to this virus in a range of specific clinical settings and gives an important reference point for analysis of peptide-specific CD4(+) T cells during acute and persistent virus infections of humans.


In vitro incorporation of molybdate into demolybdoproteins in Escherichia coli.
When Escherichia coli was grown in the presence of tungstate, inactive forms of two molybdoenzymes, nitrate reductase and formate dehydrogenase, accumulated and were converted to their active forms upon incubation of cell suspensions with molybdate and chloramphenicol. The conversion to the active enzymes did not occur in cell extracts. When incubated with [(99)Mo]molybdate and chloramphenicol, the tungstate-grown cells incorporated (99)Mo into protein components which were released from membranes by procedures used to release nitrate reductase and formate dehydrogenase and which migrated with these activities on polyacrylamide gels. Although neither activity was formed during incubation of the crude extract with molybdate, (99)Mo was incorporated into protein components which were released from the membrane fraction under the same conditions and were similar to the active enzymes in their electrophoretic properties. The in vitro incorporation of (99)Mo occurred specifically into these components and was equal to or greater than the amount incorporated in vivo under the same conditions. Molybdenum in preformed, active nitrate reductase and formate dehydrogenase did not exchange with [(99)Mo]molybdate, demonstrating that the observed incorporation depended on the demolybdo forms of the enzymes. We conclude that molybdate may be incorporated into the demolybdo forms both in vivo and in vitro; some unknown additional factor or step, required for active enzyme formation, occurs in vivo but not in vitro under the conditions employed.


A complex regional intervention to implement advance care planning in one town's nursing homes: Protocol of a controlled inter-regional study.
Advance Care Planning (ACP) is an emerging strategy to ensure that well-reflected, meaningful and clearly documented treatment preferences are available and respected when critical decisions about life-sustaining treatment need to be made for patients unable to consent. In Germany, recent legislation confirms that advance directives (AD) have to be followed if they apply to the medical situation, but implementation of ACP has not yet been described. In a longitudinal controlled study, we compare 1 intervention region (4 nursing homes [n/hs], altogether 421 residents) with 2 control regions (10 n/hs, altogether 985 residents). Inclusion went from 01.02.09 to 30.06.09, observation lasted until 30.06.10. Primary endpoint is the prevalence of ADs at follow-up, 17 (12) months after the first (last) possible inclusion. Secondary endpoints compare relevance and validity of ADs, process quality, the rate of life-sustaining interventions and, in deceased residents, location of death and intensity of treatment before death. The regional multifaceted intervention on the basis of the US program Respecting Choices® comprises training of n/h staff as facilitators, training of General Practitioners, education of hospital and ambulance staff, and development of eligible tools, including Physician Orders for Life-Sustaining Treatment in case of Emergency (POLST-E). Participation data: Of 1406 residents reported to live in the 14 n/hs plus an estimated turnover of 176 residents until the last possible inclusion date, 645 (41%) were willing to participate. Response rates were 38% in the intervention region and 42% in the control region. Non-responder analysis shows an equal distribution of sex and age but a bias towards dependency on nursing care in the responder group. Outcome analysis of this study will become available in the course of 2011. Implementing an ACP program for the n/hs and related health care providers of a region requires a complex community intervention with the effect of nothing less than a cultural shift in this health care sector. This study is to our knowledge the first to develop a strategy for regional implementation of ACP, and to evaluate its feasibility in a controlled design.


Genome-wide association study of breakfast skipping links clock regulation with food timing.
Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.


Antioxidant supplementation and immunoendocrine responses to prolonged exercise.
Antioxidant supplementation may modulate systemic cortisol and interleukin-6 (IL-6) responses to prolonged exercise, but it is unclear whether such effects are also associated with a reduction in the magnitude of immunodepression. The purpose of the present study was to examine the effects of daily vitamin C (L-ascorbic acid, 1000 mg x d(-1)) and vitamin E (RRR-alpha-tocopherol, 400 IU x d(-1)) supplementation on immunoendocrine responses to prolonged exercise. Twenty healthy, recreationally active males cycled for 2.5 h at approximately 60% of maximal oxygen uptake after 4 wk of placebo (PLA, N=10) or antioxidant (AO, N=10) supplementation. A significant group x time interaction was observed for plasma cortisol concentration (P=0.008), and the postexercise increase was greater (P<0.05) in the PLA compared with AO group (approximately 170% compared with an approximately 120% increase above baseline). Plasma IL-6 concentration was significantly increased after exercise to a similar extent in both groups. Plasma free F2-isoprostane concentration was significantly increased after exercise and was unaffected by AO supplementation, whereas plasma TBARS was unaffected by exercise in the PLA group but was lower after exercise in the AO group than in the PLA group. Circulating neutrophil count was significantly increased after exercise, and in vitro bacteria-stimulated elastase release per neutrophil was significantly decreased to a similar extent in both groups. These results suggest that 4 wk of AO supplementation may blunt the cortisol response to a single 2.5-h bout of prolonged exercise independently of changes in oxidative stress or plasma IL-6 concentration, but it is not effective at modulating the exercise-induced neutrophilia or depression of neutrophil function.


