Adaptive intertemporal preferences in foraging-style environments.
Decision makers often face choices between smaller more immediate rewards and larger more delayed rewards. For example, when foraging for food, animals must choose between actions that have varying costs (e.g., effort, duration, energy expenditure) and varying benefits (e.g., amount of food intake). The combination of these costs and benefits determine what optimal behavior is. In the present study, we employ a foraging-style task to study how humans make reward-based choices in response to the real-time constraints of a dynamic environment. On each trial participants were presented with two rewards that differed in magnitude and in the delay until their receipt. Because the experiment was of a fixed duration, maximizing earnings required decision makers to determine how to trade off the magnitude and the delay associated with the two rewards on each trial. To evaluate the extent to which participants could adapt to the decision environment, specific task characteristics were manipulated, including reward magnitudes (Experiment 1) and the delay between trials (Experiment 2). Each of these manipulations was designed to alter the pattern of choices made by an optimal decision maker. Several findings are of note. First, different choice strategies were observed with the manipulated environmental constraints. Second, despite contextually-appropriate shifts in behavior between conditions in each experiment, choice patterns deviated from theoretical optimality. In particular, the delays associated with the rewards did not exert a consistent influence on choices as required by exponential discounting. Third, decision makers nevertheless performed surprisingly well in all task environments with any deviations from strict optimality not having particularly deleterious effects on earnings. Taken together, these results suggest that human decision makers are capable of exhibiting intertemporal preferences that reflect a variety of environmental constraints.


Transcription of two blue copper-binding protein isogenes is highly correlated with arbuscular mycorrhizal development in Medicago truncatula.
Expression profiling of two paralogous arbuscular mycorrhizal (AM)-specific blue copper-binding gene (MtBcp1a and MtBcp1b) isoforms was performed by real-time quantitative polymerase chain reaction in wild-type Medicago truncatula Jemalong 5 (J5) during the mycorrhizal development with Glomus intraradices for up to 7 weeks. Time-course analysis in J5 showed that expression of both MtBcp1 genes increased continuously and correlated strongly with the colonization intensity and arbuscule content. MtPT4, selected as a reference gene of the functional plant-fungus association, showed a weaker correlation to mycorrhizal development. In a second experiment, a range of mycorrhizal mutants of the wild-type J5 was assessed. Strictly AM-penetration-defective TRV25-C and TRV25-D (dmi3, Mtsym13), hypomycorrhizal TR25 and TR89 (dmi2, Mtsym2) mutants, and a hypermycorrhizal mutant TRV17 (sunn, Mtsym12) were compared with J5 3 and 7 weeks after inoculation. No MtBcp1 transcripts were detected in the mutants blocked at the appressoria stage. Conversely, TR25, TR89, and J5 showed a gradual increase of the expression of both MtBcp1 genes in 3- and 7-week-old plants, similar to the increase in colonization intensity and arbuscule abundance. The strong correlation between the expression level of AM-specific blue copper-binding protein-encoding genes and AM colonization may imply a basic role in symbiotic functioning for these genes, which may serve as new molecular markers of arbuscule development in M. truncatula.


A Path Towards Clinical Adaptation of Accelerated MRI.
Accelerated MRI reconstructs images of clinical anatomies from sparsely sampled signal data to reduce patient scan times. While recent works have leveraged deep learning to accomplish this task, such approaches have often only been explored in simulated environments where there is no signal corruption or resource limitations. In this work, we explore augmentations to neural network MRI image reconstructors to enhance their clinical relevancy. Namely, we propose a ConvNet model for detecting sources of image artifacts that achieves a classifier F 2 score of 79.1%. We also demonstrate that training reconstructors on MR signal data with variable acceleration factors can improve their average performance during a clinical patient scan by up to 2%. We offer a loss function to overcome catastrophic forgetting when models learn to reconstruct MR images of multiple anatomies and orientations. Finally, we propose a method for using simulated phantom data to pre-train reconstructors in situations with limited clinically acquired datasets and compute capabilities. Our results provide a potential path forward for clinical adaptation of accelerated MRI.


