On the state of water in 2.4 nm cylindrical pores of MCM from dynamic and normal specific heat studies.
Relaxation phenomenon, thermodynamics, and phase transformation of water in nanopores has been studied by differential scanning calorimetry, usually on heating a precooled sample. Interpretation of such results is ambiguous, because the data do not indicate whether or not there is a thermal hysteresis between the heating and cooling paths. We argue that measurements on both the cooling and heating paths are needed, particularly for complex systems, and also measurements of the complex quantity are needed to ascertain that the Kramers-Kronig relations for a relaxation process are obeyed. We report a study of the real and imaginary components of the complex specific heat, C(p)' and C(p)", and the time-dependent C(p,app) of water confined to 2.4 nm diameter cylindrical pores on both the cooling and heating paths, and use different thermal histories. C(p,app) of nanoconfined water shows two exothermic peaks during cooling below 255 K at 12 K/h and only one endothermic peak on heating, and the enthalpy change determined from the exotherm is more than that determined from the endotherm. C(p,app) and C(p)' of the partially crystallized water is higher at 240 K than at 275 K on the cooling path, and C(p,app) and C(p)' of the partially crystalline water are lower at 240 K than at 275 K on the heating path, thus showing a thermal hysteresis in this range. Studies by using 60 K/h cooling and heating rates and the effect of heat treatment at selected temperatures confirm that the features observed are due to slow crystallization and slow melting. The endotherm observed on the heating path with onset at 220 K and peak at 227 K is due to gradual melting of the ice in nanopores, and not due to glass-softening transition, a liquid-liquid transition, or an approach toward the conjectured critical point of the supercooled water in the 2.4 nm pores.


Molecular hydrodynamics: Vortex formation and sound wave propagation.
In the present study, quantitative feasibility tests of the hydrodynamic description of a two-dimensional fluid at the molecular level are performed, both with respect to length and time scales. Using high-resolution fluid velocity data obtained from extensive molecular dynamics simulations, we computed the transverse and longitudinal components of the velocity field by the Helmholtz decomposition and compared them with those obtained from the linearized Navier-Stokes (LNS) equations with time-dependent transport coefficients. By investigating the vortex dynamics and the sound wave propagation in terms of these field components, we confirm the validity of the LNS description for times comparable to or larger than several mean collision times. The LNS description still reproduces the transverse velocity field accurately at smaller times, but it fails to predict characteristic patterns of molecular origin visible in the longitudinal velocity field. Based on these observations, we validate the main assumptions of the mode-coupling approach. The assumption that the velocity autocorrelation function can be expressed in terms of the fluid velocity field and the tagged particle distribution is found to be remarkably accurate even for times comparable to or smaller than the mean collision time. This suggests that the hydrodynamic-mode description remains valid down to the molecular scale.


Validation of the Food Allergy Quality of Life-Parental Burden Questionnaire in the UK.
Food allergy can have a profound effect on quality of life (QoL) of the family. The Food Allergy Quality of Life-Parental Burden Questionnaire (FAQL-PB) was developed on a US sample to assess the QoL of parents with food allergic children. The aim of this study was to examine the reliability and validity of the FAQL-PB in a UK sample and to assess the effect of asking about parental burden in the last week compared with parental burden in general, with no time limit for recall given. A total of 1,200 parents who had at least one child with food allergy were sent the FAQL-PB and the Child Health Questionnaire (CHQ-PF50); of whom only 63% responded. Factor analysis of the FAQL-PB revealed two factors: limitations on life and emotional distress. The total scale and the two sub-scales had high internal reliability (all α > 0.85). There were small to moderate but significant correlations between total FAQL-PB scores and health and parental impact measures on the CHQ-PF50 (p < 0.01). Significantly greater parental burden was reported for the no-time limited compared with the time-limited version (p < 0.01). The FAQL-PB is a reliable and valid measure for use in the UK. The scale could be used in clinic to assess the physical and emotional quality of life in addition to the impact on total quality of life.


High HbA1c at onset cannot be used as a predictor for future metabolic control for the individual child with type 1 diabetes mellitus.
To study how metabolic control at onset of type 1 diabetes correlates to metabolic control and clinical parameters during childhood until transition from pediatric care to adult diabetes care. Data at onset, three months, one, three, and five years after diagnosis and at transition, on HbA1c and clinical parameters, on 8084 patients in the Swedish pediatric quality registry, SWEDIABKIDS, were used. Of these patients, 26% had been referred to adult diabetes care by 2014. Children with HbA1c < 72 mmol/mol (8.7%) (20% of patients, low group) at diagnosis continued to have good metabolic control during childhood, in contrast to children with HbA1c > 114 mmol/mol (12.6%) (20% of patients, high group) at diagnosis, who continued to have high HbA1c at follow-up. For the individual, there was no significant correlation between high HbA1c at onset and during follow-up. During follow-up, children in the high group were more often smokers, less physically active, and more often had retinopathy than children in the low group (P < .01, .01, .03 respectively). High HbA1c at onset was associated with high HbA1c during follow-up on a group level, but it cannot be used as a predictor of future metabolic control on an individual level. These results emphasize the important work done by the diabetes team in the first years after diagnosis. It is important to continuously set high goals for the achievement of tight metabolic control, in order to decrease the risk of microvascular complications.


The enzymatic preparation of isolated intact parenchymal cells from rat liver.
Suspensions of isolated parenchymal cells were prepared from rat liver by incubation with collagenase and hyaluronidase followed by mechanical treatment. Utilization of 0.15% collagenase together with 0.15% hyaluronidase yielded adequate numbers of cells for experimental purposes. As shown by light and electron microscopy, approximately 75% of the isolated cells retain their structural integrity. The cell suspensions are capable of maintaining endogenous respiration in the presence of 1% albumin for periods of time up to 8 hr. These cell preparations consist almost entirely of parenchymal cells and offer a unique tissue preparation for the study of hepatic metabolism.


A combination DNA and attenuated simian immunodeficiency virus vaccine strategy provides enhanced protection from simian/human immunodeficiency virus-induced disease.
Among the most effective vaccine candidates tested in the simian immunodeficiency virus (SIV)/macaque system, live attenuated viruses have been shown to provide the best protection from challenge. To investigate if preimmunization would increase the level of protection afforded by live attenuated SIVmac239Deltanef (Deltanef), macaques were given two priming immunizations of DNA encoding SIV Gag and Pol proteins, with control macaques receiving vector DNA immunizations. In macaques receiving the SIV DNA inoculation, SIV-specific cellular but not humoral responses were readily detectable 2 weeks after the second DNA inoculation. Following boosting with live attenuated virus, control of Deltanef replication was superior in SIV-DNA-primed macaques versus vector-DNA-primed macaques and was correlated with higher levels of CD8+/gamma-interferon-positive and/or interleukin-2-positive cells. Challenge with an intravenous inoculation of simian/human immunodeficiency virus (SHIV) strain SHIV89.6p resulted in infection of all animals. However, macaques receiving SIV DNA as the priming immunizations had statistically lower viral loads than control animals and did not develop signs of disease, whereas three of seven macaques receiving vector DNA showed severe CD4+ T-cell decline, with development of AIDS in one of these animals. No correlation of immune responses to protection from disease could be derived from our analyses. These results demonstrate that addition of a DNA prime to a live attenuated virus provided better protection from disease following challenge than live attenuated virus alone.


Aspect controls the survival of ice cliffs on debris-covered glaciers.
Supraglacial ice cliffs exist on debris-covered glaciers worldwide, but despite their importance as melt hot spots, their life cycle is little understood. Early field observations had advanced a hypothesis of survival of north-facing and disappearance of south-facing cliffs, which is central for predicting the contribution of cliffs to total glacier mass losses. Their role as windows of energy transfer suggests they may explain the anomalously high mass losses of debris-covered glaciers in High Mountain Asia (HMA) despite the insulating debris, currently at the center of a debated controversy. We use a 3D model of cliff evolution coupled to very high-resolution topographic data to demonstrate that ice cliffs facing south (in the Northern Hemisphere) disappear within a few months due to enhanced solar radiation receipts and that aspect is the key control on cliffs evolution. We reproduce continuous flattening of south-facing cliffs, a result of their vertical gradient of incoming solar radiation and sky view factor. Our results establish that only north-facing cliffs are recurrent features and thus stable contributors to the melting of debris-covered glaciers. Satellite observations and mass balance modeling confirms that few south-facing cliffs of small size exist on the glaciers of Langtang, and their contribution to the glacier volume losses is very small ([Formula: see text]1%). This has major implications for the mass balance of HMA debris-covered glaciers as it provides the basis for new parameterizations of cliff evolution and distribution to constrain volume losses in a region where glaciers are highly relevant as water sources for millions of people.


A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs.
Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents.


Hallmarks of mechanochemistry: from nanoparticles to technology.
The aim of this review article on recent developments of mechanochemistry (nowadays established as a part of chemistry) is to provide a comprehensive overview of advances achieved in the field of atomistic processes, phase transformations, simple and multicomponent nanosystems and peculiarities of mechanochemical reactions. Industrial aspects with successful penetration into fields like materials engineering, heterogeneous catalysis and extractive metallurgy are also reviewed. The hallmarks of mechanochemistry include influencing reactivity of solids by the presence of solid-state defects, interphases and relaxation phenomena, enabling processes to take place under non-equilibrium conditions, creating a well-crystallized core of nanoparticles with disordered near-surface shell regions and performing simple dry time-convenient one-step syntheses. Underlying these hallmarks are technological consequences like preparing new nanomaterials with the desired properties or producing these materials in a reproducible way with high yield and under simple and easy operating conditions. The last but not least hallmark is enabling work under environmentally friendly and essentially waste-free conditions (822 references).