Power over reproduction in social hymenoptera.
Inclusive fitness theory has been very successful in predicting and explaining much of the observed variation in the reproductive characteristics of insect societies. For example, the theory correctly predicts sex-ratio biasing by workers in relation to the queen's mating frequency. However, within an insect society there are typically multiple reproductive optima, each corresponding to the interest of different individual(s) or parties of interest. When multiple optima occur, which party's interests prevail? Presumably, the interests of the party with the greatest 'power'; the ability to do or act. This article focuses on factors that influence power over colony reproduction. In particular, we seek to identify the principles that may cause different parties of interest to have greater or lesser power. In doing this, we discuss power from two different angles. On the one hand, we discuss general factors based upon non-idiosyncratic biological features (e.g. information, access to and ability to process food) that are likely to be important to all social Hymenoptera. On the other hand, we discuss idiosyncratic factors that depend upon the biology of a taxon at any hierarchical level. We propose that a better understanding of the diversity of reproductive characteristics of insect societies will come from combining inclusive fitness theory with a wide range of other factors that affect relative power in a conflict situation.


Real-time restoration method for image transmission in a multimode optical fiber.
A new restoration method for a distorted image transmitted through a single step-index multimode fiber is presented. The transmission of the reference beam along with the image enables one to compensate on a real-time basis for the distortion caused by the fiber modal phase dispersion. At the receiver end the interference between the Fourier-transformed image and the reference beam creates gratings in a photorefractive crystal. It is theoretically shown that, owing to the spatial segregation characteristic of the Fourier-transformed mode distribution of the step-index fiber, the phase conjugation of thetransmitted image through four-wave mixing obtained from the crystal reconstructs the original image.


The consilia attributed to Arnau de Vilanova.
Four of the works attributed to Arnau de Vilanova may be considered consilia, which is the name of the genre of texts that expound medical treatments for illnesses suffered by specific individuals. In this paper, I first address the problem of their autheticity within the framework of the so-called "Arnaldian question". The evidence presented here confirms that Arnau de Vilanova was the author of the Regimen podagre and the Epistola ad Bremundum Montisferrarii, while the question regarding the authorship of the Regimen quartane and the Cura febris ethice remains unresolved. This article furthermore documents the degree to which the actual cures prescribed by the physician in the consilia agreed with the doctrinal works of the Galenic tradition. It is explained how medieval university-trained physician had to compete with other practitioners and how they tried to outrival them by applying the doctrines of learned medicine to the individual cases at hand.


Rickettsia aeschlimannii sp. nov., a new spotted fever group rickettsia associated with Hyalomma marginatum ticks.
We formally propose the name Rickettsia aeschlimannii sp. nov. for a new spotted fever group (SFG) rickettsia, strain MC16T, isolated from Hyalomma marginatum marginatum ticks collected in Morocco. This organism shows a typical rickettsial morphology when analyzed by electron microscopy. After characterization by serotyping, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western immunoblotting, PCR-restriction fragment length polymorphism (RFLP), pulsed-field gel electrophoresis, and 16S rDNA sequencing, this organism was found to be different from all of the recognized SFG rickettsiae. Identical PCR-RFLP profiles have, however, been found in H. marginatum marginatum from Portugal and H. marginatum rufipes from Zimbabwe, which suggests that the distribution of this rickettsia reaches from the Mediterranean to southern Africa.


Keep it simple with time: a reexamination of probabilistic topic detection models.
Topic detection (TD) is a fundamental research issue in the Topic Detection and Tracking (TDT) community with practical implications; TD helps analysts to separate the wheat from the chaff among the thousands of incoming news streams. In this paper, we propose a simple and effective topic detection model called the temporal Discriminative Probabilistic Model (DPM), which is shown to be theoretically equivalent to the classic vector space model with feature selection and temporally discriminative weights. We compare DPM to its various probabilistic cousins, ranging from mixture models like von-Mises Fisher (vMF) to mixed membership models like Latent Dirichlet Allocation (LDA). Benchmark results on the TDT3 data set show that sophisticated models, such as vMF and LDA, do not necessarily lead to better results; in the case of LDA, notably worst performance was obtained under variational inference, which is likely due to the significantly large number of LDA model parameters involved for document-level topic detection. On the contrary, using a relatively simple time-aware probabilistic model such as DPM suffices for both offline and online topic detection tasks, making DPM a theoretically elegant and effective model for practical topic detection.


Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer.
Gene expression profile (GEP) testing is a relatively new technology that offers the potential of personalized medicine to patients, yet little is known about its adoption into routine practice. One of the first commercially available GEP tests, a 21-gene profile, was developed to estimate the benefit of adjuvant chemotherapy for hormone receptor-positive breast cancer (HR-positive BC). By using a prospective registry data set outlining the routine care provided to women diagnosed from 2006 to 2008 with HR-positive BC at 17 comprehensive and community-based cancer centers, we assessed GEP test adoption and the association between testing and chemotherapy use. Of 7,375 women, 20.4% had GEP testing and 50.2% received chemotherapy. Over time, testing increased (14.7% in 2006 to 27.5% in 2008; P < .01) and use of chemotherapy decreased (53.9% in 2006 to 47.0% in 2008; P < .01). Characteristics independently associated with lower odds of testing included African American versus white race (odds ratio [OR], 0.70; 95% CI, 0.54 to 0.92) and high school or less versus more than high school education (OR, 0.63; 95% CI, 0.52 to 0.76). Overall, testing was associated with lower odds of chemotherapy use (OR, 0.70; 95% CI, 0.62 to 0.80). Stratified analyses demonstrated that for small, node-negative cancers, testing was associated with higher odds of chemotherapy use (OR, 11.13; 95% CI, 5.39 to 22.99), whereas for node-positive and large node-negative cancers, testing was associated with lower odds of chemotherapy use (OR, 0.11; 95% CI, 0.07 to 0.17). There has been a progressive increase in use of this GEP test and an associated shift in the characteristics of and overall reduction in the proportion of women with HR-positive BC receiving adjuvant chemotherapy.


