Differential neuroprotective effects of a minocycline-based drug cocktail in transient and permanent focal cerebral ischemia.
Considering that several pathways leading to cell death are activated in cerebral ischemia, we tested in mouse models of transient and permanent ischemia a drug cocktail aiming at distinct pharmacological targets during the evolution of ischemic injury. It consists of minocycline--an antibiotic with anti-inflammatory properties, riluzole--a glutamate antagonist, and nimodipine--a blocker of voltage-gated calcium channels. Administered 2 h after transient or permanent MCAO, it significantly decreased the size of infarction, by approximately 65% after transient and approximately 35% after permanent ischemia and markedly improve clinical recovery of mice. In both experimental models a three-drug cocktail achieved significantly more efficient neuroprotection than any of the components tested alone. However, some interesting observation emerged from the single-drug studies. Treatment with minocycline alone was efficient in both experimental models while treatment with glutamate antagonist riluzole conferred neuroprotection only after transient MCAO. Immunohistochemical analysis following three-drug treatment revealed reduced microglia/macrophages and caspase-3 activation as well as preserved GFAP immunoreactivity following transient ischemia. No detectable differences in the levels of Mac-2, GFAP and caspase-3 immunoreactivities were observed 72 h after permanent MCAO. These marked differences in the brain tissue responses to ischemic injury and to treatments suggest that different pathological mechanisms may be operating in transient and permanent ischemia. However, the three-drug cocktail exerted significant neuroprotection in both experimental models thus demonstrating that simultaneous targeting of several pathophysiological pathways involved in the evolution of ischemic injury may represent a rational therapeutic strategy for stroke.


Recombination and nucleotide diversity in the sex chromosomal pseudoautosomal region of the emu, Dromaius novaehollandiae.
Pseudoautosomal regions (PARs) shared by avian Z and W sex chromosomes are typically small homologous regions within which recombination still occurs and are hypothesized to share the properties of autosomes. We capitalized on the unusual structure of the sex chromosomes of emus, Dromaius novaehollandiae, which consist almost entirely of PAR shared by both sex chromosomes, to test this hypothesis. We compared recombination, linkage disequilibrium (LD), GC content, and nucleotide diversity between pseudoautosomal and autosomal loci derived from 11 emu bacterial artificial chromosome (BAC) clones that were mapped to chromosomes by fluorescent in situ hybridization. Nucleotide diversity (pi = 4N(e)mu) was not significantly lower in pseudoautosomal loci (14 loci, 1.9 +/- 2.4 x 10(-3)) than autosomal loci (8 loci, 4.2 +/- 6.1 x 10(-3)). By contrast, recombination per site within BAC-end sequences (rho = 4Nc) (pseudoautosomal, 3.9 +/- 6.9 x 10(-2); autosomal, 2.3 +/- 3.7 x 10(-2)) was higher and average LD (D') (pseudoautosomal, 4.2 +/- 0.2 x 10(-1); autosomal, 4.7 +/- 0.5 x 10(-1)) slightly lower in pseudoautosomal sequences. We also report evidence of deviation from a simple neutral model in the PAR and in autosomal loci, possibly caused by departures from demographic equilibrium, such as population growth. This study provides a snapshot of the population genetics of avian sex chromosomes at an early stage of differentiation.


A selection of forest condition indicators for monitoring.
Regional monitoring and assessments of the health of forested ecosystems require indicators of forest conditions and environmental stresses. Indicator selections depend on objectives and the strategy for data collection and analysis. This paper recommends a set of indicators to signal changes in forest ecosystem distribution, productivity, and disturbance. Additional measurements are recommended to help ascribe those changes to climate variation, atmospheric deposition, and land use patterns. The rationale for these indicators is discussed in the context of a sequential monitoring and assessment strategy.


Rsv1-mediated resistance against soybean mosaic virus-N is hypersensitive response-independent at inoculation site, but has the potential to initiate a hypersensitive response-like mechanism.
Rsv1, a single dominant gene in soybean PI 96983, confers resistance to most strains of Soybean mosaic virus (SMV), including strain G2. The phenotypic response includes the lack of symptoms and virus recovery from mechanically inoculated leaves. To study the resistance mechanism, SMV-N (an isolate of strain G2) was introduced into PI 96983 by grafting. Hypersensitive response (HR)-like lesions occurred on the stems, petioles, and leaf veins, and virus was recovered from these lesions. The response demonstrated the cytological and histological characteristics of HR as well as elevated transcription of a soybean salicylic acid-inducible, pathogenesis-related (PR-1) protein gene. Mechanical inoculation of PI 96983 primary leaves with a high level of SMV-N virions caused no symptoms or up regulation of the PR-1 protein gene transcript. Furthermore, inoculation with infectious viral RNA did not alter the resistance phenotype. The data suggest that interaction of SMV-N with Rsv1 has the potential to induce an HR-like defense reaction. Rsv1-mediated resistance in the inoculated leaf, however, is HR-independent and operates after virion disassembly.


Injectable biocompatible and biodegradable pH-responsive hollow particle gels containing poly(acrylic acid): the effect of copolymer composition on gel properties.
The potential of various pH-responsive alkyl (meth)acrylate ester- and (meth)acrylic acid-based copolymers, including poly(methyl methacrylate-co-acrylic acid) (PMMA-AA) and poly(n-butyl acrylate-co-methacrylic acid) (PBA-MAA), to form pH-sensitive biocompatible and biodegradable hollow particle gel scaffolds for use in non-load-bearing soft tissue regeneration have been explored. The optimal copolymer design criteria for preparation of these materials have been established. Physical gels which are both pH- and redox-sensitive were formed only from PMMA-AA copolymers. MMA is the optimal hydrophobic monomer, whereas the use of various COOH-containing monomers, e.g., MAA and AA, will always induce a pH-triggered physical gelation. The PMMA-AA gels were prepared at physiological pH range from concentrated dispersions of swollen, hollow, polymer-based particles cross-linked with either cystamine (CYS) or 3,3'-dithiodipropionic acid dihydrazide (DTP). A linear relationship between particle swelling ratios, gel elasticity, and ductility was observed. The PMMA-AA gels with lower AA contents feature lower swelling ratios, mechanical strengths, and ductilities. Increasing the swelling ratio (e.g., through increasing AA content) decreased the intraparticle elasticity; however, intershell contact and gel elasticity were found to increase. The mechanical properties and performance of the gels were tuneable upon varying the copolymers' compositions and the structure of the cross-linker. Compared to PMMA-AA/CYS, the PMMA-AA/DTP gels were more elastic and ductile. The biodegradability and cytotoxicity of the new hollow particle gels were tested for the first time and related to their composition, mechanical properties, and morphology. The new PMMA-AA/CYS and PMMA-AA/DTP gels have shown good biocompatibility, biodegradability, strength, and interconnected porosity and therefore have good potential as a tissue repair agent.


Use of behaviour change techniques in lifestyle change interventions for people with intellectual disabilities: A systematic review.
People with intellectual disabilities (ID) experience more health problems and have different lifestyle change needs, compared with the general population. To improve lifestyle change interventions for people with ID, this review examined how behaviour change techniques (BCTs) were applied in interventions aimed at physical activity, nutrition or physical activity and nutrition, and described their quality. After a broad search and detailed selection process, 45 studies were included in the review. For coding BCTs, the CALO-RE taxonomy was used. To assess the quality of the interventions, the Physiotherapy Evidence Database (PEDro) scale was used. Extracted data included general study characteristics and intervention characteristics. All interventions used BCTs, although theory-driven BCTs were rarely used. The most frequently used BCTs were 'provide information on consequences of behaviour in general' and 'plan social support/social change'. Most studies were of low quality and a theoretical framework was often missing. This review shows that BCTs are frequently applied in lifestyle change interventions. To further improve effectiveness, these lifestyle change interventions could benefit from using a theoretical framework, a detailed intervention description and an appropriate and reliable intervention design which is tailored to people with ID.


Physician variation in diagnostic testing for low back pain. Who you see is what you get.
This study examined patterns of diagnostic test use for patients with low back pain. Three specific questions were addressed: 1) What tests do physicians recommend for patients with 3 common types of low back pain? 2) Do physicians in various specialties differ in the tests they would order? and 3) How appropriate are physicians' choices of tests, based on current medical knowledge and expert recommendations? A stratified national random sample of 2,604 physicians in 8 specialties was mailed questionnaires asking about the tests they would order for hypothetical patients with acute back pain, sciatica, or chronic low back pain. Physicians were also asked which procedures they generally used to evaluate suspected lumbar nerve root compression. These responses were compared with guidelines that have been suggested by the Quebec Task Force on Spinal Disorders, based on comprehensive evaluation of the scientific literature. Approximately 1,100 physicians responded to the survey (43% response rate). Magnetic resonance imaging was the most frequently used procedure for evaluating suspected lumbar nerve root compression, although a majority of neurosurgeons would still use myelography. Neurosurgeons and neurologists were twice as likely as other specialists to order an imaging study for patients with acute nonradiating pain or chronic back pain. Physiatrists and neurologists were more than 3 times as likely as other specialists to order electromyograms for acute back pain with sciatica or chronic back pain. Rheumatologists were almost twice as likely as other specialists to order laboratory tests for both acute and chronic back pain. The reported use of imaging and electrodiagnostic tests was generally premature and more extensive than that recommended by the Quebec Task Force. There is little consensus, either within or among specialties, on the use of diagnostic tests for patients with back pain. Thus, the diagnostic evaluation depends heavily on the individual physician and his or her specialty, and not just the patient's symptoms and findings. Furthermore, many physicians may be ordering imaging studies too early and for patients who do not have the appropriate clinical indications. These results suggest a need for additional clinical guidelines as well as better adherence to existing guidelines.