The status of social well-being in Iranian nurses: a cross- sectional study.
Social well-being is one of the important aspects of individual's health. However, the social aspect of health, or social well-being, has not been attended to as equally as the other aspects. Social well-being is people's perceptions and experiences in social circumstances as well as the degree of successful responses to social challenges. The aim of the study was to investigate the social well-being of a sample of Iranian nurses. This study was a cross- sectional conducted in 2013. The study population consisted of all 1200 staff nurses working in all hospitals located in Ardabil, Iran. We invited a random sample of 281 practicing nurses to respond to the 33-item Keyes's Social Well-Being Questionnaire and the possible range of the total score is 33-165. Higher score reflect better SWB. The quantitative analysis of this study used the Statistical Package for Social Science SPSS version 13.0. The results showed that Participants' mean score of social well-being was 105.45 (15.87). Social well-being was significantly related to participants' age, gender, work experience, satisfaction with working in hospital and with income, familiarity with nursing prior to entering it, official position, and type of employment. However, there was no significant relationship between nurses' social well-being and their marital status, their parents and spouses' educational status, as well as the type of hospital. Nurses' social well-being deserves special attention. Effective well-being promotion strategies should be executed for promoting their social well-being particularly in areas of social integration and social acceptance. Moreover, nurses, particularly female nurses, need strong financial, emotional, informational, and social support for ensuring their social well-being.


Coupled abiotic-biotic mineralization of 2,4,6-trinitrotoluene (TNT) in soil slurry.
The explosive 2,4,6-trinitrotoluene (TNT) is a contaminant of soils and ground waters worldwide. To help alleviate such environmental contamination, we investigated a coupled abiotic-biotic treatment scheme for remediating TNT-contaminated soil in slurry solutions. Two types of soil were used (sandy and silt loam) to simulate different soils that might be found at actual sites. These soils were subsequently contaminated with 5000 mg kg(-1) TNT. Mineralization of TNT was initially optimized for minimum reactant use (Fe(3+) and H(2)O(2)) and maximum soil slurry percentage (percent solids) using modified Fenton reactions conducted in the absence of light followed by the addition of an uncharacterized aerobic biomass. Greater than 97% TNT degradation was observed under optimum reaction conditions for both soils. Using two optimum reactant concentrations for each soil, coupled abiotic-biotic reactions showed an increase in TNT mineralization, from 41 to 73% and 34 to 64% in the sandy soil (10 and 20% slurry, respectively, 1470 mM H(2)O(2)), and increases from 12 to 23% and 13 to 28% in the silt loam soil (5% slurry, 294 and 1470 mM H(2)O(2), respectively). These results show promise in the use of combined abiotic-biotic treatment processes for soils contaminated with high concentrations of TNT.


Inhibition of hepatitis C virus replication by single-stranded RNA structural mimics.
To examine the effect of hepatitis C virus (HCV) structural mimics of regulatory regions of the genome on HCV replication. HCV RNA structural mimics were constructed and tested in a HCV genotype 1b aBB7 replicon, and a Japanese fulminant hepatitis-1 (JFH-1) HCV genotype 2a infection model. All sequences were computer-predicted to adopt stem-loop structures identical to the corresponding elements in full-length viral RNA. Huh7.5 cells bearing the BB7 replicon or infected with JFH-1 virus were transfected with expression vectors generating HCV mimics and controls. Cellular HCV RNA and protein levels were quantified by real-time polymerase chain reaction and Western blotting, respectively. To evaluate possible antisense effects, complementary RNAs spanning a mimic were prepared. In the BB7 genotype 1b replicon system, mimics of the polymerase (NS-5B), X and BA regions inhibited replication by more than 90%, 50%, and 60%, respectively. In the JFH-1 genotype 2 infection system, mimics that were only 74% and 46% identical in sequence relative to the corresponding region in JFH-1 inhibited HCV replication by 91.5% and 91.2%, respectively, as effectively as a mimic with complete identity to HCV genotype 2a. The inhibitory effects were confirmed by NS3 protein levels. Antisense RNA molecules spanning the 74% identical mimic had no significant effects. HCV RNA structural mimics can inhibit HCV RNA replication in replicon and infectious HCV systems and do so independent of close sequence identity with the target.