[Analysis of the health and living conditions of the urban population of Botucatu, SP (Brazil). II. Knowledge and opinion of the population on symptoms of diseases].
It was verified the extent of the information of the urban population of Botucatu, SP (Brazil) on health questions. Knowledge and opinions about frequency and severity of thirteen symptoms and signs of disease were researched in 1005 families sampled. The answers were analyzed according to age, sex, level of education and socio-economic level. They showed a tendency compatible with scientific medical knowledge. In the comparison of the sexes, by age, (young adult) women gave more value to the frequency and severity of most of the symptoms than men. The high scores observed for severity showed a tendency to decrease with the increasing level of education for all the symptoms. There were variations among the symptoms in the appreciation of frequency according to the socio-economic level, with a tendency to a decrease in the high scores related to severity, according to the increase in socio-economic level. The degree of information observed in the population contradicts the prejudice, still existing in the medical area, about laymen's lack of knowledge. The hypothesis that the sample studied had access to several sources of information, among them the extensive local network of medical services, is put forward.


An atomic resolution model for assembly, architecture, and function of the Dr adhesins.
Pathogenic bacteria possess adhesion protein complexes that play essential roles in targeting host cells and in propagating infection. Although each family of adhesion proteins is generally associated with a specific human disease, the Dr family from Escherichia coli is a notable exception, as its members are associated with both diarrheal and urinary tract infections. These proteins are reported to form both fimbrial and afimbrial structures at the bacterial cell surface and target a common host cell receptor, the decay-accelerating factor (DAF or CD55). Using the newly solved three-dimensional structure of AfaE, we have constructed a robust atomic resolution model that reveals the structural basis for assembly by donor strand complementation and for the architecture of capped surface fibers.


High-Sensitivity Cardiac Troponin, Natriuretic Peptide, and Long-Term Risk of Acute Kidney Injury: The Atherosclerosis Risk in Communities (ARIC) Study.
Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized. We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996-1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs). During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59-2.21] for ≥14 ng/L, 1.36 [1.18-1.57] for 9-13 ng/L, and 1.16 [1.03-1.30] for 5-8 ng/L compared to <5 ng/L). The graded association was also observed for NTproBNP (HR, 2.27 [1.93-2.68] for ≥272.7 pg/mL, 1.67 [1.45-1.93] for 142.4-272.6 pg/mL, and 1.31 [1.17-1.47] for 64.0-142.3 pg/mL compared to <64.0 pg/mL). The addition of hs-cTnT and NTproBNP to a model with established predictors significantly improved 10-year risk prediction for hospitalization with AKI (Δc-statistic, 0.015 [95%CI, 0.006-0.024]). In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population.


Analysis of genetic diversity of Leuciscus leuciscus baicalensis using novel microsatellite markers with cross-species transferability.
We used next-generation sequencing technology to characterize 19 genomic simple sequence repeat (SSR) markers and 11 expressed sequence tag (EST) SSR markers from Leuciscus leuciscus baicalensis, a small freshwater fish that is widely distributed in Xinjiang, China. Primers were used to test for polymorphisms in three L. leuciscus baicalensis populations in Xinjiang. There were 4-27 (average 11.3) alleles (NA), the expected heterozygosity (HE) was 0.36-0.94 (average 0.75 ± 0.14), the observed heterozygosity (HO) was 0.37-1.00 (average 0.68 ± 0.18), and the polymorphism information content (PIC) was 0.31-0.93 (average 0.71). The averages of HE and PIC for the EST-SSR markers were slightly lower than for the genomic SSR markers. Genetic analysis of the three populations showed similar results for PIC, HE, and NA. Amplifications were performed in nine other species; the top three transferability values were for Rutilus lacustris (80%), Leuciscus idus (76.7%), and Phoxinus ujmonensis (63.3%), with the following average values: PIC (0.56, 4.46, and 0.52); NA (0.40, 3.00, and 0.32); and HO (0.44, 2.74, and 0.22), respectively. L. leuciscus baicalensis is one of the most important commercial fish in Xinjiang, but in recent years, fishery resources have decreased sharply owing to water conservation projects, unreasonable utilization, and invasion by alien species. These novel SSR markers are appropriate for studies involving fingerprinting, gene flow, genetic diversity, population structure, and molecular-assisted breeding, and could contribute to the conservation of L. leuciscus baicalensis.