Measuring attitudes, behaviours, and influences in inner city victims of interpersonal violence (VIVs) - a Swiss emergency room pilot study.
Switzerland is confronted with the problem of interpersonal violence. Violence is in the increase and the potential for aggression seems to be rising. Observations by hospitals discern an appalling increase of the severity of the injuries. The aim of this study is to collect accurate information about the social environment, the motivation and possible reasons for violence. We also intend to investigate whether sociocultural, or ethnic differences among male victims exist. For the first time in Switzerland, this survey employed a validated questionnaire from the division of violence prevention, Atlanta, Georgia. The first part of the questionnaire addressed social and demographic factors which could influence the risk of violence: age, gender, duration of stay in Switzerland, nationality and educational level. Beside these social structural factors, the questionnaire included questions on experience of violent offences in the past, information about the most recent violent offence and intra and interpersonal facts. The questionnaire itself consists of 27 questions, translated into German and French. In a pilot study, the questionnaire was checked with adolescents for feasibility and comprehensibility. 69 male VIVs were interviewed at two hospitals in the Canton of Bern. Most of the adolescents emphasised that weapons were not used during their confrontations. It is astonishing that all of the young men considered themselves to be victims. Most of the brawls were incited after an exchange of verbal abuse and provocations with unfamiliar individuals. The rivals could neither be classified with the help of ethnic categories nor identifiable groups of the youth scenes. The incidents took place in scenes, where violence was more likely to happen. Interestingly and contrary to a general perception the offenders are well integrated into sport and leisure clubs. A further surprising result of our research is that the attitude towards religion differs between young men with experience of violence and non-violent men. Youth violence is a health issue, which concerns us globally. The human and economic toll of violence on victims and offenders, their families, and on society in general is high. The economic costs associated with violence-related illness and disability is estimated to be millions of Swiss francs each year. Physicians and psychologists are compelled to identify the factors, which cause young people to be violent, to find out which interventions prove to be successful, and to design effective prevention programs. The identification of effective programs depends on the availability of reliable and valid measures to assess changes in violence-related attitudes. In our efforts to create healthier communities, we need to investigate; document and do research on the causes and circumstances of youth violence.


Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial.
Background and Purpose- ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths. Methods- Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed. Results- After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67-0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66-1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77-1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64-1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days; P<0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11-7.11]). Conclusions- These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding.


Measurement of the bottom-strange meson mixing phase in the full CDF data set.
We report a measurement of the bottom-strange meson mixing phase β(s) using the time evolution of B(s)(0)→J/ψ(→μ(+)μ(-))φ(→K(+)K(-)) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at √s=1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb(-1) of integrated luminosity. We report confidence regions in the two-dimensional space of β(s) and the B(s)(0) decay-width difference ΔΓ(s) and measure β(s)∈[-π/2,-1.51]∪[-0.06,0.30]∪[1.26,π/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of β(s), we also determine ΔΓ(s)=0.068±0.026(stat)±0.009(syst) ps(-1) and the mean B(s)(0) lifetime τ(s)=1.528±0.019(stat)±0.009(syst) ps, which are consistent and competitive with determinations by other experiments.


Role of the fourth transmembrane domain in proton-coupled folate transporter function as assessed by the substituted cysteine accessibility method.
The proton-coupled folate transporter (PCFT, SLC46A1) mediates folate transport across the apical brush-border membrane of the proximal small intestine and the basolateral membrane of choroid plexus ependymal cells. Two loss-of-function mutations in PCFT, which are the basis for hereditary folate malabsorption, have been identified within the fourth transmembrane domain (TMD4) in subjects with this disorder. We have employed the substituted Cys accessibility method (SCAM) to study the accessibilities of all residues in TMD4 and their roles in folate substrate binding to the carrier. When residues 146-167 were replaced by Cys, all except R148C were expressed at the cell surface. Modification of five of these substituted Cys residues (positions 147, 152, 157, 158, and 161) by methanethiosulfonate (MTS) reagents led to reduction of PCFT function. All five residues could be labeled with N-biotinylaminoethyl-MTS, and this could be blocked by the high-affinity PCFT substrate pemetrexed. Pemetrexed also protected PCFT mutant function from inhibitory modification of the substituted Cys at positions 157, 158, and 161 by a MTS. The findings indicate that these five residues in TMD4 are accessible to the aqueous translocation pathway, play a role in folate substrate binding, and are likely located within or near the folate binding pocket. A homology model of PCFT places three of these residues, Phe¹⁵⁷, Gly¹⁵⁸, and Leu¹⁶¹, within a breakpoint in the midportion of TMD4, a region that likely participates in alterations in the PCFT conformational state during carrier cycling.


Establishment and characterization of clinically relevant models of ependymoma: a true challenge for targeted therapy.
The development of new therapies for ependymoma is dramatically limited by the absence of optimal in vivo and in vitro models. Successful ependymoma treatment requires a profound understanding of the disease's biological characteristics. This study focuses on the establishment and characterization of in vivo and in vitro models of ependymoma to study the molecular pathways necessary for growth and progression in ependymoma. In addition, this study also emphasizes the use of these models for therapeutic intervention of ependymomas. We established optimal conditions for the long-term growth of 2 tumor xenografts and cultures of 2 human ependymoma cell lines. This study also describes the establishment of in vivo models. Histopathologic features of tumors from both intracranial and subcutaneous sites in mice revealed perivascular pseudorosettes and ependymal rosettes, which are typical morphologic features of ependymoma similar to those observed in human specimens. The in vitro models revealed glial fibrillary acidic protein and vimentin expression, and ultrastructural studies demonstrated numerous microvilli, caveolae, and microfilaments commonly seen in human ependymoma. To study signaling pathway alterations in ependymoma, we profiled established ependymoma models with Western blot analysis that demonstrated aberrant activation mainly of the phosphoinositide 3-kinase and epidermal growth factor receptor signaling pathways. Targeting phosphoinositide 3-kinase and epidermal growth factor receptor signaling pathways with small molecule inhibitors showed growth inhibitory effects. These models can also be used to study the standard therapies used for ependymomas, as shown by some of the drugs used in this study. Therefore, the models developed will assist in the biological studies and preclinical drug screening for ependymomas.


Assessing risks to non-target species during poison baiting programs for feral cats.
Poison baiting is used frequently to reduce the impacts of pest species of mammals on agricultural and biodiversity interests. However, baiting may not be appropriate if non-target species are at risk of poisoning. Here we use a desktop decision tree approach to assess the risks to non-target vertebrate species in Australia that arise from using poison baits developed to control feral house cats (Felis catus). These baits are presented in the form of sausages with toxicant implanted in the bait medium within an acid-soluble polymer capsule (hard shell delivery vehicle, or HSDV) that disintegrates after ingestion. Using criteria based on body size, diet and feeding behaviour, we assessed 221 of Australia's 3,769 native vertebrate species as likely to consume cat-baits, with 47 of these likely to ingest implanted HSDVs too. Carnivorous marsupials were judged most likely to consume both the baits and HSDVs, with some large-bodied and ground-active birds and reptiles also consuming them. If criteria were relaxed, a further 269 species were assessed as possibly able to consume baits and 343 as possibly able to consume HSDVs; most of these consumers were birds. One threatened species, the Tasmanian devil (Sarcophilus harrisii) was judged as definitely able to consume baits with implanted HSDVs, whereas five threatened species of birds and 21 species of threatened mammals were rated as possible consumers. Amphibia were not considered to be at risk. We conclude that most species of native Australian vertebrates would not consume surface-laid baits during feral cat control programs, and that significantly fewer would be exposed to poisoning if HSDVs were employed. However, risks to susceptible species should be quantified in field or pen trials prior to the implementation of a control program, and minimized further by applying baits at times and in places where non-target species have little access.


Interdomain association in fibronectin: insight into cryptic sites and fibrillogenesis.
The process by which fibronectin (FN), a soluble multidomain protein found in tissue fluids, forms insoluble fibrillar networks in the extracellular matrix is poorly understood. Cryptic sites found in FN type III domains have been hypothesized to function as nucleation points, thereby initiating fibrillogenesis. Exposure of these sites could occur upon tension-mediated mechanical rearrangement of type III domains. Here, we present the solution structures of the second type III domain of human FN ((2)FNIII), and that of an interaction complex between the first two type III domains ((1-2)FNIII). The two domains are connected through a long linker, flexible in solution. A weak but specific interdomain interaction maintains (1-2)FNIII in a closed conformation that associates weakly with the FN N-terminal 30 kDa fragment (FN30 kDa). Disruption of the interdomain interaction by amino-acid substitutions dramatically enhances association with FN30 kDa. Truncation analysis of (1-2)FNIII reveals that the interdomain linker is necessary for robust (1-2)FNIII-FN30 kDa interaction. We speculate on the importance of this interaction for FN function and present a possible mechanism by which tension could initiate fibrillogenesis.