Activities of the Wnt-1 class of secreted signaling factors are antagonized by the Wnt-5A class and by a dominant negative cadherin in early Xenopus development.
When overexpressed in Xenopus embryos, Xwnt-1, -3A, -8 and -8b define a functional class of Wnts (the Wnt-1 class) that promotes duplication of the embryonic axis, whereas Xwnt-5A, -4, and -11 define a distinct class (the Wnt-5A class) that alters morphogenetic movements (Du, S., S. Purcell, J. Christian, L. McGrew, and R. Moon. 1995. Mol. Cell. Biol. 15:2625-2634). Since come embryonic cells may be exposed to signals from both functional classes of Wnt during vertebrate development, this raises the question of how the signaling pathways of these classes of Wnts might interact. To address this issue, we coexpressed various Xwnts and components of the Wnt-1 class signaling pathway in developing Xenopus embryos. Members of the Xwnt-5A class antagonized the ability of ectopic Wnt-1 class to induce goosecoid expression and a secondary axis. Interestingly, the Wnt-5A class did not block goosecoid expression or axis induction in response to overexpression of cytoplasmic components of the Wnt-1 signaling pathway, beta-catenin or a kinase-dead gsk-3, or to the unrelated secreted factor, BVg1. The ability of the Wnt-5A class to block responses to the Wnt-1 class may involve decreases in cell adhesion, since ectopic expression of Xwnt-5A leads to decreased Ca2+-dependent cell adhesion and the activity of Xwnt-5A to block Wnt-1 class signals is mimicked by a dominant negative N-cadherin. These data underscore the importance of cell adhesion in modulating the responses of embryonic cells to signaling molecules and suggest that the Wnt-5A functional class of signaling factors can interact with the Wnt-1 class in an antagonistic manner.


Photon-correlation Fourier spectroscopy.
We describe a method to probe the spectral fluctuations of a transition over broad ranges of frequencies and timescales with the high spectral resolution of Fourier spectroscopy, and a temporal resolution as high as the excited state lifetime, even in the limit of very low photocounting rates. The method derives from a simple relation between the fluorescence spectral dynamics of a single radi-ating dipole and its fluorescence intensity correlations at the outputs of a continuously scanning Michelson interferometer. These findings define an approach to investigate the fast fluorescence spectral dynamics of single molecules and other faint light sources beyond the time-resolution capabilities of standard spectroscopy experiments.


Social Values and Determinants of Cultural Fit in Quebec: The Roles of Ancestry, Linguistic Group, and Mental Health Status.
Many quantitative cross-cultural research studies assume that cultural groups consist of anyone born and raised in the same country. Applying these criteria to the formation of study samples may produce cohorts that share a country but are heterogeneous in relevant domains of culture. For example, in Canada, Franco- and Anglo-Canadians are generally assumed to represent different linguistic groups but the same cultural group. However, speaking a different first language also can mean exposure to different media, information, and conventions, which are known to shape certain cultural domains, such as social values. Other factors may also produce cultural heterogeneity. For example, ancestral origins and recency of familial migration may influence endorsed social values after exposure to diverse cultures or norms. Mental health status or psychiatric conditions may also influence subscription of social values due to different lifestyle demands. Understanding the nuanced contributions of diverse backgrounds to cultural membership and fit (i.e., the degree to which an individual behaves like other cultural members) is useful when performing quantitative cross-cultural studies to minimize alternative explanations for statistical outcomes. This study used Cultural Consensus Analysis (CCA) to assess the cultural fit of social values for 222 Canadians, who had participated in cross-cultural neuropsychological experiments. CCA is an anthropological statistical method for evaluating cultural agreement of a sample. Participants were systematically evaluated by linguistic groups (French and English), migratory generation (1st-3rd+), and mental health status (healthy and patient). Group and individual variances were statistically interrogated. Results demonstrated that Franco- and Anglo-Canadians represent different cultural groups cohabitating in Quebec. Social values dividing Franco- and Anglo-Canadians were also identified. Second and third generation Canadians held more heterogeneous social values than Canadians, whose families had migrated earlier. Second generation Canadians with psychiatric disorders showed notably reduced cultural fit with other Canadians, which supports other literature reporting difficulties experienced by second generation migrants. However, third and later generations of Canadians with psychiatric disorders held a greater range of social values compared to healthy Canadians but still were good fits for Canadian culture. This study concluded that linguistic group and migratory generation partially determines cultural group for the social values domain while mental health status does not, contrary to theories proposed by previous literature.