Avoiding high ozone pollution in Delhi, India.
Surface ozone is a major pollutant threatening public health, agricultural production and natural ecosystems. While measures to improve air quality in megacities such as Delhi are typically aimed at reducing levels of particulate matter (PM), ozone could become a greater threat if these measures focus on PM alone, as some air pollution mitigation steps can actually lead to an increase in surface ozone. A better understanding of the factors controlling ozone production in Delhi and the impact that PM mitigation measures have on ozone is therefore critical for improving air quality. Here, we combine in situ observations and model analysis to investigate the impact of PM reduction on the non-linear relationship between volatile organic compounds (VOC), nitrogen oxides (NOx) and ozone. In situ measurements of NOx, VOC, and ozone were conducted in Delhi during the APHH-India programme in summer (June) and winter (November) 2018. We observed hourly averaged ozone concentrations in the city of up to 100 ppbv in both seasons. We performed sensitivity simulations with a chemical box model to explore the impacts of PM on the non-linear VOC-NOx-ozone relationship in each season through its effect on aerosol optical depth (AOD). We find that ozone production is limited by VOC in both seasons, and is particularly sensitive to solar radiation in winter. Reducing NOx alone increases ozone, such that a 50% reduction in NOx emissions leads to 10-50% increase in surface ozone. In contrast, reducing VOC emissions can reduce ozone efficiently, such that a 50% reduction in VOC emissions leads to ∼60% reduction in ozone. Reducing PM alone also increases ozone, especially in winter, by reducing its dimming effects on photolysis, such that a 50% reduction in AOD can increase ozone by 25% and it also enhances VOC-limitation. Our results highlight the importance of reducing VOC emissions alongside PM to limit ozone pollution, as well as benefitting control of PM pollution through reducing secondary organic aerosol. This will greatly benefit the health of citizens and the local ecosystem in Delhi, and could have broader application for other megacities characterized by severe PM pollution and VOC-limited ozone production.


Uncertainties in volume delineation in radiation oncology: A systematic review and recommendations for future studies.
Volume delineation is a well-recognised potential source of error in radiotherapy. Whilst it is important to quantify the degree of interobserver variability (IOV) in volume delineation, the resulting impact on dosimetry and clinical outcomes is a more relevant endpoint. We performed a literature review of studies evaluating IOV in target volume and organ-at-risk (OAR) delineation in order to analyse these with respect to the metrics used, reporting of dosimetric consequences, and use of statistical tests. Medline and Pubmed databases were queried for relevant articles using keywords. We included studies published in English between 2000 and 2014 with more than two observers. 119 studies were identified covering all major tumour sites. CTV (n=47) and GTV (n=38) were most commonly contoured. Median number of participants and data sets were 7 (3-50) and 9 (1-132) respectively. There was considerable heterogeneity in the use of metrics and methods of analysis. Statistical analysis of results was reported in 68% (n=81) and dosimetric consequences in 21% (n=25) of studies. There is a lack of consistency in conducting and reporting analyses from IOV studies. We suggest a framework to use for future studies evaluating IOV.


Iliotibial band friction syndrome--a systematic review.
Iliotibial band friction syndrome (ITBFS) is a common injury of the lateral aspect of the knee particularly in runners, cyclists and endurance sports. A number of authors suggest that ITBFS responds well to conservative treatment, however, much of this opinion appears anecdotal and not supported by evidence within the literature. The purpose of this paper is to provide a systematic review of the literature pertaining to the conservative treatment of ITBFS. A search to identify clinical papers referring to the iliotibial band (ITB) and ITBFS was conducted in a number of electronic databases using the keyword: iliotibial. The titles and abstracts of these papers were reviewed to identify papers specifically detailing conservative treatments of ITBFS. The PEDro Scale, a systematic tool used to critique randomized controlled trials (RCTs), was employed to investigate both the therapeutic effect of conservative treatment of ITBFS and also to critique the methodological quality of available RCTs examining the conservative treatment of ITBFS. With respect to the management of ITBFS, four RCTs were identified. The interventions examined included the use of non-steroidal anti-inflammatory drugs (NSAIDs), deep friction massage, phonophoresis versus immobilization and corticosteroid injection. This review highlights both the paucity in quantity and quality of research regarding the conservative treatment of ITBFS. There seems limited evidence to suggest that the conservative treatments that have been studied offer any significant benefit in the management of ITBFS. Future research will need to re-examine those conservative therapies, which have already been examined, along with others, and will need to be of sufficient quality to enable accurate clinical judgements to be made regarding their use.


DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane.
CRK belongs to a family of adaptor proteins that consist mostly of SH2 and SH3 domains. Far Western blotting with CRK SH3 has demonstrated that it binds to 135- to 145-, 160-, and 180-kDa proteins. The 135- to 145-kDa protein is C3G, a CRK SH3-binding guanine nucleotide exchange protein. Here, we report on the molecular cloning of the 180-kDa protein, which is designated DOCK180 (180-kDa protein downstream of CRK). The isolated cDNA contains a 5,598-bp open reading frame encoding an 1,866-amino-acid protein. The deduced amino acid sequence did not reveal any significant homology to known proteins, except that an SH3 domain was identified at its amino terminus. To examine the function of DOCK180, a Ki-Ras farnesylation signal was fused to the carboxyl terminus of DOCK180, a strategy that has been employed successfully for activation of adaptor-binding proteins in vivo. Whereas wild-type DOCK180 accumulated diffusely in the cytoplasm and did not have any effect on cell morphology, farnesylated DOCK180 was localized on the cytoplasmic membrane and changed spindle 3T3 cells to flat, polygonal cells. These results suggest that DOCK180 is a new effector molecule which transduces signals from tyrosine kinases through the CRK adaptor protein.