Microwave-assisted group-transfer cyclization of organotellurium compounds.
Primary- and secondary-alkyl aryl tellurides, prepared by arenetellurolate ring-opening of epoxides/ O-allylation, were found to undergo rapid (3-10 min) group-transfer cyclization to afford tetrahydrofuran derivatives in 60-74% yield when heated in a microwave cavity at 250 degrees C in ethylene glycol or at 180 degrees C in water. To go to completion, similar transformations had previously required extended photolysis in refluxing benzene containing a substantial amount of hexabutylditin. The only drawback of the microwave-assisted process was the loss in diastereoselectivity which is a consequence of the higher reaction temperature. Substitution in the Te-aryl moiety of the secondary-alkyl aryl tellurides (4-OMe, 4-H, 4-CF(3)) did not affect the outcome of the group-transfer reaction in ethylene glycol. However, at lower temperature, using water as a solvent, the CF(3) derivative failed to react. The microwave-assisted group-transfer cyclization was extended to benzylic but not to primary- and secondary-alkyl phenyl selenides.


Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice.
Humanin (HN), an endogenous antiapoptotic peptide, has previously been shown to protect against Alzheimer's disease and a variety of cellular insults. We evaluated the effects of a potent analog of HN (HNG) in an in vivo murine model of myocardial ischemia and reperfusion. Male C57BL6/J mice (8 to 10 week old) were subjected to 45 minutes of left coronary artery occlusion followed by a 24-hour reperfusion. HNG or vehicle was administered IP 1 hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hours using Evans Blue dye and 2-3-5-triphenyl tetrazolium chloride staining. Left ventricular function was evaluated at 1 week after ischemia using high-resolution, 2D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0 to 24 hours) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. HNG reduced infarct size relative to the area-at-risk in a dose-dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced left ventricular ejection fraction and preserved postischemic left ventricular dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased phosphorylation of AMPK and phosphorylation of endothelial nitric oxide synthase in the heart and attenuated Bcl-2-associated X protein and B-cell lymphoma-2 levels following myocardial ischemia and reperfusion. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. These data show that HNG provides cardioprotection in a mouse model of myocardial ischemia and reperfusion potentially through activation of AMPK-endothelial nitric oxide synthase-mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.


A Web-Based Intervention for Relatives of People Experiencing Psychosis or Bipolar Disorder: Design Study Using a User-Centered Approach.
Relatives of people experiencing bipolar mood episodes or psychosis face a multitude of challenges (eg, social isolation, limited coping strategies, and issues with maintaining relationships). Despite this, there is limited informational and emotional support for people who find themselves in supporting or caring roles. Digital technologies provide us with an opportunity to offer accessible tools, which can be used flexibly to provide evidence-based information and support, allowing relatives to build their understanding of mental health problems and learn from others who have similar experiences. However, to design tools that are useful to relatives, we first need to understand their needs. The aim of this study was to use a user-centered design approach to develop an accessible Web-based intervention, based on the Relatives Education And Coping Toolkit (REACT) booklet, to support the informational and emotional needs of relatives of people experiencing psychosis or bipolar disorder. We engaged relatives of people with experiences of bipolar disorder or psychosis in workshops to identify their needs and design requirements for developing a Web-based version of a paper-based toolkit. We used a 2-phase qualitative approach to explore relatives' views on content, design, and functionalities, which are considered to be engaging and useful in a Web-based intervention. In phase 1, we consulted 24 relatives in 2 workshops to better understand their existing support infrastructure, their barriers for accessing support, unmet needs, and relatives' views on online support. On the basis of the results of these workshops, we developed a set of design considerations to be explored in a smaller workshop. Workshop 3 then involved working with 2 digitally literate relatives to design a usable and acceptable interface for our Web-based toolkit. Finally, in phase 2, we conducted a heuristic evaluation to assess the usability of the toolkit. Our findings indicated that relatives require technologies that (1) they can place their trust in, particularly when discussing a highly sensitive topic, (2) enable learning from the lived experiences of others while retaining confidentiality, and (3) they can work through at their own pace in a personalized manner. Our study highlights the need for providing a trustworthy, supportive tool where relatives can engage with people who have similar experiences to their own. Our heuristic evaluation showed promise in terms of perceived usability of the REACT Web-based intervention. Through this work, we emphasize the need to involve stakeholders with various characteristics, including users with limited computer literacy or experience in online support.


The natural history of respiratory syncytial virus in a birth cohort: the influence of age and previous infection on reinfection and disease.
This study aimed to quantify the effect of age, time since last infection, and infection history on the rate of respiratory syncytial virus infection and the effect of age and infection history on the risk of respiratory syncytial virus disease. A birth cohort of 635 children in Kilifi, Kenya, was monitored for respiratory syncytial virus infections from January 31, 2002, to April 22, 2005. Predictors of infection were examined by Cox regression and disease risk by binomial regression. A total of 598 respiratory syncytial virus infections were identified (411 primary, 187 repeat), with 409 determined by antigen assay and 189 by antibody alone (using a "most pragmatic" serologic definition). The incidence decreased by 70% following a primary infection (adjusted hazard ratio = 0.30, 95% confidence interval: 0.21, 0.42; P < 0.001) and by 59% following a secondary infection (hazard ratio = 0.41, 95% confidence interval: 0.22, 0.73; P = 0.003), for a period lasting 6 months. Relative to the age group <6 months, all ages exhibited a higher incidence of infection. A lower risk of severe disease following infection was independently associated with increasing age (P < 0.001) but not reinfection. In conclusion, observed respiratory syncytial virus incidence was lowest in the first 6 months of life, immunity to reinfection was partial and short lived, and disease risk was age related.


The consultative work of occupational therapists working in municipal healthcare.
The work of occupational therapists (OTs) in municipal healthcare has become more consultative in recent years. The aim of this study is to explore the content of the OTs' consultative role in everyday activities in municipal healthcare. The study is based on data consisting of diary notes with additional reflections made by 23 OTs during three days. The data were subjected to content analysis. OTs are contacted via referrals (telephone calls or personal communication) to arrange consultations with patients, relatives, assistant staff, and colleagues. The OTs' consultative work consists of discussion, negotiation, information, or instruction, in relation to the advice and recommendations given. They also provide supervision and support to patients, relatives, and assistant staff. The advice and recommendations are evaluated. Thus, OTs' counselling consists of more than assessments and advice, as it also includes information, instruction, supervision, support, and evaluation. Further investigations are necessary in order to understand the competence that is needed and used in the consultative role of OTs in municipal healthcare. An implication for practice is that the healthcare managers need to support the OTs' possibility to provide supervision and support, especially in relation to assistant staff as they are responsible for everyday rehabilitation.


In vitro downregulated hypoxia transcriptome is associated with poor prognosis in breast cancer.
Hypoxia is a characteristic of breast tumours indicating poor prognosis. Based on the assumption that those genes which are up-regulated under hypoxia in cell-lines are expected to be predictors of poor prognosis in clinical data, many signatures of poor prognosis were identified. However, it was observed that cell line data do not always concur with clinical data, and therefore conclusions from cell line analysis should be considered with caution. As many transcriptomic cell-line datasets from hypoxia related contexts are available, integrative approaches which investigate these datasets collectively, while not ignoring clinical data, are required. We analyse sixteen heterogeneous breast cancer cell-line transcriptomic datasets in hypoxia-related conditions collectively by employing the unique capabilities of the method, UNCLES, which integrates clustering results from multiple datasets and can address questions that cannot be answered by existing methods. This has been demonstrated by comparison with the state-of-the-art iCluster method. From this collection of genome-wide datasets include 15,588 genes, UNCLES identified a relatively high number of genes (>1000 overall) which are consistently co-regulated over all of the datasets, and some of which are still poorly understood and represent new potential HIF targets, such as RSBN1 and KIAA0195. Two main, anti-correlated, clusters were identified; the first is enriched with MYC targets participating in growth and proliferation, while the other is enriched with HIF targets directly participating in the hypoxia response. Surprisingly, in six clinical datasets, some sub-clusters of growth genes are found consistently positively correlated with hypoxia response genes, unlike the observation in cell lines. Moreover, the ability to predict bad prognosis by a combined signature of one sub-cluster of growth genes and one sub-cluster of hypoxia-induced genes appears to be comparable and perhaps greater than that of known hypoxia signatures. We present a clustering approach suitable to integrate data from diverse experimental set-ups. Its application to breast cancer cell line datasets reveals new hypoxia-regulated signatures of genes which behave differently when in vitro (cell-line) data is compared with in vivo (clinical) data, and are of a prognostic value comparable or exceeding the state-of-the-art hypoxia signatures.


Infrared Lorentz violation and slowly instantaneous electricity.
We study a modification of electromagnetism which violates Lorentz invariance at large distances. In this theory, electromagnetic waves are massive, but the static force between charged particles is Coulomb, not Yukawa. At very short distances the theory looks just like QED. But for distances larger than 1/m the massive dispersion relation of the waves can be appreciated, and the Coulomb force can be used to communicate faster than the speed of light. In fact, electrical signals are transmitted instantly, but take a time approximately 1/m to build up to full strength. After that, undamped oscillations of the electric field are set in and continue until they are dispersed by the arrival of the Lorentz-obeying part of the transmission. Experimental constraints imply that the Compton wavelength of the photon may be as small as 6000 km. This bound is weaker than for a Lorentz-invariant mass, essentially because the Coulomb constraint is removed.


Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study.
In light of increasing cannabis use among pregnant women, the US Surgeon General recently issued an advisory against the use of marijuana during pregnancy. To evaluate whether cannabis use during pregnancy is associated with adverse outcomes among offspring. In this cross-sectional study, data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development Study, which recruited 11 875 children aged 9 to 11 years, as well as a parent or caregiver, from 22 sites across the United States between June 1, 2016, and October 15, 2018. Prenatal cannabis exposure prior to and after maternal knowledge of pregnancy. Symptoms of psychopathology in children (ie, psychotic-like experiences [PLEs] and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index, and brain structure (ie, total intracranial volume, white matter volume, and gray matter volume). Covariates included familial (eg, income and familial psychopathology), pregnancy (eg, prenatal exposure to alcohol and tobacco), and child (eg, substance use) variables. Among 11 489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal cannabis exposure data, 655 (5.7%) were exposed to cannabis prenatally. Relative to no exposure, cannabis exposure only before (413 [3.6%]) and after (242 [2.1%]) maternal knowledge of pregnancy were associated with greater offspring psychopathology characteristics (ie, PLEs and internalizing, externalizing, attention, thought and, social problems), sleep problems, and body mass index, as well as lower cognition and gray matter volume (all |β| > 0.02; all false discovery rate [FDR]-corrected P < .03). Only exposure after knowledge of pregnancy was associated with lower birth weight as well as total intracranial volume and white matter volumes relative to no exposure and exposure only before knowledge (all |β| > 0.02; all FDR-corrected P < .04). When including potentially confounding covariates, exposure after maternal knowledge of pregnancy remained associated with greater PLEs and externalizing, attention, thought, and social problems (all β > 0.02; FDR-corrected P < .02). Exposure only prior to maternal knowledge of pregnancy did not differ from no exposure on any outcomes when considering potentially confounding variables (all |β| < 0.02; FDR-corrected P > .70). This study suggests that prenatal cannabis exposure and its correlated factors are associated with greater risk for psychopathology during middle childhood. Cannabis use during pregnancy should be discouraged.


Relaxing the Molecular Clock to Different Degrees for Different Substitution Types.
Rates of molecular evolution can vary over time. Diverse statistical techniques for divergence time estimation have been developed to accommodate this variation. These typically require that all sequence (or codon) positions at a locus change independently of one another. They also generally assume that the rates of different types of nucleotide substitutions vary across a phylogeny in the same way. This permits divergence time estimation procedures to employ an instantaneous rate matrix with relative rates that do not differ among branches. However, previous studies have suggested that some substitution types (e.g., CpG to TpG changes in mammals) are more clock-like than others. As has been previously noted, this is biologically plausible given the mutational mechanism of CpG to TpG changes. Through stochastic mapping of sequence histories from context-independent substitution models, our approach allows for context-dependent nucleotide substitutions to change their relative rates over time. We apply our approach to the analysis of a 0.15 Mb intergenic region from eight primates. In accord with previous findings, we find comparatively little rate variation over time for CpG to TpG substitutions but we find more for other substitution types. We conclude by discussing the limitations and prospects of our approach.


De novo mutations in regulatory elements in neurodevelopmental disorders.
We previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.


TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK.
Toll-like receptors (TLRs) play an important role in immune responses to pathogens by transducing signals in innate immune cells in response to microbial products. TLRs are also expressed on B cells, and TLR signaling in B cells contributes to antibody-mediated immunity and autoimmunity. The SYK tyrosine kinase is essential for signaling from the B cell antigen receptor (BCR), and thus for antibody responses. Surprisingly, we find that it is also required for B cell survival, proliferation, and cytokine secretion in response to signaling through several TLRs. We show that treatment of B cells with lipopolysaccharide, the ligand for TLR4, results in SYK activation and that this is dependent on the BCR. Furthermore, we show that B cells lacking the BCR are also defective in TLR-induced B cell activation. Our results demonstrate that TLR4 signals through two distinct pathways, one via the BCR leading to activation of SYK, ERK, and AKT and the other through MYD88 leading to activation of NF-κB.


Self-management of diabetes in children and young adults using technology and smartphone applications.
Treatment compliance and adherence are often a challenge in patients with type 1 diabetes, particularly for adolescent and young adult patients. With the availability of the internet and smart phone applications (apps) there is a hope that such technology could provide a means to encourage treatment adherence in this group of patients. This review focuses on whether telemedicine and smartphone technology in diabetes can influence self-management in young people with diabetes. A large number of smartphone apps are targeted at people with diabetes, but a limited number of well designed evaluation studies have been performed. As our review shows, the evidence base for efficacy of most of these applications is minimal and improvement in hard outcomes such as HbA1c and complication development is largely lacking.


Visceral metastases and prostate cancer treatment: 'die hard,' 'tough neighborhoods,' or 'evil humors'?
Men with metastatic castration-resistant prostate cancer have multiple treatment options, and the expanding palate of available therapies renders careful patient selection imperative. Men with visceral (especially hepatic) metastases have a particularly poor prognosis, regardless of the treatment selected. Retrospective analyses of datasets from large phase III randomized trials showed that men with visceral metastases appear to derive clinical benefit from second-generation antiandrogens as well as from docetaxel chemotherapy, but not from immunotherapy. The mechanistic underpinnings of these observations are currently not clear, but could involve factors that are intrinsic to the tumor cell, the tumor microenvironment, and/or systemic factors. Regardless of the underlying mechanism(s), a better understanding of the basic biology of visceral vs bone metastases will be critical in improving prostate cancer treatment in the setting of advanced disease.


Gastric carcinogenesis and the cancer stem cell hypothesis.
Normal stem cells (NSCs) are reported to exist in most tissues, including the brain, bone marrow, and probably the gastrointestinal tract. In the latter case, they are thought to possess both the self-renewal capacity and asymmetrical division capacity to generate progenitor cells which differentiate into epithelial cells. NSCs in the normal gastric mucosa are thought to be present in the proliferative zone of the neck/isthmus region, and to undergo a complex bipolar migration from the neck/isthmus region either upward or downward, becoming differentiated normal epithelial cells. NSCs in human gastric mucosa are difficult to identify due to the current lack of a useful marker. A precise definition of cancer stem cells (CSCs) is still under discussion. CSCs are generally defined as malignant cells with NSC capacity. However, many studies of CSCs have demonstrated their rapid growth and high metastatic potential, while NSCs are thought to be slow-growing and self-renewing, and to lack functional capacities such as cell migration and attachment. Recent evidence suggests the existence of CSCs in a wide variety of solid tumors. In this review, we will discuss the existence and cell biology of gastric NSCs and CSCs. We will also discuss whether gastric CSCs originate as organ-specific stem cells or as bone marrow-derived cells (BMDCs). Under certain conditions, the local microenvironment may promote the development of gastric cancer. Thus, Helicobacter pylori infection and the accompanying chronic inflammatory processes will supply critical initiators inducing cell growth and the tissue repair response, leading to carcinogenesis. This mechanism will be discussed in light of stem cell research. Progress in stem cell research in the gastric field is still limited to experimental animal models. However, recent studies should enhance our understanding of human cancer biology, and provide novel tools for the treatment of incurable gastric cancer.


Aqueous synthesis of zinc blende CdTe/CdS magic-core/thick-shell tetrahedral-shaped nanocrystals with emission tunable to near-infrared.
We demonstrate the synthesis of near-IR-emitting zinc blende CdTe/CdS tetrahedral-shaped nanocrystals with a magic-sized (approximately 0.8 nm radius) CdTe core and a thick CdS shell (up to 5 nm). These high-quality water-soluble nanocrystals were obtained by a simple but reliable aqueous method at low temperature. During the growth of the shell over the magic core, the core/shell nanocrystals change from type I to type II, as revealed by their enormous photoluminescence (PL) emission peak shift (from 480 to 820 nm) and significant increase in PL lifetime (from approximately 1 to approximately 245 ns). These thick-shell nanocrystals have a high PL quantum yield, high photostability, compact size (hydrodynamic diameter less than 11.0 nm), and reduced blinking behavior. The magic-core/thick-shell nanocrystals may represent an important step toward the synthesis and application of next-generation colloidal nanocrystals from solar cell conversion to intracellular imaging.


The CHRNA3 rs578776 Variant is Associated with an Intrinsic Reward Sensitivity Deficit in Smokers.
A compromised brain reward system has been postulated as a key feature of drug dependence. We examined whether several polymorphisms of genes found to regulate nicotinic acetylcholine receptor (nAChR) and dopamine expression were related to an intrinsic reward sensitivity (IRS) deficit we previously identified among a subgroup of smokers using event-related potentials (ERPs). We examined genetic polymorphisms within the CHRNA5-A3-B4 gene cluster (CHRNA3 rs578776, CHRNA5 rs16969968, LOC123688 rs8034191, and CHRNA3 rs1051730), the ANKK1 gene (rs1800497), and the D2 dopamine receptor gene (DRD2 rs1079597, DRD2 rs1799732) from 104 smokers of European ancestry in a smoking cessation trial. Prior to treatment, we recorded ERPs evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related pictures. Smokers were assigned to two groups (IRS+/IRS-) based on the amplitude of the late positive potential (LPP) component to the pictures, a neural marker of motivational salience. Smokers (n = 42) with blunted brain responses to intrinsically rewarding (pleasant) pictures and enhanced responses to cigarette pictures were assigned to the IRS- group, while smokers (n = 62) with the opposite pattern of LPP responding were assigned to the IRS+ group. Carriers of the protective minor T allele (T/T, C/T) of the CHRNA3 rs578776 were less likely to be members of the IRS- group than those homozygous for the at-risk C allele (C/C). The CHRNA3 rs578776 polymorphism did not differ on questionnaires of nicotine dependence, depressed mood, or trait affective disposition and did not predict abstinence at 6 months after the quit date. These results suggest that polymorphisms of genes influencing nAChR expression are related to an endophenotype of reward sensitivity in smokers.