Patient Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer.
There is considerable interest in very short (ultrahypofractionated) radiation therapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience, and resource allocation benefits. Our objective is to demonstrate that detectable changes in health-related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline scores. NRG Oncology's RTOG 0938 is a nonblinded randomized phase 2 study of National Comprehensive Cancer Network low-risk prostate cancer in which each arm is compared with a historical control. Patients were randomized to 5 fractions (7.25 Gy in 2 weeks) or 12 fractions (4.3 Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC-50 bowel score at 1 year (baseline to 1 year) >5 points and in EPIC-50 urinary score >2 points tested with a 1-sample binomial test. The study enrolled 127 patients to 5 fractions (121 analyzed) and 128 patients to 12 fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The 1-year frequency for >5 point change in bowel score were 29.8% (P < .001) and 28.4% (P < .001) for 5 and 12 fractions, respectively. The 1-year frequencies for >2 point change in urinary score were 45.7% (P < .001) and 42.2% (P < .001) for 5 and 12 fractions, respectively. For 5 fractions, 32.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥11 points (P = .34); for 12 fractions, 30.9% of patients had a drop in 1-year EPIC-50 sexual score of ≥ 11 points (P = .20). Disease-free survival at 2 years is 99.2% (95% confidence interval: 97.5-100) in the 5-fraction arm and 97.5% (95% confidence interval: 94.6-100) in the 12-fraction arm. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. This study confirms that, based on changes in bowel and urinary domains and toxicity (acute and late), the 5- and 12-fraction regimens are well tolerated. These ultrahypofractionated approaches need to be compared with current standard radiation therapy regimens.


N-acetyltransferase polymorphism among northern Sudanese.
Interindividual and interethnic differences in allele frequencies of N-acetyltransferase (NAT2) single nucleotide polymorphisms (SNPs) are responsible for phenotypic variability of adverse drug reactions and susceptibility to cancer. We genotyped the seven NAT2 common SNPs in 127 randomly selected unrelated northern Sudanese subjects using allele-specific and RFLP polymerase chain reaction (PCR) based methods. Molecular genotyping was enough to designate alleles for 41 individuals unambiguously, whereas 63 individuals' alleles were inferred from haplotypes previously described. In the remaining 23 individuals, however, the phase of the SNPs could not be decided because of multiple SNP heterozygotes. Using computational methods in the HAP and Phase programs, we confirmed the inferred alleles of the 62 individuals and predicted the remaining 23 ambiguous alleles. Twelve NAT2 alleles were identified. Four alleles coded for rapid acetylators (18%), and eight alleles coded for slow acetylators (82%). Two genotypes coded for rapid acetylation (3.9%), 10 for intermediate acetylation (27.6%), and 13 for slow acetylation (68.5%). The G191A African SNP and the G857A predominantly Asian SNP were each detected at a low frequency of 3.1%. The combination of molecular and computational analysis was useful in resolving ambiguous genotypes of NAT2 in multiple SNP heterozygotes. Among the northern Sudanese the SNPs associated with slow acetylation are more prevalent than in Caucasians and Asians. This and other African studies are suggestive of an African origin for NAT2-associated polymorphism.


Reconditioning of an injured lung graft with intrabronchial surfactant instillation in an ex vivo lung perfusion system followed by transplantation.
We tested whether an injured lung graft from category-3 donation after cardiac death donor could be reconditioned with an ex vivo lung perfusion (EVLP) system by intrabronchial diluted surfactant lavage before transplantation. In a pig model, cardiac arrest was induced by deconnecting from the ventilator. Left lung injury was done by intrabronchial instillation of 1 mL/kg pepsin + HCl. After retrieval, the heart-lung block was stored at 4°C for 2 h. In the treated group, transplantation was performed after reconditioning with intrabronchial diluted surfactant lavage in EVLP system. During EVLP, surfactant group showed better oxygenation and lower pulmonary vascular resistance. After transplantation, better oxygenation, lower mean pulmonary artery pressure, and lower lung edema were observed in surfactant group. Lower blood IL-1 beta and IL-6 cytokine levels were measured in the surfactant group. In bronchoalveolar lavage, the percentage of neutrophils, IL-1 beta and IL-6 cytokine levels, amount of protein, and neutrophil infiltration in the lung tissue at the end of the experiment were significantly lower in the surfactant group. Our data demonstrate the feasibility of reconditioning and transplantation of an acutely damaged lung graft due to aspiration from a category-3 DCD donor. Implementation of an EVLP system is an efficacious tool to recondition and assess a questionable graft before transplantation.