Quality control, modeling, and visualization of CRISPR screens with MAGeCK-VISPR.
High-throughput CRISPR screens have shown great promise in functional genomics. We present MAGeCK-VISPR, a comprehensive quality control (QC), analysis, and visualization workflow for CRISPR screens. MAGeCK-VISPR defines a set of QC measures to assess the quality of an experiment, and includes a maximum-likelihood algorithm to call essential genes simultaneously under multiple conditions. The algorithm uses a generalized linear model to deconvolute different effects, and employs expectation-maximization to iteratively estimate sgRNA knockout efficiency and gene essentiality. MAGeCK-VISPR also includes VISPR, a framework for the interactive visualization and exploration of QC and analysis results. MAGeCK-VISPR is freely available at http://bitbucket.org/liulab/mageck-vispr .


Evaluation of Kinase Activity Profiling Using Chemical Proteomics.
Protein kinases are important mediators of intracellular signaling and are reversibly activated by phosphorylation. Immobilized kinase inhibitors can be used to enrich these often low-abundance proteins, to identify targets of kinase inhibitors, or to probe their selectivity. It has been suggested that the binding of kinases to affinity beads reflects a kinase's activation status, a concept that is under considerable debate. To assess the merits of the idea, we performed a series of experiments including quantitative phosphoproteomics and purification of kinases by single or mixed affinity matrices from signaling activated or resting cancer cells. The data show that mixed affinity beads largely bind kinases independent of their activation status, and experiments using individual immobilized kinase inhibitors show mixed results in terms of preference for binding the active or inactive conformation. Taken together, activity- or conformation-dependent binding to such affinity resins depends (i) on the kinase, (ii) on the affinity probe, and (iii) on the activation status of the lysate or cell. As a result, great caution should be exercised when inferring kinase activity from such binding data. The results also suggest that assaying kinase activity using binding data is restricted to a limited number of well-chosen cases.


Recovery of Populus tremuloides seedlings following severe drought causing total leaf mortality and extreme stem embolism.
In contrast with other native Populus species in North America, Populus tremuloides (aspen) can successfully establish itself in drought-prone areas, yet no comprehensive analysis has been performed on the ability of seedlings to withstand and recover from a severe drought resulting in complete leaf mortality. Here, we subjected 4-month-old aspen seedlings grown in two contrasting soil media to a progressive drought until total leaf mortality, followed by a rewatering cycle. Stomatal conductance (g(s) ), photosynthesis and transpiration followed a sigmoid decline with declining fraction of extractable soil water values. Cessation of leaf expansion occurred close to the end of the linear-decrease phase, when g(s) was reduced by 95%. Leaf mortality started after g(s) reached the lowest values, which corresponded to a stem-xylem pressure potential (Ψ(xp)) of -2.0 MPa and a percent loss of stem hydraulic conductivity (PLC) of 50%. In plants with 50% leaf mortality, PLC values remained around 50%. Complete leaf mortality occurred at an average stem PLC of 90%, but all seedlings were able to resprout after 6-10 days of being rewatered. Plants decapitated at soil level before rewatering developed root suckers, while those left with a 4-cm stump or with their stems intact resprouted exclusively from axillary buds. Resprouting was accompanied by recovery of stem hydraulic conductivity, with PLC values around 30%. The percentage of resprouted buds was negatively correlated with the stem %PLC. Thus, the recovery of stem hydraulic conductivity appears as an important factor in the resprouting capacity of aspen seedlings following a severe drought.


Economic analysis of complementary, alternative, and integrative medicine: considerations raised by an expert panel.
An international panel of experts was convened to examine the challenges faced in conducting economic analyses of Complementary, Alternative and Integrative Medicine (CAIM). A one and a half-day panel of experts was convened in early 2011 to discuss what was needed to bring about robust economic analysis of CAIM. The goals of the expert panel were to review the current state of the science of economic evaluations in health, and to discuss the issues involved in applying these methods to CAIM, recognizing its unique characteristics. The panel proceedings were audiotaped and a thematic analysis was conducted independently by two researchers. The results were then discussed and differences resolved. This manuscript summarizes the discussions held by the panel members on each theme. The panel identified seven major themes regarding economic evaluation that are particularly salient to determining the economics of CAIM: standardization (in order to compare CAIM with conventional therapies, the same basic economic evaluation methods and framework must be used); identifying the question being asked, the audience targeted for the results and whose perspective is being used (e.g., the patient perspective is especially relevant to CAIM because of the high level of self-referral and out-of-pocket payment); the analytic methods to be used (e.g., the importance of treatment description and fidelity); the outcomes to be measured (e.g., it is important to consider a broad range of outcomes, particularly for CAIM therapies, which often treat the whole person rather than a specific symptom or disease); costs (e.g., again because of treating the whole person, the impact of CAIM on overall healthcare costs, rather than only disease-specific costs, should be measured); implementation (e.g., highlighting studies where CAIM allows cost savings may help offset its image as an "add on" cost); and generalizability (e.g., proper reporting can enable study results to be useful beyond the study sample). The business case for CAIM depends on economic analysis and standard methods for conducting such economic evaluations exist. The challenge for CAIM lies in appropriately applying these methods. The deliberations of this panel provide a list of factors to be considered in meeting that challenge.