Geographical variation in body size and sexual size dimorphism in an Australian lizard, Boulenger's Skink (Morethia boulengeri).
Ecogeographical rules help explain spatial and temporal patterns in intraspecific body size. However, many of these rules, when applied to ectothermic organisms such as reptiles, are controversial and require further investigation. To explore factors that influence body size in reptiles, we performed a heuristic study to examine body size variation in an Australian lizard, Boulenger's Skink Morethia boulengeri from agricultural landscapes in southern New South Wales, south-eastern Australia. We collected tissue and morphological data on 337 adult lizards across a broad elevation and climate gradient. We used a model-selection procedure to determine if environmental or ecological variables best explained body size variation. We explored the relationship between morphology and phylogenetic structure before modeling candidate variables from four broad domains: (1) geography (latitude, longitude and elevation), (2) climate (temperature and rainfall), (3) habitat (vegetation type, number of logs and ground cover attributes), and (4) management (land use and grazing history). Broad phylogenetic structure was evident, but on a scale larger than our study area. Lizards were sexually dimorphic, whereby females had longer snout-vent length than males, providing support for the fecundity selection hypothesis. Body size variation in M. boulengeri was correlated with temperature and rainfall, a pattern consistent with larger individuals occupying cooler and more productive parts of the landscape. Climate change forecasts, which predict warmer temperature and increased aridity, may result in reduced lizard biomass and decoupling of trophic interactions with potential implications for community organization and ecosystem function.


Patterns of coral ecological immunology: variation in the responses of Caribbean corals to elevated temperature and a pathogen elicitor.
Disease epizootics are increasing with climatic shifts, yet within each system only a subset of species are identified as the most vulnerable. Understanding ecological immunology patterns as well as environmental influences on immune defenses will provide insight into the persistence of a functional system through adverse conditions. Amongst the most threatened ecosystems are coral reefs, with coral disease epizootics and thermal stress jeopardizing their survival. Immune defenses were investigated within three Caribbean corals, Montastraea faveolata, Stephanocoenia intersepta and Porites astreoides, which represent a range of disease and bleaching susceptibilities. Levels of several immune parameters were measured in response to elevated water temperature and the presence of a commercial pathogen-associated molecular pattern (PAMP) - lipopolysaccharide (LPS) - as an elicitor of the innate immune response. Immune parameters included prophenoloxidase (PPO) activity, melanin concentration, bactericidal activity, the antioxidants peroxidase and catalase, and fluorescent protein (FP) concentration. LPS induced an immune response in all three corals, although each species responded differently to the experimental treatments. For example, M. faveolata, a disease-susceptible species, experienced significant decreases in bactericidal activity and melanin concentration after exposure to LPS and elevated temperature alone. Porites astreoides, a disease-resistant species, showed increased levels of enzymatic antioxidants upon exposure to LPS independently and increased PPO activity in response to the combination of LPS and elevated water temperature. This study demonstrates the ability of reef-building corals to induce immune responses in the presence of PAMPs, indicating activation of PAMP receptors and the transduction of appropriate signals leading to immune effector responses. Furthermore, these data address the emerging field of ecological immunology by highlighting interspecific differences in immunity and immunocompetences among Caribbean corals, which are reflected in their life-history characteristics, disease susceptibilities and bleaching-induced mortality.


A versatile assay for RNA-binding proteins in living cells.
RNA-binding proteins (RBPs) control RNA fate from synthesis to decay. Since their cellular expression levels frequently do not reflect their in vivo activity, methods are needed to assess the steady state RNA-binding activity of RBPs as well as their responses to stimuli. While electrophoresis mobility shift assays (EMSA) have been used for such determinations, their results serve at best as proxies for the RBP activities in living cells. Here, we describe a quantitative dual fluorescence method to analyze protein-mRNA interactions in vivo. Known or candidate RBPs are fused to fluorescent proteins (eGFP, YFP), expressed in cells, cross-linked in vivo to RNA by ultraviolet light irradiation, and immunoprecipitated, after lysis, with a single chain antibody fragment directed against eGFP (GFP-binding protein, GBP). Polyadenylated RNA-binding activity of fusion proteins is assessed by hybridization with an oligo(DT) probe coupled with a red fluorophore. Since UV light is directly applied to living cells, the assay can be used to monitor dynamic changes in RNA-binding activities in response to biological or pharmacological stimuli. Notably, immunoprecipitation and hybridization can also be performed with commercially available GBP-coupled 96-well plates (GFP-multiTrap), allowing highly parallel RNA-binding measurements in a single experiment. Therefore, this method creates the possibility to conduct in vivo high-throughput RNA-binding assays. We believe that this fast and simple radioactivity-free method will find many useful applications in RNA biology.


Synthesis and functionalization of dendritic polyglycerol-based nanogels: application in T cell activation.
The concept of multivalency finds various applications in the fields of chemistry and biology, relying on the principle that multiple weak interactions can lead to strong adhesive forces. Polymeric carriers are promising tools to translate these properties into the field of biomedicine, especially upon functionalization by active biomolecules, such as antibodies. In this study we report on the synthesis of dendritic polyglycerol (dPG) and dPG-based nanogels (NGs) as platforms for the multivalent display of molecules and their potential application as carrier units. Macromolecules based on dPG were synthesized and NGs were generated by strain-promoted azide-alkyne cycloaddition (SPAAC) by inverse nanoprecipitation under mild conditions. Scale-up screening rendered a reproducible method for a batch size of up to 50 mg for the formation of NGs in a size range of 150 nm with narrow dispersity. Dye-labelled bovine serum albumin (FITC-BSA) was chosen as a model protein and showed successful conjugation to the carriers, while the protein's secondary structure was not affected. Consequently, cyanine-5-amine (Cy5-NH2) and avidin (Av) were conjugated in order to exploit the strong avidin-biotin interaction, facilitating the directed attachment of a myriad of biotinylated (bio)molecules. As a proof-of-concept, the biotinylated monoclonal antibodies (mAbs) α-CD3 and α-CD28 were attached to the platforms and their capability to activate T cells was assessed. Experiments were performed with a Jurkat reporter cell line which expresses green fluorescent protein (GFP) upon activation, providing a rapid and reliable readout by flow cytometry. Carriers clearly outperformed conventional compounds for activation (i.e. antibodies crosslinked with anti-IgG antibody) at significantly lower dosages. These findings could be confirmed by confocal laser scanning microscopy (CLSM), showing accumulation of the functional nanoplatforms at the cell surface and cytoplasmic GFP expression (>95% activation of cells for the multivalent conjugates at 10 μg mL-1 compared to 37% activation with conventionally crosslinked mAbs at 25 μg mL-1), whereas carriers without mAbs could not activate cells. As the attachment of biotinylated molecules to the functional nanoplatforms is straightforward, the results obtained show the great potential of our platforms for a broad range of applications.


Effects of In Vitro Polyploidization on Agronomic Characteristics and Fruit Carotenoid Content; Implications for Banana Genetic Improvement.
Bananas (Musa spp.), native to South East Asia, have spread worldwide and are integrated into the diets of millions of people in tropical regions. Carotenoid content varies dramatically between different banana genotypes, providing an opportunity for vitamin A biofortification. Polyploidization is a useful tool for crop improvement with potential to generate new diversity, especially in a polyploid crop like bananas. Ten induced tetraploids generated from six diploid banana genotypes were evaluated for their agronomic attributes and fruit carotenoid content in comparison to their diploid progenitors. Tetraploids had distinct plant morphology, but generally displayed inferior vegetative and yield characteristics with 20% lower bunch weights than their original diploids. Similarly, a 50% decrease in fruit provitamin A carotenoids (α-carotene, 13-cis β-carotene, 9-cis β-carotene, trans-β-carotene) accompanied by a corresponding increase in lutein was recorded in induced tetraploids in comparison to their original diploids. Additionally, all lines were subjected to pollen viability tests to assess their fertility. Pollen viability tests indicated over 70% viability for induced tetraploids and diploid controls, suggesting their possible use in crosses. These findings provide a basis for the application of induced polyploidization in bananas to generate useful genetic material for integration in hybridization programmes aiming to produce vitamin A enriched triploids valuable to malnourished populations.


Canadian Helicobacter Study Group Consensus Conference: Update on the approach to Helicobacter pylori infection in children and adolescents--an evidence-based evaluation.
As an update to previously published recommendations for the management of Helicobacter pylori infection, an evidence-based appraisal of 14 topics was undertaken in a consensus conference sponsored by the Canadian Helicobacter Study Group. The goal was to update guidelines based on the best available evidence using an established and uniform methodology to address and formulate recommendations for each topic. The degree of consensus for each recommendation is also presented. The clinical issues addressed and recommendations made were: population-based screening for H. pylori in asymptomatic children to prevent gastric cancer is not warranted; testing for H. pylori in children should be considered if there is a family history of gastric cancer; the goal of diagnostic interventions should be to determine the cause of presenting gastrointestinal symptoms and not the presence of H. pylori infection; recurrent abdominal pain of childhood is not an indication to test for H. pylori infection; H. pylori testing is not required in patients with newly diagnosed gastroesophageal reflux disease; H. pylori testing may be considered before the use of long-term proton pump inhibitor therapy; testing for H. pylori infection should be considered in children with refractory iron deficiency anemia when no other cause has been found; when investigation of pediatric patients with persistent or severe upper abdominal symptoms is indicated, upper endoscopy with biopsy is the investigation of choice; the 13C-urea breath test is currently the best noninvasive diagnostic test for H. pylori infection in children; there is currently insufficient evidence to recommend stool antigen tests as acceptable diagnostic tools for H. pylori infection; serological antibody tests are not recommended as diagnostic tools for H. pylori infection in children; first-line therapy for H. pylori infection in children is a twice-daily, triple-drug regimen comprised of a proton pump inhibitor plus two antibiotics (clarithromycin plus amoxicillin or metronidazole); the optimal treatment period for H. pylori infection in children is 14 days; and H. pylori culture and antibiotic sensitivity testing should be made available to monitor population antibiotic resistance and manage treatment failures.