Latitudinal fractionation of polychlorinated biphenyls in surface seawater along a 62 degrees N-89 degrees N transect from the southern Norwegian Sea to the North Pole area.
Surface seawater concentrations of PCBs, relative congener abundance, and possible effects of cold condensation were studied along a transect from the southern Norwegian Sea to the central Arctic Ocean (62 degrees N-89 degrees N). Large volume samples were collected from an ice breaker using a stainless steel surface seawater intake connected online to an ultra-clean laboratory. Concentrations of all studied PCB congeners, except for trichlorinated PCB 18, decreased with latitude. For instance, PCB 52 decreased from 470 fg L(-1) at 62 degrees N to 110 fg L(-1) at 89 degrees N and PCB 180 from 110 to 12 fg L(-1). Concentrations in the central Arctic Ocean were on the order of 10-100 fg L(-1) for the most abundant congeners. The relative contribution oftrichlorinated PCBs to the total PCB concentration increased with latitude, the tetrachlorinated contribution to the total PCBs did not show any correlation to latitude, and the relative contribution of heavier congeners decreased with latitude. This study establishes the occurrence at very low abundances of PCBs in seawater in the central Arctic Ocean and demonstrates a northward concentration decrease. The latitudinal shift in congener pattern is reflecting the relative propensity of the PCB congeners to undergo long-range transport in the Arctic and is consistent with their relative vapor pressures.


Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology.
RING (really interesting new gene) and U-box E3 ligases bridge E2 ubiquitin-conjugating enzymes and substrates to enable the transfer of ubiquitin to a lysine residue on the substrate or to one of the seven lysine residues of ubiquitin for polyubiquitin chain elongation. Different polyubiquitin chains have different functions. Lys(48)-linked chains target proteins for proteasomal degradation, and Lys(63)-linked chains function in signal transduction, endocytosis and DNA repair. For this reason, chain topology must be tightly controlled. Using the U-box E3 ligase CHIP [C-terminus of the Hsc (heat-shock cognate) 70-interacting protein] and the RING E3 ligase TRAF6 (tumour-necrosis-factor-receptor-associated factor 6) with the E2s Ubc13 (ubiquitin-conjugating enzyme 13)-Uev1a (ubiquitin E2 variant 1a) and UbcH5a, in the present study we demonstrate that Ubc13-Uev1a supports the formation of free Lys(63)-linked polyubiquitin chains not attached to CHIP or TRAF6, whereas UbcH5a catalyses the formation of polyubiquitin chains linked to CHIP and TRAF6 that lack specificity for any lysine residue of ubiquitin. Therefore the abilities of these E2s to ubiquitinate a substrate and to elongate polyubiquitin chains of a specific topology appear to be mutually exclusive. Thus two different classes of E2 may be required to attach a polyubiquitin chain of a particular topology to a substrate: the properties of one E2 are designed to mono-ubiquitinate a substrate with no or little inherent specificity for an acceptor lysine residue, whereas the properties of the second E2 are tailored to the elongation of a polyubiquitin chain using a defined lysine residue of ubiquitin.


Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer.
Ginsenoside compound K (C-K) is an intestinal microbiota metabolite of ginsenoside Rb1, a major constituent in American ginseng. However, previous ginseng anti-cancer observations were largely focused on ginseng parent compounds but not metabolites, and anti-colorectal cancer studies on C-K were limited. This study investigated the anti-proliferative effects of C-K when compared to those of Rb1, and the related mechanisms of action, in HCT-116 and SW-480 colorectal cancer cells. The effects of Rb1 and C-K on the proliferation of HCT-116 and SW-480 human colorectal cancer cells were compared using an MTS assay. Cell cycle and cell apoptosis were assayed using flow cytometry. Enzymatic activities of caspases were determined by colorimetric assay, and interactions of C-K and caspases were explored by docking analysis. C-K showed significant anti-proliferative effects in HCT-116 and SW-480 cells at concentrations of 30-50 µM. At the same concentrations, Rb1 did not show any effects, while C-K arrested the cells in the G1 phase, and significantly induced cell apoptosis. Compared to HCT-116 (p53 wild-type), the p53 mutant cell line SW-480 was more sensitive to C-K as assessed by cell cycle regulation and apoptosis induction. C-K activated expression of caspases 8 and 9, consistent with docking analysis. The docking data suggested that C-K forms hydrogen bonds with Lys253, Thr904 and Gly362 in caspase 8, and with Thr62, Ser63 and Arg207 in caspase 9. C-K, but not its parent ginsenoside Rb1, showed significant anti-proliferative and pro-apoptotic effects in human colorectal cancer cells. These results suggest that C-K could be a potentially effective anti-colorectal cancer agent.