Barriers to mental health treatment: results from the WHO World Mental Health surveys.
To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders. Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 63,678) and analyzed at different levels of clinical severity. Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders). Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.


Pleiotropic effects of cancer cells' secreted factors on human stromal (mesenchymal) stem cells.
Studying cancer tumors' microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor cells' secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs. Morphological changes were assessed using fluorescence microscopy. Changes in gene expression were assessed using Agilent microarray and qRT-PCR. GeneSpring 12.1 and DAVID tools were used for bioinformatic and signaling pathway analyses. Cell migration was assessed using a transwell migration system. SB-431542, PF-573228 and PD98059 were used to inhibit transforming growth factor β (TGFβ), focal adhesion kinase (FAK), and mitogen activated protein kinase kinase (MAPKK) pathways, respectively. Interleukin-1β (IL1β) was measured using ELISA. MSCs exposed to secreted factors present in conditioned media (CM) from FaDu, MDA-MB-231, PC-3 and NCI-H522, but not from MCF7 and HT-29, developed an elongated, spindle-shaped morphology with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (approximately 80% to 99%, and 55% to 88% inhibition, respectively), while inhibition of the TGFβ pathway was found to promote the pro-inflammatory response (approximately 3-fold increase). In addition, bioinformatics and pathway analysis of gene expression data from tumor cell lines combined with experimental validation revealed tumor-derived IL1β as one mediator of the pro-inflammatory phenotype observed in MSCs exposed to tumor CM. Our data revealed tumor-derived IL1β as one mediator of the pro-inflammatory response in MSCs exposed to tumor CM, which was found to be positively regulated by FAK and MAPK signaling and negatively regulated by TGFβ signaling. Thus, our data support a model where MSCs could promote cancer progression through becoming pro-inflammatory cells within the cancer stroma.


Acute Cerebral Venous Sinus Thrombosis: A Rare Complication of Primary Varicella Zoster Virus Infection.
Varicella-Zoster is a benign self limiting exanthematous illness in pediatric population which can rarely present with severe neurological manifestations such as cerebral venous thrombosis(CVT).We report the case of a 17-years old adolescent male with left hemiparesis, cranial nerve palsies associated with primary Varicella infection. MRI revealed cerebral venous thrombosis involving right transverse sinus, sigmoid sinus, internal jugular vein and infarct involving right cerebral hemisphere, Midbrain and Pons. The patient responded well to Acyclovir, cerebral decongestants and oral anticoagulant therapy.CVT is a rare but the most life threatening complication following primary Varicella infection and early diagnosis is essential for proper management of the patient.


Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study.
The common cold is one of the most frequent human illnesses and is responsible for substantial morbidity and economic loss. No consistently effective therapy for the common cold has been well documented, but evidence suggests that several possible mechanisms may make zinc an effective treatment. To test the efficacy of zinc gluconate lozenges in reducing the duration of symptoms caused by the common cold. Randomized, double-blind, placebo-controlled study. Outpatient department of a large tertiary care center. 100 employees of the Cleveland Clinic who developed symptoms of the common cold within 24 hours before enrollment. Patients in the zinc group (n = 50) received lozenges (one lozenge every 2 hours while awake) containing 13.3 mg of zinc from zinc gluconate as long as they had cold symptoms. Patients in the placebo group (n = 50) received similarly administered lozenges that contained 5% calcium lactate pentahydrate instead of zinc gluconate. Subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever (assessed by oral temperature). The time to complete resolution of symptoms was significantly shorter in the zinc group than in the placebo group (median, 4.4 days compared with 7.6 days; P < 0.001). The zinc group had significantly fewer days with coughing (median, 2.0 days compared with 4.5 days; P = 0.04), headache (2.0 days and 3.0 days; P = 0.02), hoarseness (2.0 days and 3.0 days; P = 0.02), nasal congestion (4.0 days and 6.0 days; P = 0.002), nasal drainage (4.0 days and 7.0 days; P < 0.001), and sore throat (1.0 day and 3.0 days; P < 0.001). The groups did not differ significantly in the resolution of fever, muscle ache, scratchy throat, or sneezing. More patients in the zinc group than in the placebo group had side effects (90% compared with 62%; P < 0.001), nausea (20% compared with 4%; P = 0.02), and bad-taste reactions (80% compared with 30%; P < 0.001), Zinc gluconate in the form and dosage studied significantly reduced the duration of symptoms of the common cold. The mechanism of action of this substance in treating the common cold remains unknown. Individual patients must decide whether the possible beneficial effects of zinc gluconate on cold symptoms outweigh the possible adverse effects.


Association of Craving and Depressive Symptoms in Ketamine-Dependent Patients Undergoing Withdrawal Treatment.
Ketamine has emerged as one of the major illicit substances worldwide. Craving, a primary symptom for addiction, is a key challenge for ketamine abusers attempting abstinence. A link between craving and negative affect has been suggested previously for other substances. We examined the relationship between craving and negative effect (depression and anxiety) in patients with ketamine dependence (KD) undergoing withdrawal treatment. We included 104 patients with KD (76 males and 28 females) who received inpatient treatment for ketamine withdrawal and assessed them by using Beck Depression Inventory (BDI), Beck Anxiety Inventory, and a visual analog scale (VAS; 0-100 mm) for ketamine craving on day 2 to 3 of admission. Fifty-nine (59%) and 38 (38.7%) of our patients reported moderate-to-severe depression and anxiety symptoms, respectively. Patients with greater cravings (ie, greater than the median VAS) reported spending more days on ketamine in the preceding month and displayed severer depressive symptoms than did those with lower cravings. VAS was significantly correlated with BDI scores after adjustment. Patients who stayed in the treatment longer (more than 2 weeks) experienced more cravings and depressive symptoms than those who did not. We observed a high prevalence of depression in patients with KD, particularly those with higher cravings. Patients with greater cravings and severer depression might require a longer duration of withdrawal treatment. This research provides intimal evidence for an association between depression and craving in patients with KD. Screening and management of depression are recommended for this population. (Am J Addict 2019;00:00-00).


Color-difference formula for evaluating color pairs with no separation: ΔENS.
All color-difference formulas are developed to evaluate color differences for pairs of stimuli with hairline separation. In printing applications, however, color differences are frequently judged between a pair of samples with no separation (NS) because they are printed adjacently on the same piece of paper. A new formula, ΔENS, has been developed for pairs of stimuli with NS. An experiment was conducted to investigate the effect of different color-difference magnitudes using sample pairs with NS. 1012 printed pairs with NS were prepared around 11 CIE recommended color centers. The pairs, representing four color-difference magnitudes of 1, 2, 4, and 8 CIELAB units were visually evaluated by a panel of 19 observers using the gray-scale method. Comparison of the present data based on pairs with NS, and previously generated data using pairs with hairline separation, showed a clear separation effect. A new color-difference equation for the NS viewing condition (ΔENS) is proposed by modifying the CIEDE2000 formula. The separation effect can be well described by the new formula. For a sample pair with NS, when the CIEDE2000 color difference is less than 9.1, a larger color difference leads to a larger lightness difference, but has no effect on the chromatic difference. When the CIEDE2000 color difference is greater than 9.1, the effect is the opposite. The new formula is recommended for future research to evaluate its performance in appropriate applications.


Murine developmental control genes.
Various strategies have been used to isolate genes that participate in the regulation of mouse development. Gene families that have been identified on the basis of their homology to motifs within Drosophila control genes or human transcription factor genes, namely homeobox (Hox), paired-box (Pax), and POU genes, can be compared with respect to gene organization, structure, and expression patterns. The functions of these genes can be analyzed molecularly in vitro and in vivo with the use of available mouse mutants or transgenic mice. In addition, it has been possible to generate gain- or loss-of-function mutations by random or targeted introduction of transgenes. Models derived from these studies can reveal the successive steps of developmental control on a genetic level.


Effect of the material properties on the crumpling of a thin sheet.
While simple at first glance, the dense packing of sheets is a complex phenomenon that depends on material parameters and the packing protocol. We study the effect of plasticity on the crumpling of sheets of different materials by performing isotropic compaction experiments on sheets of different sizes and elasto-plastic properties. First, we quantify the material properties using a dimensionless foldability index. Then, the compaction force required to crumple a sheet into a ball as well as the average number of layers inside the ball are measured. For each material, both quantities exhibit a power-law dependence on the diameter of the crumpled ball. We experimentally establish the power-law exponents and find that both depend nonlinearly on the foldability index. However the exponents that characterize the mechanical response and morphology of the crumpled materials are related linearly. A simple scaling argument explains this in terms of the buckling of the sheets, and recovers the relation between the crumpling force and the morphology of the crumpled structure. Our results suggest a new approach to tailor the mechanical response of the crumpled objects by carefully selecting their material properties.