Effects of insulin resistance on skeletal muscle growth and exercise capacity in type 2 diabetic mouse models.
Type 2 diabetes mellitus is associated with an accelerated muscle loss during aging, decreased muscle function, and increased disability. To better understand the mechanisms causing this muscle deterioration in type 2 diabetes, we assessed muscle weight, exercise capacity, and biochemistry in db/db and TallyHo mice at prediabetic and overtly diabetic ages. Maximum running speeds and muscle weights were already reduced in prediabetic db/db mice when compared with lean controls and more severely reduced in the overtly diabetic db/db mice. In contrast to db/db mice, TallyHo muscle size dramatically increased and maximum running speed was maintained during the progression from prediabetes to overt diabetes. Analysis of mechanisms that may contribute to decreased muscle weight in db/db mice demonstrated that insulin-dependent phosphorylation of enzymes that promote protein synthesis was severely blunted in db/db muscle. In addition, prediabetic (6-wk-old) and diabetic (12-wk-old) db/db muscle exhibited an increase in a marker of proteasomal protein degradation, the level of polyubiquitinated proteins. Chronic treadmill training of db/db mice improved glucose tolerance and exercise capacity, reduced markers of protein degradation, but only mildly increased muscle weight. The differences in muscle phenotype between these models of type 2 diabetes suggest that insulin resistance and chronic hyperglycemia alone are insufficient to rapidly decrease muscle size and function and that the effects of diabetes on muscle growth and function are animal model-dependent.


Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.
Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers. This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.


Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor for the antioxidative stress response and it activates a variety of cytoprotective genes related to redox and detoxification. NRF2 activity is regulated by the oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation of NRF2 through ubiquitinating NRF2 under unstressed conditions. Because oxidative stress is a major pathogenic and aggravating factor for kidney diseases, the KEAP1-NRF2 system has been proposed to be a therapeutic target for renal protection. Oxidative-stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models for acute kidney injury (AKI), in which NRF2 is transiently and slightly activated. Genetic or pharmacological enhancement of NRF2 activity in the renal tubules significantly ameliorates damage related to AKI and prevents AKI progression to chronic kidney disease (CKD) by reducing oxidative stress. These beneficial effects of NRF2 activation highlight the KEAP1-NRF2 system as an important target for kidney disease treatment. However, a phase-3 clinical trial of a KEAP1 inhibitor for patients with stage 4 CKD and type-2 diabetes mellitus (T2DM) was terminated due to the occurrence of cardiovascular events. Because recent basic studies have accumulated positive effects of KEAP1 inhibitors in moderate stages of CKD, phase-2 trials have been restarted. The data from the ongoing projects demonstrate that a KEAP1 inhibitor improves the glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns. Key Message: The KEAP1-NRF2 system is one of the most promising therapeutic targets for kidney disease, and KEAP1 inhibitors could be part of critical therapies for kidney disease.


Treatment of brain metastases.
Brain metastases are a very common neurological sequela in cancer patients. The ability of current anti-cancer therapies to prolong overall survival is beleaguered by this development in the case of a number of different cancers. This review provides a general overview of relevant treatment modalities, highlights major decision strategies used in selecting the optimal treatment algorithm and summarizes important steps necessary before initiating therapy. A PubMed database search was done to identify publications describing the treatment of brain metastases including surgery, radiotherapy and symptomatic care. Patient performance status and extent of disease play the most important roles in selecting between an aggressive or more conservative approach. As several other options are available, treatment decisions should be made in cooperation with multiple medical specialties and the involvement of multidisciplinary teams. In the future, brain metastases could become less of a treatment obstacle than they are today.


Prognostic value of several biomarkers for the patients with malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor of the pleura closely related to asbestos exposure. Rare as it is, the incidence of MPM is predicted to increase mainly as a result of a lengthy latency period from the initial asbestos exposure, making it a public health concern for the next decades. Moreover, the patients with MPM have an extremely poor prognosis due to its high resistance to conventional oncologic treatments and delayed diagnosis. Although the result of current therapeutic modalities based on patient features and clinical stages is very frustrating, great advances have been shown in the knowledge of molecular biology of MPM in recent years. This is accompanied by dozens of putative prognostic biomarkers that are actively involved in tumor biological activities. These prognostic candidates can offer us a new insight into the biological characteristics of MPM, contributing to development of individualized therapeutic strategies directed against oncogenesis and tumor progression. Thus, personalized approaches based on the molecular biology of the patient's tissue or body fluid will potentially improve the present disappointing outcome, bringing new hope for patients with MPM. This article reviews the principal and several novel biomarkers that can have an influence on prognosis, in the hope that they can provide us with a more profound understanding of the biology of this lethal disease.


Age-Related Differences in Systolic Blood Pressure Recovery after a Maximal-Effort Exercise Test in Non-Athletic Adults.
The present study investigated the rate of systolic blood pressure recovery (SBPR) amongst three male age groups. Ninety-six apparently healthy, non-athletic adult males (48 young [23.91±4.58 years], 32 middle-aged [41.78±5.98 years] and 16 elderly [62.87±2.57 years]) participated in the study. Subjects performed a maximal-effort ergometer exercise test. Maximal oxygen uptake (VO2max) was measured during the exercise protocol; heart rate (HR) and SBP were measured before exercise (after 10 and 15 minutes of rest), during exercise (at 2-minute intervals), and at the first minute of post-exercise recovery and subsequently at 2-minute intervals until the recovery of SBP. Results showed that third-minute SBP ratio relative to 1 minute of recovery (SBPRy) was significantly lower (p<0.01; p<0.001) in the young (0.87± 0.06) when compared to middle aged (0.91 ± 0.05) and elderly adults (0.93 ± 0.04). Using bivariate correlation analysis, VO2max and %HR decline at 1 minute and 3 minutes of recovery, correlated with SBPRy in all age groups but after controlling for their confounders, only %HR decline in 3 min remained significantly correlated with SBPR in all the age groups. This study therefore showed age differences in SBPR after exercise with younger adults indicating faster recovery than older adults. After controlling for factors influencing SBPR, %HR decline in 3 min of recovery appeared to be a stronger contributor to age differences in SBPR than %HR decline in 1 min and VO2max. The reported data indicate the need to take age into account when interpreting SBPR after exercise during physical assessment of healthy individuals.


PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation.
The first cell differentiation in mammalian embryos segregates polarized trophectoderm cells from an apolar inner cell mass (ICM). This lineage decision is specified in compacted morulae by cell polarization and adhesion acting on the Yes-associated protein in the Hippo signaling pathway, but the regulatory mechanisms are unclear. We show that morula compaction and ICM formation depend on PC7 and the related proprotein convertases (PCs) Furin and Pace4 and that these proteases jointly regulate cell-cell adhesion mediated by E-cadherin processing. We also mapped the spatiotemporal activity profiles of these proteases by live imaging of a transgenic reporter substrate in wild-type and PC mutant embryos. Differential inhibition by a common inhibitor revealed that all three PCs are active in inner and outer cells, but in partially nonoverlapping compartments. E-cadherin processing by multiple PCs emerges as a novel mechanism to modulate cell-cell adhesion and fate allocation.


Effects of osteoporosis medications on bone fracture in patients with chronic kidney disease.
The risk of bone fracture is high in patients with chronic kidney disease (CKD), and aggressive treatment to reduce fragility fracture risk is the major strategy. However, the outcomes of osteoporosis medications in patients with CKD remain unclear. Patients with stage 3-5 CKD during 2011-2019 were enrolled. Patients were divided into two groups based on receiving osteoporosis medications (bisphosphonates, raloxifene, teriparatide or denosumab) or not. Two groups were matched at a 1:1 ratio by using propensity scores. The outcomes of interest were bone fractures, cardiovascular (CV) events and all-cause mortality. Cox proportional hazard regression models were applied to identify the risk factors. Additional stratified analyses by cumulative dose, treatment length and menopause condition were performed. 67 650 patients were included. After propensity score matching, 1654 patients were included in the study and control group, respectively. The mean age was 70.2±12.4 years, and 32.0% of patients were men. After a mean follow-up of 3.9 years, the incidence rates of bone fracture, CV events and all-cause mortality were 2.0, 1.7 and 6.5 per 1000 person-months, respectively. Multivariate analysis results showed that osteoporosis medications reduced the risk of CV events (HR, 0.35; 95% CI, 0.18 to 0.71; p = 0.004), but did not alleviate the risks of bone fracture (HR, 1.48; 95% CI, 0.73 to 2.98; p = 0.28) and all-cause mortality (HR, 0.93; 95% CI, 0.67 to 1.28; p = 0.65). Stratified analysis showed that bisphosphonates users have most benefits in the reduction of CV events (HR, 0.26; 95% CI, 0.11 to 0.64; p = 0.003). In conclusion, osteoporosis medications did not reduce the risk of bone fractures, or mortality, but improved CV outcomes in patients with CKD.


Development of LEU-based targets for radiopharmaceutical manufacturing: A review.
99Mo is an essential medical isotope that comprises of at least 70% of radioactive procedures globally. Currently an essential component of 99Mo manufacturing is the uranium target from which 99Mo is produced by fission. As the world moves towards low enriched uranium (LEU) targets due to non-proliferation concerns it is becoming of interest to find methods to increase the efficiency of the LEU targets in order to reduce the ever increasing nuclear waste levels of which a long term solution for disposal or treatment has yet to be satisfactorily found. Advantages and disadvantages of various target designs are investigated and discussed along current disposal and reprocessing methods. The idea of a reusable target is introduced as a way forward in reducing the nuclear waste burden for future generations.