Antibodies with high avidity to the gp120 envelope protein in protection from simian immunodeficiency virus SIV(mac251) acquisition in an immunization regimen that mimics the RV-144 Thai trial.
The recombinant canarypox vector, ALVAC-HIV, together with human immunodeficiency virus (HIV) gp120 envelope glycoprotein, has protected 31.2% of Thai individuals from HIV acquisition in the RV144 HIV vaccine trial. This outcome was unexpected, given the limited ability of the vaccine components to induce CD8(+) T-cell responses or broadly neutralizing antibodies. We vaccinated macaques with an immunization regimen intended to mimic the RV144 trial and exposed them intrarectally to a dose of the simian immunodeficiency virus SIV(mac251) that transmits few virus variants, similar to HIV transmission to humans. Vaccination induced anti-envelope antibodies in all vaccinees and CD4(+) and CD8(+) T-cell responses. Three of the 11 macaques vaccinated with ALVAC-SIV/gp120 were protected from SIV(mac251) acquisition, but the result was not significant. The remaining vaccinees were infected and progressed to disease. The magnitudes of vaccine-induced SIV(mac251)-specific T-cell responses and binding antibodies were not significantly different between protected and infected animals. However, sera from protected animals had higher avidity antibodies to gp120, recognized the variable envelope regions V1/V2, and reduced SIV(mac251) infectivity in cells that express high levels of α(4)β(7) integrins, suggesting a functional role of antibodies to V2. The current results emphasize the utility of determining the titer of repeated mucosal challenge in the preclinical evaluation of HIV vaccines.


Diagnostic criteria and follow-up parameters in complex regional pain syndrome type I--a Delphi survey.
Although the current clinical guideline of diagnostic criteria for the complex regional pain syndrome I (CRPS I) is a landmark endeavour to define this complex condition it does not prioritise its most important clinical manifestations. We set out to obtain an expert agreed priority list of diagnostic and follow-up parameters in the diagnosis and management of CRPS I. A two round Delphi survey: We asked international experts to list (first round) and weight (second round) parameters (scale 1-10) they believed to be relevant in diagnosis and follow-up. Median ratings and interquartile ranges (IQR) were calculated. Rates 7 and IQR 3 depicted important and expert agreed parameters. Thirty-two diagnostic and 23 follow-up listings and ratings of 13 experts were available for analysis. In three domains (clinical presentation, further examinations and follow-up) experts agreed on the following parameters, pain (10; 9-10) with its subcategories hyperesthesia (7; 5-8) hyperalgesia (8; 8-8) and allodynia (8; 7-10), signs with oedema (9; 8-10) and colour change (8; 5-8) and mobility with its categories motor change (7; 5-8) and decreased range of motion (8; 8-8). The experts agreed that no further examinations were necessary for diagnosis (10; 8-10). The agreed important follow-up parameter was clinical course (10; 8-10) with its categories decrease in pain (8; 8-9) and hyperalgesia (8; 6-8), decreased oedema (8; 7-10) and improvements in motor function (10; 8-10) and strength (8; 6-9). This expert survey conveys an agreed set of relevant diagnostic parameters of CRPS I and proposes that in follow-up examinations treatment success should be based on restoration of those manifestations.


Deep-sea hydrothermal vent Epsilonproteobacteria encode a conserved and widespread nitrate reduction pathway (Nap).
Despite the frequent isolation of nitrate-respiring Epsilonproteobacteria from deep-sea hydrothermal vents, the genes coding for the nitrate reduction pathway in these organisms have not been investigated in depth. In this study we have shown that the gene cluster coding for the periplasmic nitrate reductase complex (nap) is highly conserved in chemolithoautotrophic, nitrate-reducing Epsilonproteobacteria from deep-sea hydrothermal vents. Furthermore, we have shown that the napA gene is expressed in pure cultures of vent Epsilonproteobacteria and it is highly conserved in microbial communities collected from deep-sea vents characterized by different temperature and redox regimes. The diversity of nitrate-reducing Epsilonproteobacteria was found to be higher in moderate temperature, diffuse flow vents than in high temperature black smokers or in low temperatures, substrate-associated communities. As NapA has a high affinity for nitrate compared with the membrane-bound enzyme, its occurrence in vent Epsilonproteobacteria may represent an adaptation of these organisms to the low nitrate concentrations typically found in vent fluids. Taken together, our findings indicate that nitrate reduction is widespread in vent Epsilonproteobacteria and provide insight on alternative energy metabolism in vent microorganisms. The occurrence of the nap cluster in vent, commensal and pathogenic Epsilonproteobacteria suggests that the ability of these bacteria to respire nitrate is important in habitats as different as the deep-sea vents and the human body.