Nurses helping nurses: development of internal specialists in long-term care.
1. Too often, expert assistance provided by psychiatrists and psychiatric nurse specialists to long-term care (LTC) providers of geriatric patients is short-lived and not effective in helping LTC staff deal with their patient's behavioral and psychological problems. 2. One of the main objectives of the study--and one that was found to have positive results--was to provide a mechanism by which LTC staff could develop their own expertise in the management of behaviorally difficult residents. 3. More collaborative efforts among nursing specialists, subspecialists, and generalists are needed to empower those who work in LTC to utilize the abilities and strengths inherent in their positions.


The Development of a Multilingual Tool for Facilitating the Primary-Specialty Care Interface in Low Resource Settings: the MSF Tele-Expertise System.
In 2009, Médecins Sans Frontières (MSF) started a pilot trial of store-and-forward telemedicine to support field workers. One network was operated in French and one in English; a third, Spanish network was brought into operation in 2012. The three telemedicine pilots were then combined to form a single multilingual tele-expertise system, tailored to support MSF field staff. We conducted a retrospective analysis of all telemedicine cases referred from April 2010 to March 2014. We also carried out a survey of all users in December 2013. A total of 1039 referrals were received from 41 countries, of which 89% were in English, 10% in French, and 1% in Spanish. The cases covered a very wide range of medical and surgical specialties. The median delay in providing the first specialist response to the referrer was 5.3 h (interquartile range 1.8, 16.4). The survey was sent to 294 referrers and 254 specialists. Of these, 224 were considered as active users (41%). Out of the 548 users, 163 (30%) answered the survey. The majority of referrers (79%) reported that the advice received via the system improved their management of the patient. The main concerns raised by referrers and specialists were the lack of support or promotion of system at headquarters' level and the lack of feedback about patient follow-up. Because of the size of the MSF organization, it is clear that there is potential for further organizational adoption.


Genetic variants of folate and methionine metabolism and PCNSL incidence in a German patient population.
Functional genetic polymorphisms involved in folate and methionine metabolism play an important role in both DNA synthesis and methylation, and affect the risk of various malignancies including lymphoproliferative disorders such as systemic non-Hodgkin's lymphoma. In a retrospective analysis of 185 immunocompetent patients with primary central nervous system lymphoma (PCNSL) and 212 population controls we therefore investigated eight genetic polymorphisms affecting methionine metabolism for potential association with the development of PCNSL. We observed underrepresentation of the G-allele of the methyltetrahydrofolate homocysteine S-methyltransferase (MTR) c.2756A > G (D919G) missense polymorphism among PCNSL patients (P = 0.045; odds ratio (OR) = 0.65; 0.43-0.99). Furthermore, for the methylenetetrahydrofolate reductase (MTHFR) c.1298A > C (E429A) polymorphism the mutated C-allele was found more frequently among PCNSL patients than among population controls (P = 0.026; OR = 1.57; 1.05-2.34). There were no associations of the other polymorphisms investigated (MTHFR c.677C > T, transcobalamin 2 (Tc2) c.776C > G, cystathionin beta-synthase (CBS) c.844_855ins68, reduced folate carrier-1 (RFC-1) c.80G > A, thymidylate synthase (TYMS) 28-bp repeat, and dihydrofolate reductase (DHFR) c.594 + 59del19 bp) and the presence of PCNSL. This analysis is the largest to date to evaluate associations between genetic variants of folate and methionine metabolism and PCNSL. Our results suggest the hypothesis that folate and methionine metabolism is relevant to susceptibility to PCNSL.


Smoking-cessation media campaigns and their effectiveness among socioeconomically advantaged and disadvantaged populations.
We examined whether the impact of televised smoking cessation ads differed by a population's education and income. We used longitudinal data from the Wisconsin Behavioral Health Survey, a statewide sample of 452 adult smokers who were interviewed in 2003 to 2004 and followed up 1 year later. Logistic regression was used to assess whether baseline recall of secondhand smoke ads and "keep trying to quit" ads was associated with quit attempts and smoking abstinence at 1 year. Interaction terms were used to assess whether these associations differed by the smokers' education and income levels. Overall, neither keep-trying-to-quit nor secondhand smoke ad recall was associated with quit attempts or smoking abstinence. Keep-trying-to-quit ads were significantly more effective in promoting quit attempts among higher-versus lower-educated populations. No differences were observed for secondhand smoke ads by the smokers' education or income levels. Some media campaign messages appear less effective in promoting quit attempts among less-educated populations compared with those who have more education. There is a need to develop media campaigns that are more effective with less-educated smokers.


Identification of vaccine-related polioviruses by hybridization with specific RNA probes.
We developed RNA probes for the identification of poliovirus isolates by blot hybridization. Two sets of vaccine strain-specific probes were prepared. They complemented variable genomic domains within (i) the 5'-untranslated region and (ii) the amino-terminal codons of VP1. An enterovirus group probe (EV/5UT) matching highly conserved 5'-untranslated region sequences was used to estimate the quantities of poliovirus (or enterovirus) RNA in the samples. Poliovirus sequences amplified from Sabin strain virion RNA templates by PCR were inserted into the pUC18 plasmid vector. The antisense PCR primer for each probe set contained sequences encoding a T7 promoter. Hybrids were detected by a sensitive nonisotopic method. RNA probes were labeled by incorporation of digoxigenin-uridylate into the transcripts. The binding of probe to immobilized poliovirus RNAs was visualized by hydrolysis of the chemiluminescent substrate 4-methoxy-4-(3-phosphate-phenyl)-spiro-(1,2-dioxetane-3,2'-adamant ane) catalyzed by alkaline phosphatase conjugated to anti-digoxigenin (Fab) fragments. The specificities of the probes were evaluated with a panel of poliovirus isolates that had previously been characterized by sequence analysis. The RNAs of vaccine-related isolates hybridized with the appropriate probe sets. Wild polioviruses representing a broad spectrum of contemporary genotypes were recognized by the inabilities of their genomes to form stable hybrids with the Sabin strain-specific probes.


A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1.
Although the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear. We sought to determine whether immune cell-derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31-induced itch. We used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects. Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31-induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)-deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca(2+) release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31-induced scratching in vivo. IL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA(+)/TRPV1(+)/TRPA1(+) neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma.


Advance Care Planning and Decision-Making in a Home-Based Primary Care Service in a Canadian Urban Centre.
Advance care planning (ACP) is a process that enables individuals to describe, in advance, the kind of health care they would want in the future, and has been shown to reduce hospital-based interventions at the end of life. Our goal was to describe the current state of ACP in a home-based primary care program for frail homebound older people in Vancouver, Canada. We did this by identifying four key elements that should be essential to ACP in this program: frailty stage, documentation of substitute decision-makers, and decision-making with regard to both resuscitation (i.e., do not resuscitate (DNR)) and hospitalization (i.e., do not hospitalize (DNH)). While these elements are an important part of the ACP process, they are often excluded from common practice. This was a cross-sectional, observational study of data abstracted from 200 randomly selected patient electronic medical records between July 1 and September 30, 2017. We describe the association between demographic characteristics, comorbidities, and four key elements of ACP documentation and decision-making as documented in the clinical record using bivariate comparison, a logistic regression model and multiple logistic regression analysis. In 73% (n=146) of the patient records, there was no explicit documentation of frailty stage. Sixty-four per cent had documentation of a substitute decision-maker. Of those who had their preferences documented, 90.6% (n=144/159) indicated a preference for DNR, and 23.6% (n=29/123) indicated a preference for DNH. In multiple regression modeling, a diagnosis of dementia and older age were associated with documentation of a DNR preference, adjusted odds ratio (AOR) = 4.79 (95% CI 1.37, 16.71) and AOR = 1.14 (95% CI 1.05, 1.24), respectively. Older age, male sex, and English identified as the main language spoken were associated with a DNH preference. AOR = 1.17 (95% CI 1.06, 1.28), AOR = 4.19 (95% CI 1.41, 12.42), and AOR = 3.42 (95% CI 1.14, 10.20), respectively. Clinician documentation of some elements of ACP, such as identification of a substitute decision-maker and resuscitation status, have been widely adopted, while other elements that should be considered essential components of ACP, such as frailty staging and preferences around hospitalization, are infrequent and provide an opportunity for practice improvement initiatives. The significant association between language and ACP decisions suggests an important role for supporting cross-cultural fluency in the ACP process.


[Effect of allicin on ethanol-induced hepatotoxicity in mice].
To study the effect of allicin, an effective component of garlic, on ethanol-induced hepatotoxicity in mice. The results showed that allicin (10 mg/kg ig, qd x 10) could reverse the higher activities of serum ALT and glutathione s-transferase (GST) in ethanol-treated mice. Furthermore, allicin could significantly enhance the content of hepatic reduced glutathione (GSH), and the activities of hepatic glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Re) and GST in ethanol-induced hepatotoxicity mice. There were no remarkable changes in the hepatic catalase (Cat) and superoxide dismutase(SOD) activities. These results suggested that allicin have the effective hepato-protection on ethanol-induced hepatotoxicity, which is related to its selective effect on the glutathione-related enzyme system.