Safety of traditional arab herbal medicine.
Herbal remedies are widely used for the treatment and prevention of various diseases and often contain highly active pharmacological compounds. Many medicinal herbs and pharmaceutical drugs are therapeutic at one dose and toxic at another. Toxicity related to traditional medicines is becoming more widely recognized as these remedies become popular in the Mediterranean region as well as worldwide. Most reports concerning the toxic effects of herbal medicines are associated with hepatotoxicity although reports of other toxic effects including kidney, nervous system, blood, cardiovascular and dermatologic effects, mutagenicity and carcinogenicity have also been published in the medical literature. This article presents a systematic review on safety of traditional Arab medicine and the contribution of Arab scholars to toxicology. Use of modern cell biological, biochemical, in vitro and in vivo techniques for the evaluation of medicinal plants safety is also discussed.


Association between intake of nutrients and food groups and liking for fat (The Nutrinet-Santé Study).
Apart from the established association between liking for fat and fat intake, little is known about the association between liking for fat and intake of specific nutrients or food groups. We investigated the association between dietary intake and liking for fat, fat-and-sweet and fat-and-salt. Liking scores were constructed using a validated preference questionnaire administered to 41,595 French adults participating in the Nutrinet-Santé study. Dietary data were collected using web-based 24 h records. Relationships between liking and dietary intake were assessed using linear regression adjusted for age and energy intake. Results are expressed in percentage difference of intake between individuals with low liking and those with high liking. Compared with participants with low liking for fat, individuals with a strong liking for fat had higher intakes of total energy (+10.1% in women (W); +8.4% in men (M)), fats (W: +7.3%; M: +10.0%), saturated fats (W: +10.8%; M+15.4%), meat (W: +13.0%; M: +12.6%), butter (W: +34.0%; M: +48.1%), sweetened cream desserts (W: +14.8%; M: +21.1%) and croissant-like pastries (W: +27.2%; M: +36.9). They also consumed lower quantities of omega-3 fatty acids (W: -6.2%;M: -6.0%), fiber (W: -16.4%; M: -18.9%), fruits (W: -28.8%; M: -29.5%), vegetables (W: -16.4%; M: -19.7%) and yogurt (W: -12.1%; M: -14.8%). Participants with high liking for fat-and-salt had higher intakes of total energy, sodium and alcoholic beverages and lower consumption of total and simple carbohydrates and fruit and vegetables than persons with high liking for fat-and-sweet. Our study contributes to the understanding of liking as a determinant of dietary intake. It highlighted that increased liking for fat, especially fat-and-salt liking, was associated with a lower intake of healthy foods, such as fruit and vegetables.


The chromatin environment shapes DNA replication origin organization and defines origin classes.
To unveil the still-elusive nature of metazoan replication origins, we identified them genome-wide and at unprecedented high-resolution in mouse ES cells. This allowed initiation sites (IS) and initiation zones (IZ) to be differentiated. We then characterized their genetic signatures and organization and integrated these data with 43 chromatin marks and factors. Our results reveal that replication origins can be grouped into three main classes with distinct organization, chromatin environment, and sequence motifs. Class 1 contains relatively isolated, low-efficiency origins that are poor in epigenetic marks and are enriched in an asymmetric AC repeat at the initiation site. Late origins are mainly found in this class. Class 2 origins are particularly rich in enhancer elements. Class 3 origins are the most efficient and are associated with open chromatin and polycomb protein-enriched regions. The presence of Origin G-rich Repeated elements (OGRE) potentially forming G-quadruplexes (G4) was confirmed at most origins. These coincide with nucleosome-depleted regions located upstream of the initiation sites, which are associated with a labile nucleosome containing H3K64ac. These data demonstrate that specific chromatin landscapes and combinations of specific signatures regulate origin localization. They explain the frequently observed links between DNA replication and transcription. They also emphasize the plasticity of metazoan replication origins and suggest that in multicellular eukaryotes, the combination of distinct genetic features and chromatin configurations act in synergy to define and adapt the origin profile.


Hysteroscopic sterilization using a micro-insert device: results of a multicentre Phase II study.
Unlike laparoscopic surgery for interval tubal sterilization, a hysteroscopic approach obviates surgical incision and requires only local anaesthesia or intravenous sedation. The safety, tolerability and efficacy of an hysteroscopically placed micro-insert device was evaluated. A cohort of 227 previously fertile women participated in this prospective international multicentre trial. Micro-inserts were placed bilaterally into the proximal Fallopian tube lumens under hysteroscopic visualization in outpatient procedures. Successful bilateral micro-insert placement was achieved in 88% of women. The majority of women reported that intraprocedural pain was less than or equal to that expected, and 90% rated tolerance of the device placement procedure as good to excellent. Most women could be discharged in an ambulatory state within 1-2 h. Adverse events occurred in 7% of the women, but none was serious. Correct device placement was confirmed in 97% of cases at 3 months. Over 24 months follow-up, 98% of study participants rated their tolerance of the micro-insert as very good to excellent. After 6015 woman-months of exposure to intercourse, no pregnancies have been recorded. Hysteroscopic sterilization resulted in rapid patient recovery without unacceptable post-procedure pain, as well as high long-term patient tolerability, satisfaction and effective permanent contraception.


Association study of the 5-HT(2A) receptor gene polymorphism, T102C and essential hypertension.
Serotonin dysfunction has been implicated in hypertension due to its ability to induce vasoconstriction via stimulation of 5-HT(2) receptors and due to the antihypertensive effect of ketanserin, an antagonist at the 5-HT(2A) receptor subtype, expressed both on arteries and the brain. The silent T102C polymorphism in the 5-HT(2A) gene is in absolute linkage disequilibrium with a polymorphism in the promoter and may contribute to genetic predisposition possibly by modifying the transcription of the gene. To examine the genetic contribution of the T102C 5-HT(2A)polymorphism in essential hypertension in a case-control sample of UK residents. The hypertensive group consisted of 342 subjects over 75 years and the community-based control group consisted of 319 subjects. Subjects were genotyped for the T102C polymorphism by Mspl restriction enzyme digestion following PCR amplification. Sex-specific association analysis revealed significant differences between hypertensive and normotensive subjects in the genotypes distribution (P = 0.016) and allelic frequencies (P = 0.007) in the female group. The direction of significance was increased frequency of the 102-C allele in the hypertensive subjects. There were no association between haplotype and age or body mass index, which suggest that the effect of the T102C variant is not influenced by these variables. This data indicates that the T102C polymorphism in the 5-HT(2A) gene might be an independent risk factor for increased blood pressure in female individuals with essential hypertension.


A comparison of pregnancy dating methods commonly used in South Africa: a prospective study.
Pregnancy dating in the South African public healthcare setting is mainly based on clinical assessment. However, the accuracy of this approach is unknown. To compare the accuracy of different pregnancy dating methods. We performed a prospective comparison of 2 ultrasound policies involving consecutive low-risk women in a midwife clinic in the Metro East region, Cape Town, Western Cape. Information on the last menstrual period (LMP), the 1st symphysis-to-fundal height measurement (FH) and average gestation by ultrasonographic (US) fetal biometry was recorded. Five dating methods: LMP, FH, US and their combinations, were assessed against the actual day of delivery (ADD). The main outcome measures were: (i) the days between the ADD and estimated date of delivery in pregnancies where spontaneous labour occurred and the baby had a normal birth weight; (ii) the incidence of gestational age-related outcomes; and (iii) the influence of clinical variables on dating discrepancies. A total of 1 342 pregnancies were analysed. The accuracy of dating was similar for certain and uncertain LMP. FH was less accurate with increasing obesity. US-based dating was most accurate (for 85% of predictions within 14 days) and similarly accurate at 20 - 24 weeks and at >24 weeks. US reduced the number of assumed pre-and post-term deliveries and, in addition, was better at detecting small-for-gestational age infants (p<0.001). Pregnancy dating by US, including those in more advanced pregnancies than currently permitted, is recommended since all non-ultrasound-based estimations of gestational age were considerably less accurate.


Association of anxiety and depression with hypertension control: a US multidisciplinary group practice observational study.
The presence of a mental health disorder with hypertension is associated with higher cardiovascular disease mortality than hypertension alone. Although earlier detection of hypertension has been demonstrated in patients with anxiety and depression, the relationship of mental health disorders to hypertension control is unknown. Our objective was to evaluate rates and predictors of incident hypertension control among patients with anxiety and/or depression compared with patients without either mental health diagnosis. A 4-year retrospective analysis included 4362 patients, at least 18 years old, who received primary care in a large academic group practice from 2008 to 2011. Patients met The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria and had a hypertension diagnosis. Kaplan-Meier analysis estimated the probability of achieving control for patients with and without anxiety and/or depression. Cox proportional hazard models were fit to identify predictors of time to control. Overall, 13% (n = 573) had a baseline diagnosis of anxiety and/or depression. Those with anxiety and/or depression demonstrated more primary care and specialty visits than those without either condition. After adjustment, patients with anxiety and/or depression had faster rates of hypertension control (hazard ratio [HR] 1.22; 1.07-1.39] than patients without either diagnosis. Other associations of faster hypertension control included female gender (HR 1.32; 1.20-1.44), absence of tobacco use (HR 1.17; 1.03-1.33), Medicaid use (HR 1.27; 1.09-1.49), and a higher Adjusted Clinical Group Risk Score (HR 1.13; 1.10-1.17), a measure of healthcare utilization. Greater healthcare utilization among patients with anxiety and/or depression may contribute to faster hypertension control.