Effect of Optical Defocus on Choroidal Thickness in Healthy Adults With Presbyopia.
To investigate changes in subfoveal choroidal thickness (SFCT) induced by retinal defocus in presbyopic adults. Thirty-seven healthy presbyopic subjects (age 57.74 ± 4.06 years) with low refractive errors (+0.08 ± 1.09 Diopters [D]) viewed a distant target (video movie at 6 m) for 60 minutes on two occasions while SFCT was monitored with optical coherence tomography every 20 minutes. On each occasion, both eyes were optimally corrected for distance: one eye acted as control, while the other (experimental) eye viewed through an additional ophthalmic lens: a +2.00 D lens imposing myopic defocus on one occasion and a -2.00 D lens imposing hyperopic defocus on the other occasion. Baseline SFCT was not different between experimental and control eyes (226 ± 72 μm vs. 232 ± 75 μm; P = 0.28). Myopic defocus caused a significant (P < 0.001) increase in SFCT in the defocused eye by 20 minutes (and +10 ± 5-μm increase at 60 minutes: P < 0.001), while hyperopic defocus caused a significant decrease in SFCT by 20 minutes (and -10 ± 5-μm decrease at 60 minutes: P < 0.001) with no change in control eyes. In presbyopic subjects, imposed myopic retinal defocus caused thickening of SFCT, while hyperopic defocus caused thinning of SFCT. This implies that uncorrected presbyopia, which is associated with hyperopic retinal defocus for near objects and which is highly prevalent in the developing world, would likely be associated with choroidal thinning and possibly reduced choroidal blood flow with prolonged periods in a near visual environment.


An open trial of citalopram in adolescents with post-traumatic stress disorder.
In this preliminary, 12-week open-label study, eight adolescents with moderate to severe post-traumatic stress disorder (PTSD) were treated with citalopram (the most selective of the selective serotonin reuptake inhibitors) in a fixed daily dose of 20 mg, and rated at 2-week intervals. The Clinician-Administered PTSD Scale (Child and Adolescent Version) was the primary measure used to assess treatment outcome. Core PTSD symptoms (re-experiencing, avoidance, and hyperarousal symptoms) showed statistically significant improvement at week 12 on the Clinician-Administered PTSD Scale (Child and Adolescent Version) (CAPS-CA), with a 38% reduction in total CAPS scores between baseline and endpoint. Citalopram failed to effect improvement on self-reported depressive symptoms. All seven adolescent completers were rated as much improved or very much improved on Clinical Global Impression Improvement scores. Citalopram was well-tolerated overall with reported adverse experiences being relatively benign. However, larger, controlled trials are needed to consolidate these preliminary results.


The role of alpha-7 nicotinic receptors in food intake behaviors.
Nicotine alters appetite and energy expenditure, leading to changes in body weight. While the exact mechanisms underlying these effects are not fully established, both central and peripheral involvement of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) has been suggested. Centrally, the α7nAChR modulates activity of hypothalamic neurons involved in food intake regulation, including proopiomelanocortin and neuropeptide Y. α7nAChRs also modulate glutamatergic and dopaminergic systems controlling reward processes that affect food intake. Additionally, α7nAChRs are important peripheral mediators of chronic inflammation, a key contributor to health problems in obesity. This review focuses on nicotinic cholinergic effects on eating behaviors, specifically those involving the α7nAChR, with the hypothesis that α7nAChR agonism leads to appetite suppression. Recent studies are highlighted that identify links between α7nAChR expression and obesity, insulin resistance, and diabetes and describe early findings showing an α7nAChR agonist to be associated with reduced weight gain in a mouse model of diabetes. Given these effects, the α7nAChR may be a useful therapeutic target for strategies to treat and manage obesity.


Satisfaction with routine follow-up visits to the physician--the needs of patients with breast cancer.
Follow-up visits after surgery for breast cancer constitute a large proportion of the outpatient consultations at surgical and oncological clinics. The reasons for the follow-ups include early detection of relapse, patients' well-being, and data collection for quality assurance and scientific studies. The aim of this study was to describe the needs of the patient with breast cancer and satisfaction with routine follow-up visits to the physician. A strategic sample of 20 women with breast cancer, routinely followed-up at an oncology outpatient clinic, was interviewed. A qualitative descriptive design inspired by the phenomenographic method was used. The results identified the need for routines, accessibility, security, continuity, confidence and information. The women's views demonstrated that there are strong reasons for reviewing and changing the design of the traditional follow-up system to obtain the most effective and well-functioning system possible to better meet these women's needs.


Dynamics and heterogeneity in the process of human frailty and aging: evidence from the U.S. older adult population.
This study investigated the dynamics and heterogeneity of the frailty index (FI) conceived as a systemic indicator of biological aging in the community-dwelling older adult population in the United States. We used panel data on multiple birth cohorts from the Health and Retirement Survey 1993-2006 and growth curve models to estimate age trajectories of the FI and their differences by sex, race, and socioeconomic status (SES) within cohorts. The FI for cohorts born before 1942 exhibit quadratic increases with age and accelerated increases in the accumulation of health deficits. More recent cohorts exhibit higher average levels of and rates of increment in the FI than their predecessors do at the same ages. Females, non-Whites, and individuals with low education and income exhibit greater degrees of physiological deregulation than their male, White, and high-SES counterparts at any age. Patterns of sex, race, and SES differentials in rates of aging vary across cohorts. Adjusting for social behavioral factors, the analysis provides evidence for physiological differences in the aging process among recent cohorts of older adults, points to the need for biological explanations of female excess in general system damage, and reveals the insufficiency of any single mechanism for depicting the racial and SES differences in the process of physiological deterioration.