True XP group E patients have a defective UV-damaged DNA binding protein complex and mutations in DDB2 which reveal the functional domains of its p48 product.
Xeroderma pigmentosum (XP) is a skin cancer-prone autosomal recessive disease characterized by inability to repair UV-induced DNA damage. The major form of XP is defective in nucleotide excision repair (NER) and comprises seven complementation groups (A-G). The genes defective in all groups have been identified unambiguously with the exception of group E. The cells of some XP-E patients are deficient in a protein complex (consisting of two subunits: p127/DDBI and p48/DDB2) which binds to UV-damaged DNA (UV-DDB) and is specifically involved in the removal of photoproducts from the non-transcribed regions of the genome. However, other XP-E patients have been reported not to lack UV-damaged DNA binding activity (DDB(+)). Here we describe several genetically unrelated XP-E patients, not previously analyzed in depth, each carrying two mutated alleles for DDB2, causing either a single amino acid change or a protein truncation or internal deletion. These defects result in a severe decrease of detectable p48 protein, abolish interaction with the p127 subunit, and produce a deficiency in UV-DDB binding activity (DDB(-)). The role of p48 in the repair defect of these patients was demonstrated in vivo and in vitro. Investigation of four DDB(+) cell strains from patients previously assigned to XP-E, allowed us to reclassify all of them into other groups and to show that they do not share the molecular and biochemical features typical for XP-E. Besides confirming that the true XP-E phenotype is DDB(-), resulting from defects in a single gene, DDB2, our results identify the functional domains of the corresponding p48 protein.


Shared filtering processes link attentional and visual short-term memory capacity limits.
Both visual attention and visual short-term memory (VSTM) have been shown to have capacity limits of 4 ± 1 objects, driving the hypothesis that they share a visual processing buffer. However, these capacity limitations also show strong individual differences, making the degree to which these capacities are related unclear. Moreover, other research has suggested a distinction between attention and VSTM buffers. To explore the degree to which capacity limitations reflect the use of a shared visual processing buffer, we compared individual subject's capacities on attentional and VSTM tasks completed in the same testing session. We used a multiple object tracking (MOT) and a VSTM change detection task, with varying levels of distractors, to measure capacity. Significant correlations in capacity were not observed between the MOT and VSTM tasks when distractor filtering demands differed between the tasks. Instead, significant correlations were seen when the tasks shared spatial filtering demands. Moreover, these filtering demands impacted capacity similarly in both attention and VSTM tasks. These observations fail to support the view that visual attention and VSTM capacity limits result from a shared buffer but instead highlight the role of the resource demands of underlying processes in limiting capacity.


tRNADB-CE 2011: tRNA gene database curated manually by experts.
We updated the tRNADB-CE by analyzing 939 complete and 1301 draft genomes of prokaryotes and eukaryotes, 171 complete virus genomes, 121 complete chloroplast genomes and approximately 230 million sequences obtained by metagenome analyses of 210 environmental samples. The 287 102 tRNA genes in total, and thus two times of the tRNA genes compiled previously, are compiled, in which sequence information, clover-leaf structure and results of sequence similarity and oligonucleotide-pattern search can be browsed. In order to pool collective knowledge with help from any experts in the tRNA research field, we included a column to which comments can be added on each tRNA gene. By compiling tRNAs of known prokaryotes with identical sequences, we found high phylogenetic preservation of tRNA sequences, especially at a phylum level. Furthermore, a large number of tRNAs obtained by metagenome analyses of environmental samples had sequences identical to those found in known prokaryotes. The identical sequence group, therefore, can be used as phylogenetic markers to clarify the microbial community structure of an ecosystem. The updated tRNADB-CE provided functions, with which users can obtain the phylotype-specific markers (e.g. genus-specific markers) by themselves and clarify microbial community structures of ecosystems in detail. tRNADB-CE can be accessed freely at http://trna.nagahama-i-bio.ac.jp.


International Intercomparison of Solar UVR Spectral Measurement Systems in Melbourne in 2013.
Monitoring ambient solar UVR levels provides information on how much there is in both real time and historically. Quality assurance of ambient measurements of solar UVR is critical to ensuring accuracy and stability and this can be achieved by regular intercomparisons of spectral measurement systems with those of other organizations. In October and November of 2013 a solar UVR spectroradiometer from Public Health England (PHE) was brought to Melbourne for a campaign of intercomparisons with a new Bentham spectrometer of Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) and one at the Australian Bureau of Meteorology (BOM), supported by New Zealand's National Institute for Water and Atmosphere (NIWA). Given all three spectroradiometers have calibrations that are traceable to various national standards, the intercomparison provides a chance to determine measurement uncertainties and traceability that support UV measurement networks in Australia, New Zealand and the UK. UV Index measurements from all three systems were compared and ratios determined for clear sky conditions when the scans from each instrument were within 2 min of each other. While wavelengths below 305 nm showed substantial differences between the PHE unit and the two other systems, overall the intercomparison results were encouraging, with mean differences in measured UV Index between the BOM/NIWA and those of PHE and ARPANSA of <0.1% and 7.5%, respectively.


Late-stage [18F]Fluorination: New Solutions to Old Problems.
The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.


Presynaptic regulation of the release of catecholamines.
During norepinephrine release elecited by the arrival of nerve impulses, the neurotransmitter interacts with specific receptors (alpha1-, beta1-, beta2-adrenoceptors) located in the membrane of the postsynaptic cell to trigger the response of the effector organ. Until a few years ago, it was thought that the role of noradrenergic nerve terminals in neurotransmission is concerned exclusively with the synthesis, storage, release, and inactivation of norepinephrine and there were no indications that receptors might also be present in the presynaptic membrane. During the last decade, evidence has accumulated in favour of the view that, in addition to the classical postsynaptic adrenoceptors that mediate the responses of the effector organ, there are also receptors located on the noradrenergic nerve terminals. These presynaptic recptors are involved in the modulation of the calcium-dependent, action-potential-evoked release of norepinephrine in the peripheral as well as in the central nervous system. Presynaptic inhibitory alpha-adrenoceptors are involved in the regulation of the release of norepinephrine through a negative feedback mechanism mediated by the neuron's own transmitter. Alpha-Adrenoceptor agonists inhibit the release of norepinephrine during nerve stimulation, while alpha-adrenoceptor blocking agents enhance the stimulation-evoked release of the neurotransmitter. These results have been obtained both i vitro and in vivo. There are pharmacological differences between the postsynaptic alpha-adrenoceptors that mediate the response of the effector organ and the presynaptic inhibitory alpha-adrenoceptors that modulate the release of norepinephrine during nerve stimulation. The subclassification of alpha-adrenoceptors into alpha1- and alpha2-types is bases on differences in relative affinities for a range of alpha-adrenoceptor agoinst and antagonist durgs. The term alpha1-adrenceptor is used for a receptor that is preferentially stimulated by phenylephrine and blocked by prazosin, whereas alpha2-adrenoceptor is reserved for those preferentially stimulated by guanabenz or clonidine and blocked by rauwolscine or yohimbine. The presynaptic inhibitory alpha-adrenoceptors in the peripheral and in the central nervous system have the pharmacological characteristics of the alpha2-adrenoceptors. Presynaptic inhibiotry autoreceptors appear to be involved in the modulation of the release of dopamine and of epinephrine in the central nervous system. A short negative feedback mechanism similar to that for norepinephrine appears to regulate the stimulation-evoked release of dopamine and epinephrine in central neurons. In addition to presynaptic autoreceptors through which the transmitter can modulate its own release, a real mosaic of receptors in present on noradrenergic nerve endings...


Device design and materials optimization of conformal coating for islets of Langerhans.
Encapsulation of islets of Langerhans may represent a way to transplant islets in the absence of immunosuppression. Traditional methods for encapsulation lead to diffusional limitations imposed by the size of the capsules (600-1,000 μm in diameter), which results in core hypoxia and delayed insulin secretion in response to glucose. Moreover, the large volume of encapsulated cells does not allow implantation in sites that might be more favorable to islet cell engraftment. To address these issues, we have developed an encapsulation method that allows conformal coating of islets through microfluidics and minimizes capsule size and graft volume. In this method, capsule thickness, rather than capsule diameter, is constant and tightly defined by the microdevice geometry and the rheological properties of the immiscible fluids used for encapsulation within the microfluidic system. We have optimized the method both computationally and experimentally, and found that conformal coating allows for complete encapsulation of islets with a thin (a few tens of micrometers) continuous layer of hydrogel. Both in vitro and in vivo in syngeneic murine models of islet transplantation, the function of conformally coated islets was not compromised by encapsulation and was comparable to that of unencapsulated islets. We have further demonstrated that the structural support conferred by the coating materials protected islets from the loss of function experienced by uncoated islets during ex vivo culture.


Comparison of prevalence and resection rates in patients with esophageal squamous cell carcinoma and adenocarcinoma.
Since 1987 we have observed a predominance of adenocarcinoma in patients undergoing esophagectomy because of carcinoma at our institution. To discover whether this observation represented an actual change in the prevalence of adenocarcinoma, the Johns Hopkins Hospital pathology records were reviewed for the years 1959 to 1994. Overall, esophageal squamous cell carcinoma was the most common histologic type with 817 cases identified versus 284 cases of adenocarcinoma. The number of patients with squamous cell carcinoma rose slowly from 1959 to 1992 but since 1992 has decreased. Whereas adenocarcinoma was uncommon before 1978, its frequency has since increased markedly, exceeding that of squamous cell carcinoma in 1994. The number of patients with adenocarcinoma who underwent surgical resection has equaled or exceeded the number of those treated nonoperatively for all recorded years. Therefore the predominance of adenocarcinoma in patients undergoing esophageal resection for carcinoma appears to result from two factors: an overall increase in the prevalence of adenocarcinoma since 1978 and an increased likelihood of resection for patients with these tumors.