Effect of adding the novel fiber, PGX®, to commonly consumed foods on glycemic response, glycemic index and GRIP: a simple and effective strategy for reducing post prandial blood glucose levels--a randomized, controlled trial.
Reductions in postprandial glycemia have been demonstrated previously with the addition of the novel viscous polysaccharide (NVP), PolyGlycopleX® (PGX®), to an OGTT or white bread. This study explores whether these reductions are sustained when NVP is added to a range of commonly consumed foods or incorporated into a breakfast cereal. Ten healthy subjects (4M, 6F; age 37.3 ± 3.6 y; BMI 23.8 ± 1.3 kg/m2), participated in an acute, randomized controlled trial. The glycemic response to cornflakes, rice, yogurt, and a frozen dinner with and without 5 g of NVP sprinkled onto the food was determined. In addition, 3 granolas with different levels of NVP and 3 control white breads and one white bread and milk were also consumed. All meals contained 50 g of available carbohydrate. Capillary blood samples were taken fasting and at 15, 30, 45, 60, 90 and 120 min after the start of the meal. The glycemic index (GI) and the glycemic reduction index potential (GRIP) were calculated. The blood glucose concentrations at each time and the iAUC values were subjected to repeated-measures analysis of variance (ANOVA) examining for the effect of test meal. After demonstration of significant heterogeneity, differences between individual means was assessed using GLM ANOVA with Tukey test to adjust for multiple comparisons. Addition of NVP reduced blood glucose response irrespective of food or dose (p < 0.01). The GI of cornflakes, cornflakes+NVP, rice, rice+NVP, yogurt, yogurt+NVP, turkey dinner, and turkey dinner+NVP were 83 ± 8, 58 ± 7, 82 ± 8, 45 ± 4, 44 ± 4, 38 ± 3, 55 ± 5 and 41 ± 4, respectively. The GI of the control granola, and granolas with 2.5 and 5 g of NVP were 64 ± 6, 33 ± 5, and 22 ± 3 respectively. GRIP was 6.8 ± 0.9 units per/g of NVP. Sprinkling or incorporation of NVP into a variety of different foods is highly effective in reducing postprandial glycemia and lowering the GI of a food. NCT00935350.


The causation of disease - the practical and ethical consequences of competing explanations.
The prevention, treatment and management of disease are closely linked to how the causes of a particular disease are explained. For multi-factorial conditions, the causal explanations are inevitably complex and competing models may exist to explain the same condition. Selecting one particular causal explanation over another will carry practical and ethical consequences that are acutely relevant for health policy. In this paper our focus is two-fold; (i) the different models of causal explanation that are put forward within current scientific literature for the high and rising prevalence of the common complex conditions of coronary artery disease (CAD) and type 2 diabetes mellitus (T2D); and (ii) how these explanations are taken up (or not) within national health policy guidelines. We examine the causal explanations for these two conditions through a systematic database search of current scientific literature. By identifying different causal explanations we propose a three-tier taxonomy of the most prominent models of explanations: (i) evolutionary, (ii) lifecourse, and (iii) lifestyle and environment. We elaborate this taxonomy with a micro-level thematic analysis to illustrate how some explanations are semantically and rhetorically foregrounded over others. We then investigate the uptake of the scientific causal explanations in health policy documents with regard to the prevention and management recommendations of current National Service Frameworks for CAD and T2D. Our findings indicate a lack of congruence between the complexity and frequent overlap of causal explanations evident in the scientific literature and the predominant focus on lifestyle recommendations found in the mainstream health policy documents.


Work-related stress and quality of life among Iranian blue-collar workers with self-reported low back pain.
Background: Impairment in quality of life and mental health had been reported in the previous studies as the results of musculoskeletal disorders among workers. Mental health has a wide concept and contains different disorders including anxiety, depression or even decreased quality of life, all of which having challengeable impacts on work- related characters such as work productivity and absensism. The present study aimed at evaluating work- related stress and quality of life among Iranian blue-collar workers of Fars ABFA Company with selfreported low back pain. Methods: In the present study, we focused on the low back pain among 451 blue-collar workers and assessed their work- related stress and quality of life status using DASS-21 and short form questionnaire (SF-36), respectively. Independent sample t-test was used to compare the qualitative variables, and chi-square test was utilized for statistical analysis of the qualitative variables. Results: Mean of the total score of quality of life among workers with low back pain was significantly lower than in those workers without low back pain. The mean of work- related stress score was significantly higher in workers with low back pain than in workers without low back pain. The mean quality of life subdomains in patients with low back pain was significantly lower than in workers without low back pain. Conclusion: Findings of the present study revealed that workers with low back pain had lower quality of life score and higher work- related stress score. These findings should be considered in designing preventive programs rather than controlling the pain.


Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial.
The local failure rate in patients with locoregionally advanced cervical cancer is 41-72% after radiotherapy (RT) alone, whereas local control is a prerequisite for cure. The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia (HT) improved 3-year local control rates of 41-61%, as we reported earlier. In this study, we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up. From 1990 to 1996, a total of 114 women with locoregionally advanced cervical carcinoma were randomly assigned to RT or RT+HT. The RT was applied to a median total dose of 68 Gy. The HT was given once weekly. The primary end point was local control. Secondary end points were overall survival and late toxicity. At the 12-year follow-up, local control remained better in the RT+HT group (37% vs. 56%; p=0.01). Survival was persistently better after 12 years: 20% (RT) and 37% (RT+HT; p=0.03). World Health Organization (WHO) performance status was a significant prognostic factor for local control. The WHO performance status, International Federation of Gynaecology and Obstetrics (FIGO) stage, and tumor diameter were significant for survival. The benefit of HT remained significant after correction for these factors. European Organization for Research and Treatment of Cancer Grade 3 or higher radiation-induced late toxicities were similar in both groups. For locoregionally advanced cervical cancer, the addition of HT to RT resulted in long-term major improvement in local control and survival without increasing late toxicity. This combined treatment should be considered for patients who are unfit to receive chemotherapy. For other patients, the optimal treatment strategy is the subject of ongoing research.


Internet-Based Cognitive Therapy for Social Anxiety Disorder in Hong Kong: Therapist Training and Dissemination Case Series.
Guided internet-based psychological interventions show substantial promise for expanding access to evidence-based mental health care. However, this can only be achieved if results of tightly controlled studies from the treatment developers can also be achieved in other independent settings. This dissemination depends critically on developing efficient and effective ways to train professionals to deliver these interventions. Unfortunately, descriptions of therapist training and its evaluation are often limited or absent within dissemination studies. This study aimed to describe and evaluate a program of therapist training to deliver internet-based Cognitive Therapy for social anxiety disorder (iCT-SAD). As this treatment was developed in the United Kingdom and this study was conducted in Hong Kong with local therapists, an additional objective was to examine the feasibility, acceptability, and initial efficacy of iCT-SAD in this cultural context, based on data from a pilot case series. Training in iCT-SAD was provided to 3 therapists and included practice of the face-to-face format of therapy under clinical supervision, training workshops, and treating 6 patients with the iCT-SAD program. Training progress was evaluated using standardized and self-report measures and by reviewing patient outcomes. In addition, feedback from patients and therapists was sought regarding the feasibility and acceptability of the program. The training program was effective at increasing therapists' iCT-SAD knowledge and skills, resulting in levels of competence expected of a specialist Cognitive Behavioral Therapy practitioner. The 6 patients treated by the trainees all completed their treatment and achieved a mean pre- to posttreatment change of 53.8 points (SD 39.5) on the primary patient outcome measure, the Liebowitz Social Anxiety Scale. The within-group effect size (Cohen d) was 2.06 (95% CI 0.66-3.46). There was evidence to suggest that the patients' clinical outcomes were sustained at 3-month follow-up. These clinical results are comparable to those achieved by UK patients treated by the developers of the internet program. Patient and therapist feedback did not identify any major cultural barriers to implementing iCT-SAD in Hong Kong; some modest language suggestions were made to assist understanding. The therapist training implemented here facilitated the successful dissemination of an effective UK-developed internet intervention to Hong Kong. The treatment appeared feasible and acceptable in this setting and showed highly promising initial efficacy. A randomized controlled trial is now required to examine this more robustly. As therapist training is critical to the successful dissemination of internet interventions, further research to develop, describe, and evaluate therapist training procedures is recommended.


Characterization of an animal model of postmenopausal hypertension in spontaneously hypertensive rats.
Blood pressure (BP) increases in postmenopausal women. The mechanisms responsible are unknown. The present study was performed to characterize a model of postmenopausal hypertension in the rat and to determine the role that oxidative stress may play in mediating the postmenopausal hypertension. Spontaneously hypertensive rats were ovariectomized (ovx) or left intact (PMR) at 8 months and were aged to 18 months. These animals were compared with young females (YF; 4 or 8 months of age) and old males (18 months) for some measurements. Estradiol levels were decreased in PMR rats to levels not different from YF rats in proestrous or from old males. BP increased progressively with age in PMR rats but not in ovx or male rats, such that the gender difference in hypertension disappeared by 18 months. Glomerular filtration rate was lower in ovx and PMR rats than in YF rats. Renal plasma flow and renal vascular resistance were similar between YF and ovx rats, but lower and higher, respectively, in PMR rats. Serum testosterone increased by 60% in ovx rats and 400% in PMR rats compared with YF rats. Plasma renin activity also increased in PMR rats but not in ovx rats. Chronic treatment (for 8 months beginning at 8 months of age) of PMR rats with vitamins E and C, but not tempol, resulted in a significant reduction in BP and excretion of F2-isoprostanes. In contrast, tempol, but not vitamins E and C, reduced BP in old males. These data suggest that the PMR rats, but not ovx rats, may be a suitable model for the study of postmenopausal hypertension, and that oxidative stress plays a role in the increased BP.


Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma.
Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 mg/day, 20 mg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8(+) T-cell reactivity to tumor antigens were evaluated before and after treatment. MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8(+) T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8(+) T cells in a dose-dependent fashion.


Contribution of smoking to excess mortality in Harlem.
The New York City neighborhood of Harlem has mortality rates that are among the highest in the United States. In absolute numbers, cardiovascular disease and cancer account for the overwhelming majority of deaths, especially among men, and these deaths occur at relatively young ages. The aim of this research was to examine self-reported smoking habits according to measures of socioeconomic status among Harlem men and women, in order to estimate the contribution of tobacco consumption to Harlem's remarkably high excess mortality. During 1992-1994, in-person interviews were conducted among 695 Harlem adults aged 18-65 years who were randomly selected from dwelling unit enumeration lists. The self-reported prevalence of current smoking was strikingly high among both men (48%) and women (41%), even among highly educated men (38%). The 21% of respondents without working telephones reported an even higher prevalence of current smoking (61%), indicating that national and state-based estimates which rely on telephone surveys may seriously underestimate the prevalence of smoking in poor urban communities. Among persons aged 35-64 years, the smoking attributable fractions for selected causes of death were larger in Harlem than in either New York City as a whole or the entire United States for both men and women. Tobacco consumption is likely to be one of several important mediators of the high numbers of premature deaths in Harlem.


Rapid excision of massive localized lymphedema of the male genitalia with vessel sealing device.
To present a series of patients who underwent surgical treatment for massive localized lymphedema (MLL) of the male genitalia and explore the utility of the LigaSure hemostatic vessel sealing device (VSD) for resection of advanced cases. Although conservative and microsurgical treatments have been reported, MLL of the male genitalia requires open surgical resection with primary reconstruction. We reviewed our prospectively maintained database of all lymphedema excisions performed between January 2007 and December 2014 comparing resection with Bovie electrocautery to resection with the LigaSure VSD. Our analysis focused on any significant differences in rate of resection, estimated blood loss (EBL), and recurrence. Nineteen patients with MLL of the male genitalia underwent excision with either LigaSure (8 patients) or conventional Bovie electrocautery (11 patients). Rate of resection was significantly faster with LigaSure compared to Bovie (33.74 g/min versus 5.32 g/min, p = .035). Additionally, estimated EBL per gram of tissue resected was decreased in the LigaSure group (0.41 mL/g versus 0.17 mL/g, p = .057). Two of the 11 Bovie patients (18%) had recurrence of lymphedema requiring repeat resection, while none of the LigaSure patients developed recurrence. Resection of genital lymphedema using the LigaSure device offers promising results in managing advanced MLL of the male genitalia with the potential for faster resections, less EBL per tissue resected, and a lower rate of recurrence.


Functional MRI language mapping in pre-surgical epilepsy patients: findings from a series of patients in the Epilepsy Unit at Mediclinic Constantiaberg.
Functional magnetic resonance imaging (fMRI) is commonly applied to study the neural substrates of language in clinical research and for neurosurgical planning. fMRI language mapping is used to assess language lateralisation, or determine hemispheric dominance, and to localise regions of the brain involved in language. Routine fMRI has been introduced in the Epilepsy Unit at Mediclinic Constantiaberg to contribute to the current functional mapping procedures used in pre-surgical planning. In this paper we describe the language paradigms used in these routine studies as well as the results from 22 consecutive epilepsy patients. Multi-subject analyses were performed to assess the reliability of activation patterns generated by two language mapping paradigms, namely a verb generation task and passive listening task. Results from a finger-tapping task are also presented. The paradigms generate reliable and robust signal changes, enabling both the lateralisation of language and localisation of expressive and receptive language cortex. The fMRI results are meaningful at the group and individual level and can be recommended for language mapping in pre-surgical patients.


Levetiracetam-responding paroxysmal nonkinesigenic dyskinesia.
We report on a patient with 7-year history of short-lasting paroxysmal nonkinesigenic dyskinesia. The episodes occurred 100 to 125 times per day, lasted from 5 seconds to 3 minutes, and were not suppressed with sleeping, underlining the heterogeneity of phenomenology in paroxysmal dyskinesias. Neuroimaging studies showed calcifications in the basal ganglia, thalamus, brain stem, and subcortical and cerebellar regions. He was diagnosed with idiopathic hypoparathyroidism. After failure of valproate, he responded well to levetiracetam (1000 mg/d). This report revealed that intracerebral calcifications secondary to hypoparathyroidism could present as paroxysmal nonkinesigenic dyskinesia, and levetiracetam could be effective in this particular entity.


Race-ethnicity and cerebral small vessel disease--comparison between Chinese and White populations.
Studies in stroke patients suggest that lacunar stroke and intracerebral hemorrhage might be more common in Chinese than Whites. We hypothesized that other manifestations of subclinical cerebral small vessel disease, namely white matter hyperintensities (WMH), lacunes, and microbleeds, are also more common in Chinese than Whites. We compared the community prevalence of these lesions between Han Chinese and White Australians. Magnetic resonance imaging (1·5-Tesla) was performed on participants of the Shanghai Aging Study (n = 321, mean age 69 ± 6 years) and Tasmanian Study of Cognition and Gait (n = 397, mean age 72 ± 7 years). A single-rater recorded measures of WMH, lacunes, and microbleeds. We compared lesion prevalence between age- and gender-matched subgroups from the two cohorts. Among all subjects (n = 718), we performed multivariable logistic regression to examine if race-ethnicity was independently associated with these lesions. Among age- and gender-matched subjects, confluent WMH were significantly more prevalent in Chinese (38·5%) than Whites (28·4%; P = 0·01). There was no difference in the prevalence of lacunes (Chinese 29·1% vs. Whites 29·5%, P = 0·93) and microbleeds (Chinese 10·1% vs. 9·0%, P = 0·67) between Chinese and Whites. In multivariable logistic regression, Chinese ethnicity was associated with confluent WMH (odds ratio 1·7, 95% confidence interval 1·1-2·6, P = 0·01), but no differences were seen for lacunes and microbleeds. The association between Chinese ethnicity with confluent WMH became insignificant when subjects with history of stroke were excluded. In this population-based cross-national comparison, Han Chinese had a higher prevalence of confluent WMH than White Australians, but had a similar prevalence of lacunes and microbleeds.


Hypoxia Up-Regulates Galectin-3 in Mammary Tumor Progression and Metastasis.
The tumor microenvironment encompasses several stressful conditions for cancer cells such as hypoxia, oxidative stress and pH alterations. Galectin-3, a well-studied member of the beta-galactoside-binding animal family of lectins has been implicated in multiple steps of metastasis as cell-cell and cell-ECM adhesion, promotion of angiogenesis, cell proliferation and resistance to apoptosis. However, both its aberrantly up- and down-regulated expression was observed in several types of cancer. Thus, the mechanisms that regulate galectin-3 expression in neoplastic settings are not clear. In order to demonstrate the putative role of hypoxia in regulating galectin-3 expression in canine mammary tumors (CMT), in vitro and in vivo studies were performed. In malignant CMT cells, hypoxia was observed to induce expression of galectin-3, a phenomenon that was almost completely prevented by catalase treatment of CMT-U27 cells. Increased galectin-3 expression was confirmed at the mRNA level. Under hypoxic conditions the expression of galectin-3 shifts from a predominant nuclear location to cytoplasmic and membrane expressions. In in vivo studies, galectin-3 was overexpressed in hypoxic areas of primary tumors and well-established metastases. Tumor hypoxia thus up-regulates the expression of galectin-3, which may in turn increase tumor aggressiveness.


Expression, purification and some properties of fluorescent chimeras of human small heat shock proteins.
Small heat shock proteins (sHsp) are ubiquitously expressed in all human tissues and have an important housekeeping role in preventing the accumulation of aggregates of improperly folded or denatured proteins. They also participate in the regulation of the cytoskeleton, proliferation, apoptosis and many other vital processes. Fluorescent chimeras composed of sHsp and enhanced fluorescent proteins have been used to determine the intracellular locations of small heat shock proteins and to analyse the hetero-oligomeric complexes formed by different sHsp. However, the biochemical properties and chaperone-like activities of these chimeras have not been investigated. To determine the properties of these chimeras, we fused enhanced yellow and cyan fluorescent proteins (EYFP and ECFP) to the N-termini of four ubiquitously expressed human small heat shock proteins: HspB1, HspB5, HspB6, and HspB8. The eight fluorescent chimeras of small heat shock proteins and isolated fluorescent proteins were expressed in Escherichia coli. The chimeric proteins were isolated and purified via ammonium sulphate fractionation, ion exchange and size-exclusion chromatography. This method provided 20-100 mg of fluorescent chimeras from 1L of bacterial culture. The spectral properties of the chimeras were similar to those of the isolated fluorescent proteins. The fusion of fluorescent proteins to HspB6 and HspB8, which typically form dimers, did not affect their quaternary structures. Oligomers of the fluorescent chimeras of HspB1 and HspB5 were less stable and contained fewer subunits than oligomers formed by the wild-type proteins. Fusion with EYFP decreased the chaperone-like activity of HspB5 and HspB6 whereas fusion with ECFP increased chaperone-like activity. All fluorescent chimeras of HspB1 and HspB8 had higher chaperone-like activity than the wild-type proteins. Thus, although fluorescent chimeras are useful for many purposes, the fluorescent proteins used to form these chimeras may affect certain important properties of sHsp.