[Percutaneous inferior vena cava filters: indications and results in 287 patients].
Anticoagulation is the treatment of choice for deep vein thrombosis (DVT) and pulmonary embolism (PE). Occasionally this treatment is contraindicated or fails to prevent PE. In these patients, inferior vena caval (IVC) interruption is indicated and insertion of a filter is the most commonly performed procedure. To report the experience with IVC filters. Retrospective review of all medical records and operative protocols of patients subjected to IVC filter implantations. Follow up was performed by telephone contact with the patient, relatives or primary physicians, ambulatory consultation or by death certificates. During the period 1993-2005 we implanted IVC filters on 287 patients, 55.4% male, average age: 62.1 yrs (17-99). Indications for the procedure were DVT or PE and contraindication of anticoagulation in 141 patients (49.1%), DVT or PE and complication of anticoagulation in 65 patients (22.6%), prophylaxis in 39 patients (13.6%), massive PE or poor respiratory function in 31 patients (10.8%), paradoxal emboli in 4 patients (1.4%) and other causes in seven patients. All percutaneous devices were successfully inserted. There was no morbidity or mortality related to the procedure. The most frequent access site was the internal jugular vein (66.6%). In 24 patients (8.4%) the filter was intentionally deployed above the renal veins. Six patients (2.1%) were lost to follow up after discharge. A mean follow up of 41.5 months was achieved. Ninety one patients died, with a 5 years survival of 64.7%. Symptomatic recurrent PE occurred in 6 patients (2.1%) and was the cause of death on 3 of them (1%), DVT has been detected in 22 patients (7.7%) during the follow up period. IVC filter implantation is a safe and effective short and long term measure to prevent PE and its consequences.


Technical issues stemming from endoscopic-ultrasound-guided gallbladder drainage: A single center experience.
This study was conducted to evaluate the outcomes of endoscopic-ultrasound-guided gallbladder drainage (EUS-GBD) using traditional biliary stents without lumen-apposing stents and to determine technical issues. All 18 patients who underwent EUS-GBD at our center between 2012 and 2018 were evaluated. After the clinical outcomes (including technical success, clinical effectiveness, adverse events, and recurrence) were analyzed, technical countermeasures for problems extracted from the analysis were developed. The rates of technical success, clinical effectiveness, severe adverse event occurrence, and recurrence of acute cholecystitis were 94% (17/18), 88% (15/17), 6% (1/18, massive bile leakage), and 27% (4/15), respectively. Distal gastrectomy causing scope instability, the non-swollen gallbladder, and double pigtail stent use caused technical difficulties. A fully covered metal stent (fcMS) should be placed in a shallow position so that it does not wedge into the opposite site. When the puncture route involves the gastric wall, the proximal portion of an fcMS located in the stomach can migrate toward the abdominal cavity. Although the clinical outcomes of EUS-GBD were relatively favorable, several technical issues related specifically to EUS-GBD were observed. Technical countermeasures would improve the outcomes.


Use of weaning protocols for reducing duration of mechanical ventilation in critically ill adult patients: Cochrane systematic review and meta-analysis.
To investigate the effects of weaning protocols on the total duration of mechanical ventilation, mortality, adverse events, quality of life, weaning duration, and length of stay in the intensive care unit and hospital. Systematic review. Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, LILACS, ISI Web of Science, ISI Conference Proceedings, Cambridge Scientific Abstracts, and reference lists of articles. We did not apply language restrictions. Review methods We included randomised and quasi-randomised controlled trials of weaning from mechanical ventilation with and without protocols in critically ill adults. Data selection Three authors independently assessed trial quality and extracted data. A priori subgroup and sensitivity analyses were performed. We contacted study authors for additional information. Eleven trials that included 1971 patients met the inclusion criteria. Compared with usual care, the geometric mean duration of mechanical ventilation in the weaning protocol group was reduced by 25% (95% confidence interval 9% to 39%, P=0.006; 10 trials); the duration of weaning was reduced by 78% (31% to 93%, P=0.009; six trials); and stay in the intensive care unit length by 10% (2% to 19%, P=0.02; eight trials). There was significant heterogeneity among studies for total duration of mechanical ventilation (I(2)=76%, P<0.01) and duration of weaning (I(2)=97%, P<0.01), which could not be explained by subgroup analyses based on type of unit or type of approach. There is evidence of a reduction in the duration of mechanical ventilation, weaning, and stay in the intensive care unit when standardised weaning protocols are used, but there is significant heterogeneity among studies and an insufficient number of studies to investigate the source of this heterogeneity. Some studies suggest that organisational context could influence outcomes, but this could not be evaluated as it was outside the scope of this review.


Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.
We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.