Modeling bivariate change in individual differences: Prospective associations between personality and life satisfaction.
A number of structural equation models have been developed to examine change in 1 variable or the longitudinal association between 2 variables. The most common of these are the latent growth model, the autoregressive cross-lagged model, the autoregressive latent trajectory model, and the latent change score model. The authors first overview each of these models through evaluating their different assumptions surrounding the nature of change and how these assumptions may result in different data interpretations. They then, to elucidate these issues in an empirical example, examine the longitudinal association between personality traits and life satisfaction. In a representative Dutch sample (N = 8,320), with participants providing data on both personality and life satisfaction measures every 2 years over an 8-year period, the authors reproduce findings from previous research. However, some of the structural equation models overviewed have not previously been applied to the personality-life satisfaction relation. The extended empirical examination suggests intraindividual changes in life satisfaction predict subsequent intraindividual changes in personality traits. The availability of data sets with 3 or more assessment waves allows the application of more advanced structural equation models such as the autoregressive latent trajectory or the extended latent change score model, which accounts for the complex dynamic nature of change processes and allows stronger inferences on the nature of the association between variables. However, the choice of model should be determined by theories of change processes in the variables being studied. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Vegetation changes and land surface feedbacks drive shifts in local temperatures over Central Asia.
Vegetation changes play a vital role in modifying local temperatures although, until now, the climate feedback effects of vegetation changes are still poorly known and large uncertainties exist, especially over Central Asia. In this study, using remote sensing and re-analysis of existing data, we evaluated the impact of vegetation changes on local temperatures. Our results indicate that vegetation changes have a significant unidirectional causality relationship with regard to local temperature changes. We found that vegetation greening over Central Asia as a whole induced a cooling effect on the local temperatures. We also found that evapotranspiration (ET) exhibits greater sensitivity to the increases of the Normalized Difference Vegetation Index (NDVI) as compared to albedo in arid/semi-arid/semi-humid regions, potentially leading to a cooling effect. However, in humid regions, albedo warming completely surpasses ET cooling, causing a pronounced warming. Our findings suggest that using appropriate strategies to protect vulnerable dryland ecosystems from degradation, should lead to future benefits related to greening ecosystems and mitigation for rising temperatures.


Dietary counseling in the management of moderate malnourishment in children.
Dietary counseling is an integral part of treating malnutrition. A first step toward improving the management of moderate malnutrition is to evaluate dietary messages in current programs and assess their adequacy and effectiveness. To ascertain current recommendations regarding family foods for the treatment of moderate malnutrition and assess whether these are likely to meet nutritional requirements for rehabilitation; to review the effectiveness of dietary counseling in the management of moderate malnutrition. Information was requested from 10 United Nations agencies or donors, 20 international nongovernmental organizations, 3 pediatric associations, and 6 national programs about the dietary advice they give to caregivers of moderately malnourished children. Adequacy was assessed by comparing dietary recommendations with nutritional requirements. Linear programming was used to identify problem nutrients. A literature search was conducted of studies using family foods for rehabilitating malnourished children. There was a greater emphasis on providing food supplements for rehabilitation than on utilizing family foods. Dietary recommendations were mostly vague and unlikely to be effective. Those developed by the World Health Organization and the Food and Agriculture Organization for well-nourished children may meet nutritional requirements in moderate malnutrition if the recommendations are made more prescriptive. Zinc and vitamin E emerged as possible problem nutrients. Intervention studies in wasted children suggest that counseling caregivers about family foods can achieve good rates of weight gain. Dietary counseling can be effective in managing malnutrition, but it is often weak or absent and should be strengthened. More attention will need to be given to formulating the messages and improving counseling skills.


Fragmentation of alpha-radical cations of arginine-containing peptides.
Fragmentation pathways of peptide radical cations, M(+*), with well-defined initial location of the radical site were explored using collision-induced dissociation (CID) experiments. Peptide radical cations were produced by gas-phase fragmentation of Co(III)(salen)-peptide complexes [salen = N,N'-ethylenebis (salicylideneiminato)]. Subsequent hydrogen abstraction from the beta-carbon of the side-chain followed by C(alpha)-C(beta) bond cleavage results in the loss of a neutral side chain and formation of an alpha-radical cation with the radical site localized on the alpha-carbon of the backbone. Similar CID spectra dominated by radical-driven dissociation products were obtained for a number of arginine-containing alpha-radicals, suggesting that for these systems radical migration precedes fragmentation. In contrast, proton-driven fragmentation dominates CID spectra of alpha-radicals produced via the loss of the arginine side chain. Radical-driven fragmentation of large M(+*) peptide radical cations is dominated by side-chain losses, formation of even-electron a-ions and odd-electron x-ions resulting from C(alpha)-C bond cleavages, formation of odd-electron z-ions, and loss of the N-terminal residue. In contrast, charge-driven fragmentation produces even-electron y-ions and odd-electron b-ions.


Healthy ageing and home: the perspectives of very old people in five European countries.
This paper reports on in-depth research, using a grounded theory approach, to examine the ways in which very old people perceive healthy ageing in the context of living alone at home within urban settings in five European countries. This qualitative study was part of a cross-national project entitled ENABLE-AGE which examined the relationship between home and healthy ageing. Interviews explored the notion of healthy ageing, the meaning and importance of home, conceptualisations of independence and autonomy and links between healthy ageing and home. Data analysis identified five ways in which older people constructed healthy ageing: home and keeping active; managing lifestyles, health and illness; balancing social life; and balancing material and financial circumstances. Older people reflected on their everyday lives at home in terms of being engaged in purposeful, meaningful action and evaluated healthy ageing in relation to the symbolic and practical affordances of the home, contextualised within constructions of their national context. The research suggests that older people perceive healthy ageing as an active achievement, created through individual, personal effort and supported through social ties despite the health, financial and social decline associated with growing older. The physicality and spatiality of home provided the context for establishing and evaluating the notion of healthy ageing, whilst the experienced relationship between home, life history and identity created a meaningful space within which healthy ageing was negotiated.


Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections.
Salmonella enterica infections are common causes of bloodstream infection in low-resource areas, where they may be difficult to distinguish from other febrile illnesses and may be associated with a high case fatality ratio. Microbiologic culture of blood or bone marrow remains the mainstay of laboratory diagnosis. Antimicrobial resistance has emerged in Salmonella enterica, initially to the traditional first-line drugs chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. Decreased fluoroquinolone susceptibility and then fluoroquinolone resistance have developed in association with chromosomal mutations in the quinolone resistance-determining region of genes encoding DNA gyrase and topoisomerase IV and also by plasmid-mediated resistance mechanisms. Resistance to extended-spectrum cephalosporins has occurred more often in nontyphoidal than in typhoidal Salmonella strains. Azithromycin is effective for the management of uncomplicated typhoid fever and may serve as an alternative oral drug in areas where fluoroquinolone resistance is common. In 2013, CLSI lowered the ciprofloxacin susceptibility breakpoints to account for accumulating clinical, microbiologic, and pharmacokinetic-pharmacodynamic data suggesting that revision was needed for contemporary invasive Salmonella infections. Newly established CLSI guidelines for azithromycin and Salmonella enterica serovar Typhi were published in CLSI document M100 in 2015.


The precision of the symmetry in Z-ring placement in Escherichia coli is hampered at critical temperatures.
Cell division in Escherichia coli is morphologically symmetric due to, among other things, the ability of these cells to place the Z-ring at midcell. Studies have reported that, at sub-optimal temperatures, this symmetry decreases at the single-cell level, but the causes remain unclear. Using fluorescence microscopy, we observe FtsZ-GFP and DAPI-stained nucleoids to assess the robustness of the symmetry of Z-ring formation and positioning in individual cells under sub-optimal and critical temperatures. We find the Z-ring formation and positioning to be robust at sub-optimal temperatures, as the Z-ring's mean width, density and displacement from midcell maintain similar levels of correlation to one another as at optimal temperatures. However, at critical temperatures, the Z-ring displacement from midcell is greatly increased. We present evidence showing that this is due to enhanced distance between the replicated nucleoids and, thus, reduced Z-ring density, which explains the weaker precision in setting a morphologically symmetric division site. This also occurs in rich media and is cumulative, i.e. combining richer media and critically high temperatures enhances the asymmetries in division, which is evidence that the causes are biophysical. To further support this, we show that the effects are reversible, i.e. shifting cells from optimal to critical, and then to optimal again, reduces and then enhances the symmetry in Z-ring positioning, respectively, as the width and density of the Z-ring return to normal values. Overall, our findings show that the Z-ring positioning in E. coli is a robust biophysical process under sub-optimal temperatures, and that critical temperatures cause significant asymmetries in division.