Self-harm in older adults: systematic review.
Self-harm is a major public health concern. Increasing ageing populations and high risk of suicide in later life highlight the importance of identification of the particular characteristics of self-harm in older adults.AimTo systematically review characteristics of self-harm in older adults. A comprehensive search for primary studies on self-harm in older adults was conducted in e-databases (AgeLine, CINAHL, PsycINFO, MEDLINE, Web of Science) from their inception to February 2018. Using predefined criteria, articles were independently screened and assessed for methodological quality. Data were synthesised following a narrative approach. A patient advisory group advised on the design, conduct and interpretation of findings. A total of 40 articles (n = 62 755 older adults) were included. Yearly self-harm rates were 19 to 65 per 100 000 people. Self-poisoning was the most commonly reported method. Comorbid physical problems were common. Increased risk repetition was reported among older adults with self-harm history and previous and current psychiatric treatment. Loss of control, increased loneliness and perceived burdensome ageing were reported self-harm motivations. Self-harm in older adults has distinct characteristics that should be explored to improve management and care. Although risk of further self-harm and suicide is high in all age cohorts, risk of suicide is higher in older adults. Given the frequent contact with health services, an opportunity exists for detection and prevention of self-harm and suicide in this population. These results are limited to research in hospital-based settings and community-based studies are needed to fully understand self-harm among older adults.Declaration of interestNone.


A qualitative study of patients' perceptions of the utility of patient-reported outcome measures of symptoms in primary care clinics.
Sleep, pain, anxiety, depression, and low energy/fatigue (SPADE pentad) symptoms are common, but often unrecognized and undertreated in primary care. In an effort to improve symptom outcomes, primary care clinics are integrating patient-reported outcome measures (PROs), such as the Patient-Reported Outcome Measurement Information System (PROMIS), into practice. Whether patients with SPADE symptoms perceive these measures as useful is unknown. The purpose of this qualitative study was to explore patients' perceptions of the utility of symptom-based PROs in primary care. As part of a mixed-methods study, 23 patients (age 24-77 years) with one or more SPADE symptoms participated in one-on-one interviews about the use, implementation and visual display of PROMIS. All interviews were audio-recorded, transcribed, and analyzed using thematic analysis. Five themes emerged: (1) PROs may foster communication about symptoms; (2) data from PROs may prompt clinical actions; (3) the visual display of symptom scores could be useful for patients and providers, though modifications may enhance interpretation; (4) implementation may vary according to patients' perception of PRO features (e.g., length); and (5) PROs may be useful, but only to the extent that they are valued, prioritized, and used. According to patients, the use of PROs to measure symptoms in primary care clinics has the potential to be useful. However, patients are reluctant to complete PROs if they perceive that clinicians do not use the measures to improve care. Barriers to implementation in primary care (e.g., duration of visit) should be addressed to enhance the utility of PROs. Clinical trial registration ClinicalTrials.gov ID: NCT02383862.


Arterial stiffness evaluated by pulse wave velocity is not predictive of the improvement in hypertension after adrenal surgery for primary aldosteronism: A multicentre study from the French European Society of Hypertension Excellence Centres.
Predictive factors associated with normal blood pressure (BP) after unilateral adrenalectomy for primary aldosteronism (PA) are not clearly identified. To evaluate the predictive value of arterial stiffness before surgery on BP after surgery. During 2009-2013, 96 patients with PA due to unilateral adrenal adenoma who underwent surgery were enrolled in a multicentre open-label, prospective study. Aortic pulse wave velocity (PWV) was assessed before surgery. Patients underwent ambulatory blood pressure monitoring (ABPM) before surgery and 6 and 12months after surgery. Twenty-four h SBP/DBP values were compared in subjects with PWV<vs. ≥10m/s. The primary outcome was 24-hour ABPM<130/80mmHg 6 months after adrenalectomy. BP and PWV were available for 82 patients (mean age 49±12years). Mean 24-hour systolic/diastolic BP (SBP/DBP) values decreased from 144±15/91±9 before surgery to 131±15/84±11mmHg 6months after surgery. At 6months, mean 24-hour SBP did not differ significantly between high versus low PWV groups (SBP-0.8mmHg, 95% confidence interval-6.9 to 5.2, P=0.79). A total of 42.3% of women versus 20.0% of men had 24-hour SBP/DBP<130/80mmHg at 6months (P=0.07) and 57.9% vs. 23.8% at 12months (P=0.03). Higher SBP/DBP was recorded for men versus women after 6months (P=0.01/0.001) and 1year (P=0.04/0.05). Preoperative arterial stiffness does not predict a beneficial effect of adrenalectomy on BP values.


Increased oxidative/nitrosative stress markers measured non- invasively in patients with high 2,3,7,8-tetrachloro-dibenzo-p-dioxin plasma level.
2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) is a highly toxic persistent environmental contaminant, classified as a human carcinogen affecting any target organ. The mechanism of carcinogenesis by TCDD is unclear as TCDD shows a lack of direct genotoxicity. Experimental studies also support the role of oxidative stress in TCDD neurotoxicity and vascular dysfunction. The aim was to investigate markers of oxidative/nitrosative stress and inflammation using non-invasive methods in subjects who got ill due to severe occupational exposure to TCDD in the years 1965-1968. In 11 TCDD-exposed patients, and 16 controls, the analysis of following oxidative products of lipids, proteins and nucleic acids in plasma, urine and exhaled breath condensate (EBC) was performed: 8-iso-prostaglandin F2α (8-isoprostane), 4-hydroxy-trans-2-nonenale (HNE), malondialdehyde (MDA), o-tyrosine (o-Tyr), 8-hydroxyguanosine (8-OHG), 8-hydroxy-2´-deoxy-guanosine (8-OHdG), 5-hydroxymethyluracil (5-OHMeU). In addition, nitric-oxide-tyrosine (NO-Tyr) and leukotriene (LT) B4, C4, D4, and E4 were detected by liquid chromatography-mass spectrometry/mass spectrometry (LC-ESI-MS/MS). TCDD was measured by HRGC/HRMS, body lipid content by densitometry. Single-photon emission spectrometry (SPECT) of the brain was performed and compared with the findings of the patients in 2008. Mean TCDD plasma level in 2010 was 175 ± 162 pg/g lipids (population level about 2 pg/g), total TCDD content in the body 5.16 ± 4.62 mg. Reduction of cerebral blood flow in SPECT progressed in 8 patients, finding was stable in 2 subjects, and improvement occurred in 1 patient. In the EBC, 10 from 12 markers (all except LT D4 and LT E4), were significantly increased in the patients (p<0.05). In the urine, 7 markers were significantly higher than in the controls (p<0.05): 8-isoprostane, MDA, HNE, LT C4, LT E4, o-Tyr and NO-Tyr. In plasma, only NO-Tyr and 8-OHG were elevated (p<0.05). NO-Tyr was increased in all matrices in dioxin-exposed patients. EBC is not limited to lung disorders as the markers of oxidative stress and inflammation were elevated in EBC of patients with normal lung functions. TCDD-induced oxidative stress and inflammation markers can be detected non-invasively in the EBC and urine in the follow-up of the highly-exposed patients. Their prognostic value, however, needs to be elucidated.


Magnesium bioavailability from magnesium citrate and magnesium oxide.
This study compared magnesium oxide and magnesium citrate with respect to in vitro solubility and in vivo gastrointestinal absorbability. The solubility of 25 mmol magnesium citrate and magnesium oxide was examined in vitro in solutions containing varying amounts of hydrochloric acid (0-24.2 mEq) in 300 ml distilled water intended to mimic achlorhydric to peak acid secretory states. Magnesium oxide was virtually insoluble in water and only 43% soluble in simulated peak acid secretion (24.2 mEq hydrochloric acid/300 ml). Magnesium citrate had high solubility even in water (55%) and was substantially more soluble than magnesium oxide in all states of acid secretion. Reprecipitation of magnesium citrate and magnesium oxide did not occur when the filtrates from the solubility studies were titrated to pH 6 and 7 to stimulate pancreatic bicarbonate secretion. Approximately 65% of magnesium citrate was complexed as soluble magnesium citrate, whereas magnesium complexation was not present in the magnesium oxide system. Magnesium absorption from the two magnesium salts was measured in vivo in normal volunteers by assessing the rise in urinary magnesium following oral magnesium load. The increment in urinary magnesium following magnesium citrate load (25 mmol) was significantly higher than that obtained from magnesium oxide load (during 4 hours post-load, 0.22 vs 0.006 mg/mg creatinine, p less than 0.05; during second 2 hours post-load, 0.035 vs 0.008 mg/mg creatinine, p less than 0.05). Thus, magnesium citrate was more soluble and bioavailable than magnesium oxide.


The possession of three novel coli surface antigens by enterotoxigenic Escherichia coli strains positive for the putative colonization factor PCF8775.
A possible colonization factor, E8775, has previously been described for enterotoxigenic Escherichia coli strains of serogroups O25, O115 and O167. Re-examination of these strains by immunodiffusion has revealed that the antigenic nature of this factor, renamed putative colonization factor (PCF) 8775, is more complex than was first thought. All the strains of serogroup O25 tested possessed two antigenic components, termed CS4 and CS6, and gave mannose-resistant haemagglutination (MRHA) of human and bovine erythrocytes. Spontaneous variants possessing CS6 only did not give MRHA. Strains of serogroups O115 and O167 had the antigenic components CS5 and CS6, and gave MRHA of human, bovine and guinea-pig erythrocytes. Using immune electron microscopy, the components CS4 and CS5 were identified as fimbriae. No fimbriae were associated with CS6.