Speciation of fluoride in workroom air during primary production of aluminium.
Exposure to fluorides (F(-)) and particulate matter (PM) was assessed by personal sampling with use of Respicon® sampler in Prebake and Søderberg pot rooms in seven aluminium smelters. The inhalable PM mass was dominated by the extra-thoracic aerosol sub-fraction, which contributed with around 70% for both Prebake and Søderberg pot room workers. Quantitative and qualitative differences in exposure were found between pot room workers in smelters using these two technologies. Prebake pot room workers were exposed to 1.4 to 1.7 times higher PM concentrations than Søderberg pot room workers, depending on aerosol sub-fraction. Prebake pot room workers were also exposed to 2.5 to 2.9 higher air concentrations of water-soluble F(-) (FWS(-)) and 2.8 to 5.3 higher air concentrations of non water-soluble F(-) (FAS(-)) than Søderberg pot room workers, depending on aerosol sub-fraction. However, exposure to hydrogen fluoride (HF) was 1.3 times higher among Søderberg pot room workers. The relative amount of FWS(-), however, was higher among Søderberg pot room workers, while the relative amount of particulate F(-) (sum of FWS(-) and FAS(-)) was higher among Prebake pot room workers (6.5 vs. 3.9%). Exposure to the same PM concentration yielded higher FWS(-) and FAS(-) air concentrations among Prebake compared to Søderberg pot room workers.


Facioscapulohumeral Muscular Dystrophy.
Facioscapulohumeral Muscular Dystrophy is a common form of muscular dystrophy that presents clinically with progressive weakness of the facial, scapular, and humeral muscles, with later involvement of the trunk and lower extremities. While typically inherited as autosomal dominant, facioscapulohumeral muscular dystrophy (FSHD) has a complex genetic and epigenetic etiology that has only recently been well described. The most prevalent form of the disease, FSHD1, is associated with the contraction of the D4Z4 microsatellite repeat array located on a permissive 4qA chromosome. D4Z4 contraction allows epigenetic derepression of the array, and possibly the surrounding 4q35 region, allowing misexpression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. The less common form of the disease, FSHD2, results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele, also leading to the derepression of DUX4, further supporting a central role for DUX4. How DUX4 misexpression contributes to FSHD muscle pathology is a major focus of current investigation. Misexpression of other genes at the 4q35 locus, including FRG1 and FAT1, and unlinked genes, such as SMCHD1, has also been implicated as disease modifiers, leading to several competing disease models. In this review, we describe recent advances in understanding the pathophysiology of FSHD, including the application of MRI as a research and diagnostic tool, the genetic and epigenetic disruptions associated with the disease, and the molecular basis of FSHD. We discuss how these advances are leading to the emergence of new approaches to enable development of FSHD therapeutics. © 2017 American Physiological Society. Compr Physiol 7:1229-1279, 2017.


Oligomers of the ATPase EHD2 confine caveolae to the plasma membrane through association with actin.
Caveolae are specialized domains present in the plasma membrane (PM) of most mammalian cell types. They function in signalling, membrane regulation, and endocytosis. We found that the Eps-15 homology domain-containing protein 2 (EHD2, an ATPase) associated with the static population of PM caveolae. Recruitment to the PM involved ATP binding, interaction with anionic lipids, and oligomerization into large complexes (60-75S) via interaction of the EH domains with intrinsic NPF/KPF motifs. Hydrolysis of ATP was essential for binding of EHD2 complexes to caveolae. EHD2 was found to undergo dynamic exchange at caveolae, a process that depended on a functional ATPase cycle. Depletion of EHD2 by siRNA or expression of a dominant-negative mutant dramatically increased the fraction of mobile caveolar vesicles coming from the PM. Overexpression of EHD2, in turn, caused confinement of cholera toxin B in caveolae. The confining role of EHD2 relied on its capacity to link caveolae to actin filaments. Thus, EHD2 likely plays a key role in adjusting the balance between PM functions of stationary caveolae and the role of caveolae as vesicular carriers.


Supramolecular Chemistry-Assisted Electrochemical Method for the Assay of Endogenous Peptidylarginine Deiminases Activities.
Peptidylarginine deiminase 4 (PAD4) is the only isoform of PADs located within the cell nucleus, which has been known to be related to several human diseases. In this work, we have proposed an electrochemical method for the assay of endogenous PAD4 activities as well as the studies of PAD4 inhibitors by making use of the supramolecular chemistry-assisted signal labeling. Specifically, peptide probes P1 and P2, which separately contain cysteine residues and tripeptides FGG (Phe-Gly-Gly), can be self-assembled onto the surface of the gold electrode and silver nanoparticles, respectively. In the meantime, the peptide probes can be connected together through cucurbit[8]uril-mediated host-guest interaction. Nevertheless, after trypsin-catalyzed digestion, FGG at the N-terminal of P1 will be removed from the electrode surface, thereby inhibiting the connection of P1 and P2. Since PAD4 catalyzes the citrullination of arginine residue within P1, trypsin-catalyzed digestion of P1 can be prohibited by the addition of PAD4. Consequently, an obvious change of the electrochemical response can be obtained from the silver nanoparticles (AgNPs) immobilized on the electrode surface. Experimental results have shown that our method can display an improved sensitivity and specificity for both PAD4 assay and inhibitor screening, which may effectively trace endogenous PAD4 and the inhibitors in the cancer cells. Therefore, our method may have great potential for the diagnosis and treatment of PAD4-related diseases in the future.