Phytostabilization potential of quailbush for mine tailings: growth, metal accumulation, and microbial community changes.
Abandoned mine tailings sites in semiarid regions remain unvegetated for extended periods of time and are subject to eolian dispersion and water erosion. This study examines the potential phytostabilization of a lead-zinc mine tailings site using a native, drought-tolerant halophyte, quailbush [Atriplex lentiformis (Torr.) S. Wats.]. In a greenhouse study germination, growth, and metal uptake was evaluated in two compost-amended mine tailings samples, K4 (pH 3) and K6 (pH 6) at 75, 85, 90, 95, and 100% mine tailings, and two controls, off-site and compost. Microbial community changes were monitored by performing MPN analysis of iron- and sulfur-oxidizing bacteria as well as heterotrophic plate counts. Results demonstrate that germination is not a good indicator for phytostabilization since it was only inhibited in the unamended K4 treatment. Plant growth was significantly reduced in 95 and 100% mine tailings, while growth in 75, 85, and 90% treatments was similar to the off-site control. Quailbush accumulated elevated levels of the nutrient metals Na, K, Mn, and Zn in the shoot tissues; however, metal accumulation was generally below the domestic animal toxicity limit. Initially, autotrophic population estimates were four to six logs higher than heterotrophic counts, indicating extremely stressed conditions. However, post-harvest, heterotrophic bacterial counts increased to normal levels (approximately 10(6) CFU g-1 dry tailings) and dominated the rhizosphere. Therefore, with compost amendment, quailbush has good potential as a native species candidate for phytostabilization of mine tailings in semiarid environments.


Foveated imaging demonstration.
A wide field-of-view (FOV), theoretically diffraction-limited imaging system is demonstrated using a single positive lens (a singlet), a reflective liquid crystal spatial light modulator (SLM), a turning mirror and a CCD camera. The SLM is used to correct the off-axis aberrations that would otherwise limit the useful FOV of our system. Foveated imaging refers to the variation in spatial resolution across the image caused by using the SLM in this manner.


mESAdb: microRNA expression and sequence analysis database.
microRNA expression and sequence analysis database (http://konulab.fen.bilkent.edu.tr/mirna/) (mESAdb) is a regularly updated database for the multivariate analysis of sequences and expression of microRNAs from multiple taxa. mESAdb is modular and has a user interface implemented in PHP and JavaScript and coupled with statistical analysis and visualization packages written for the R language. The database primarily comprises mature microRNA sequences and their target data, along with selected human, mouse and zebrafish expression data sets. mESAdb analysis modules allow (i) mining of microRNA expression data sets for subsets of microRNAs selected manually or by motif; (ii) pair-wise multivariate analysis of expression data sets within and between taxa; and (iii) association of microRNA subsets with annotation databases, HUGE Navigator, KEGG and GO. The use of existing and customized R packages facilitates future addition of data sets and analysis tools. Furthermore, the ability to upload and analyze user-specified data sets makes mESAdb an interactive and expandable analysis tool for microRNA sequence and expression data.


Understanding the Racial and Ethnic Differences in Cost and Mortality Among Advanced Stage Prostate Cancer Patients (STROBE).
The aims of the study were to understand the racial/ethnic differences in cost of care and mortality in Medicare elderly with advanced stage prostate cancer.This retrospective, observational study used SEER-Medicare data. Cohort consisted of 10,509 men aged 66 or older and diagnosed with advanced-stage prostate cancer between 2001and 2004. The cohort was followed retrospectively up to 2009. Racial/ethnic variation in cost was analyzed using 2 part-models and quantile regression. Step-wise GLM log-link and Cox regression was used to study the association between race/ethnicity and cost and mortality. Propensity score approach was used to minimize selection bias.Pattern of cost and mortality varies between racial/ethnic groups. Compared with other racial/ethnic groups, non-Hispanic white patients had higher unadjusted costs in treatment and follow-up phases. Quintile regression results indicated that in treatment phase, Hispanics had higher costs in the 95th quantile and non-Hispanic blacks had lower cost in the 95th quantile, compared with non-Hispanic white men. In terminal phase non-Hispanic blacks and Hispanics had higher cost. After controlling for treatment, all-cause and prostate cancer-specific mortality was not significant for non-Hispanic black men, compared with non-Hispanic white men. However, for Asians, mortality remained significantly lower compared with non-Hispanic white men.In conclusion, relationship between race/ethnicity, cost of care, and mortality is intricate. For non-Hispanic black men, disparity in mortality can be attributed to treatment differences. To reduce racial/ethnic disparities in prostate cancer care and outcomes, tailored policies to address underuse, overuse, and misuse of treatment and health services are necessary.


Reevaluating Agricultural Productivity Gaps with Longitudinal Microdata.
Recent research has pointed to large gaps in labor productivity between the agricultural and non-agricultural sectors in low-income countries, as well as between workers in rural and urban areas. Most estimates are based on national accounts or repeated cross-sections of microsurvey data, and as a result typically struggle to account for individual selection between sectors. This paper uses long-run individual-level panel data from two low-income countries (Indonesia and Kenya) to explore these gaps. Accounting for individual fixed effects leads to much smaller estimated productivity gains from moving into the non-agricultural sector (or urban areas), reducing estimated gaps by roughly 67%-92%. Furthermore, gaps do not emerge up to 5 years after a move between sectors. We evaluate whether these findings imply a re-assessment of the conventional wisdom regarding sectoral gaps, discuss how to reconcile them with existing cross-sectional estimates, and consider implications for the desirability of sectoral reallocation of labor.


Neonicotinoid Residues in Wildflowers, a Potential Route of Chronic Exposure for Bees.
In recent years, an intense debate about the environmental risks posed by neonicotinoids, a group of widely used, neurotoxic insecticides, has been joined. When these systemic compounds are applied to seeds, low concentrations are subsequently found in the nectar and pollen of the crop, which are then collected and consumed by bees. Here we demonstrate that the current focus on exposure to pesticides via the crop overlooks an important factor: throughout spring and summer, mixtures of neonicotinoids are also found in the pollen and nectar of wildflowers growing in arable field margins, at concentrations that are sometimes even higher than those found in the crop. Indeed, the large majority (97%) of neonicotinoids brought back in pollen to honey bee hives in arable landscapes was from wildflowers, not crops. Both previous and ongoing field studies have been based on the premise that exposure to neonicotinoids would occur only during the blooming period of flowering crops and that it may be diluted by bees also foraging on untreated wildflowers. Here, we show that exposure is likely to be higher and more prolonged than currently recognized because of widespread contamination of wild plants growing near treated crops.


Risky business: when mom and pop buy health insurance for their employees.
The economics of small group insurance makes offering health benefits to employees a risky business. Surveys of employers from 1989 to 2003 reveal that more rapid premium increases are forcing small firms to impose higher cost-sharing. In 2003, premiums for small firms (3-199 workers) increased 15.5 percent, outpacing the 13.2 percent increase for large firms (200+ workers). From 2000 to 2003, deductibles among small firms increased 100 percent in PPO plans when employees use in-network providers and 131 percent when they use out-of-network providers; among large firms, deductibles in PPO plans increased 33 percent and 44 percent, respectively. And in 2003, 40.3 percent of employees in the smallest firms contributed 41 percent or more of the total family premium, compared with only 11.2 percent of employees in large firms. Clearly, fundamental change in the small employer market is necessary, including new options for helping small firms gain access to the advantages large firms have in purchasing health benefits.


Collaborative care for depression in older adults: How much is enough?
Collaborative care in primary care has been shown to be effective for subthreshold depression in older adults in the 'CASPER' trial. However, to understand the impact of adherence, and to explore the minimum effective dose of collaborative care, we reanalysed the trial data using a complier average causal effect (CACE) analysis. Data were available for 705 participants, 519 with 12-month PHQ-9 scores. 'Compliance' could be observed for participants in the intervention group. Latent complier status in the control group was estimated. Completion of five or more sessions of care was defined as 'compliance'. Sensitivity analyses, using alternative cut-offs of two to eight sessions, assessed the impact of changing the definition of 'compliance'. Compliers in the intervention group had lower PHQ-9 scores at 12-month follow up than assumed compliers in the control group (1.75 lower, 95% confidence interval 0.29 to 3.21, p = 0.02), a greater effect than originally reported. Sensitivity analyses confirmed statistically significant differences between the intervention and control groups in those attending five or more sessions. We conclude that collaborative care is causally effective in reducing subthreshold depressive symptoms in older people who adhere to treatment. Our findings suggest the minimum effective dose is five sessions.


Piperine treatment suppresses Helicobacter pylori toxin entry in to gastric epithelium and minimizes β-catenin mediated oncogenesis and IL-8 secretion in vitro.
Helicobacter pylori related gastric cancer initiation has been studied widely. The objective of our present study was to evaluate the effect of a single compound piperine on H. pylori infection and its anti-inflammatory and anti-cancer effects in vitro. Cytotoxicity was tested by Ez-cytox cell viability assay kit. Effects of piperine on H. pylori toxin gene expression and IL-8 expression in mammalian cells during infection were assessed by RT-PCR. Effects of piperine on toxin entry into host cells, E-cadherin cleavage by H. pylori, and the changes in H. pylori mediated β-catenin expression and IL-8 secretion were determined by immunoblotting. Piperine treatment restrained the entry of CagA and VacA into AGS cells. Piperine administration in H. pylori infection reduced E-cadherin cleavage in stomach epithelium. In addition, H. pylori induced β-catenin up-regulation was reduced. Piperine administration impaired IL-8 secretion in H. pylori-infected gastric epithelial cells. As we reported previously piperine restrained H. pylori motility. The possible reason behind the H. pylori inhibition mechanism of piperine could be the dwindled motility, which weakened H. pylori adhesion to gastric epithelial cells. The reduced adhesion decreased the toxin entry thereby secreting less amount of IL-8. In addition, piperine treatment suppressed H. pylori protease led to reduction of E-cadherin cleavage and β-catenin expression resulting in diminished β-catenin translocation into the nucleus thus decreasing the risk of oncogenesis. To our knowledge, this is the preliminary report of piperine mediated H. pylori infection control on gastric epithelial cells in-vitro.