Styles of Leadership, Fears of Compassion, and Competing to Avoid Inferiority.
There is general agreement that styles of leadership evolved from mammalian group living strategies that form social ranks. In both non-human primates and humans, different styles of hierarchical dominant-subordinate and leader-follower behavior can be observed. These can be described in terms of dimensions of antisocial (relatively self-focused, aggressive and threat-based) and prosocial (relatively empathic, caring, and supportive) interpersonal styles. The aim of this study was to explore how a set of established self-report questionnaires might relate to these two dimensions. Two hundred and nineteen students completed questionnaires assessing ruthless self-advancement, coalition building, and dominant leadership styles, as well as hypercompetitiveness, narcissism, striving to avoid inferiority, compassion focused and ego focused goals, fears of compassion, social safeness and attachment (in)security. A principal component analysis supported an antisocial leadership style factor which comprised of ruthless self-advancement, narcissism and hypercompetitiveness. This was significantly correlated with fears of compassion, ego focused goals, insecure striving (striving to avoid inferiority), fears of losing out, fears of being overlooked, fears of being rejected, and avoidant relating in close relationships. It was significantly negatively correlated with compassionate goals. As the results did not reveal a clear factor solution for a prosocial leadership style, we chose to use the coalition building leadership style variable. This showed the opposite pattern, being significantly negatively correlated with narcissism, hypercompetitiveness, fears of compassion, fears of active rejection, and avoidance in close relationships. It was significantly positively correlated with secure striving, compassionate goals, and social safeness. We also found that fears of compassion for others was a partial mediator of the relationship between insecure striving with antisocial leadership style. Moreover, lower fears of compassion for the self emerged as a key mediator for the relationship between non-avoidant attachment with coalition building leadership style and, secure non-striving with coalition building leadership style. While the motive to accumulate social power, resources and dominance may be linked to antisocial forms of leadership, the intensity of the drive may also be linked to unaddressed threats and fears of rejection and fears of compassion. Efforts to promote more ethical, moral and prosocial forms of leadership may falter if such fears are left unaddressed.


Anti-inflammatory effect of diclofenac drops after argon laser trabeculoplasty.
Using a laser flare-cell meter, the anti-inflammatory effect of diclofenac sodium drops was evaluated after argon laser trabeculoplasty in a double-masked placebo-controlled study. Fifty-three eyes with pseudoexfoliative (43 eyes) or pigmentary glaucoma (10 eyes) were randomly assigned to treatment (n = 27) or placebo (n = 26) groups. Diclofenac (0.1%) or placebo drops were administered once before and after trabeculoplasty and then four times daily for a total of 4 days. Visual acuity, intraocular pressure, and anterior chamber flare, measured with the laser flare-cell meter, were evaluated before trabeculoplasty, 3 and 6 hours after trabeculoplasty, and 1, 2, 4, 7, and 14 days after trabeculoplasty. Flare increase after argon laser trabeculoplasty was completely blocked by 0.1% topical diclofenac and the mean of maximal flare increases was reduced significantly in the diclofenac group. Therefore, 0.1% diclofenac drops represent a very efficient anti-inflammatory therapy after argon laser trabeculoplasty.


Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells.
For glucose-stimulated insulin secretion (GSIS), insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In β cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration at exocytic sites, and dramatically enhances GSIS in vitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional β cells of diabetic mice.


Design of aging intervention studies: the NIA interventions testing program.
The field of biogerontology has made great strides towards understanding the biological processes underlying aging, and the time is ripe to look towards applying this knowledge to the pursuit of aging interventions. Identification of safe, inexpensive, and non-invasive interventions that slow the aging process and promote healthy aging could have a significant impact on quality of life and health care expenditures for the aged. While there is a plethora of supplements and interventions on the market that purport to slow aging, the evidence to validate such claims is generally lacking. Here we describe the development of an aging interventions testing program funded by the National Institute on Aging (NIA) to test candidate interventions in a model system. The development of this program highlights the challenges of long-term intervention studies and provides approaches to cope with the stringent requirements of a multi-site testing program.


Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders.
Merimepodib (MMPD) is an orally administered, inosine monophosphate dehydrogenase inhibitor that has shown antiviral activity in nonresponders with chronic hepatitis C (CHC) when combined with pegylated interferon alfa 2a (Peg-IFN-alfa-2a) and ribavirin (RBV). We conducted a randomized, double-blind, multicenter, phase 2b study to evaluate the antiviral activity, safety, and tolerability of MMPD in combination with Peg-IFN-alfa-2a and RBV in patients with genotype 1 CHC who were nonresponders to prior therapy with Peg-IFN and RBV. Patients received 50 mg MMPD, 100 mg MMPD, or placebo every 12 hours, in addition to Peg-IFN-alfa-2a and RBV, for 24 weeks. Patients with a 2-log or more decrease from baseline or undetectable hepatitis C virus (HCV) RNA levels at week 24 were then eligible to continue Peg-IFN-alfa-2a and RBV for a further 24 weeks, followed by 24 weeks of follow-up. The primary efficacy endpoint was sustained virological response (SVR) rate at week 72 in all randomized patients who received at least one dose of study drug and had a history of nonresponse to standard therapy. A total of 354 patients were randomized to treatment (117 to placebo; 119 to 50 mg MMPD; 118 to 100 mg MMPD), and 286 completed the core study. The proportion of patients who achieved SVR was similar among the treatment groups: 6% (6/107) for 50 mg MMPD, 4% (5/112) for 100 mg MMPD, and 5% (5/104) for placebo (P = 0.8431). Adverse-event profiles for the MMPD combination groups were similar to that for Peg-IFN-alfa and RBV alone. Nausea, arthralgia, cough, dyspnea, neutropenia, and anemia were more common in patients taking MMPD. The addition of MMPD to Peg-IFN-alfa-2a and RBV combination therapy did not increase the proportion of nonresponder patients with genotype 1 CHC achieving an SVR.


The cellular basis of hearing: the biophysics of hair cells.
A crucial event in the hearing process is the transduction of mechanical stimuli into electrical signals by hair cells, the sensory receptors of the internal ear. Stimulation results in the rapid opening of ionic channels in the mechanically sensitive organelles of these cells, their hair bundles. These transduction channels, which are nonselectively permeable, are directly excited by hair-bundle displacement. Hair cells are selectively responsive to particular frequencies of stimulation, both due to the mechanical properties of their hair bundles and because of an ensemble of ionic channels that constitute an electrical resonator.


[Cost-effectiveness of mammography screening in Norway].
Since January 1996, mammography screening every second year has been offered to women aged 50 to 69 in four counties in Norway. As an input to the evaluation of the programme, medical authorities commissioned an analysis of the cost-efficacy of screening. The results are presented in this paper. This study of the screening in the City of Oslo is based on registration of time used on various procedure, data for all procedure performed, and financial accounting data. The result have been recalculated for a simulated nation-wide project. Only costs up to the time of diagnosis (malignant/benign) have been included. The total cost of the Oslo programme 1996/97 was NOK 12.1 m (USD 1.6 m). Cost per women examined was NOK 395 and per cancer detected NOK 57,639. Cost per life saved was estimated at NOK 680,000, per year-of-life saved NOK 30,000. Based on accounting data only, comparisons could be made between counties. Costs in other counties were between 39 and 73% higher than in Oslo. Using an estimate of a 40% higher costs nation-wide, we find that the total cost of one year of nation-wide (population 4.5 m) screening would amount to NOK 83 m, cost per life saved to NOK 950,000, and per year-of-life saved to NOK 41,000. Estimated cost per life saved by traffic safety measures has been NOK 10 m. On this basis, mammography screening in Norway seems to be a highly cost-effective measure.


The origins of high hardening and low ductility in magnesium.
Magnesium is a lightweight structural metal but it exhibits low ductility-connected with unusual, mechanistically unexplained, dislocation and plasticity phenomena-which makes it difficult to form and use in energy-saving lightweight structures. We employ long-time molecular dynamics simulations utilizing a density-functional-theory-validated interatomic potential, and reveal the fundamental origins of the previously unexplained phenomena. Here we show that the key 〈c + a〉 dislocation (where 〈c + a〉 indicates the magnitude and direction of slip) is metastable on easy-glide pyramidal II planes; we find that it undergoes a thermally activated, stress-dependent transition to one of three lower-energy, basal-dissociated immobile dislocation structures, which cannot contribute to plastic straining and that serve as strong obstacles to the motion of all other dislocations. This transition is intrinsic to magnesium, driven by reduction in dislocation energy and predicted to occur at very high frequency at room temperature, thus eliminating all major dislocation slip systems able to contribute to c-axis strain and leading to the high hardening and low ductility of magnesium. Enhanced ductility can thus be achieved by increasing the time and temperature at which the transition from the easy-glide metastable dislocation to the immobile basal-dissociated structures occurs. Our results provide the underlying insights needed to guide the design of ductile magnesium alloys.


Patients with mental health conditions in the emergency department: Why so long a wait?
Patients presenting with a mental health disorder (MHD) wait longer in the ED compared to those presenting for other reasons, potentially placing vulnerable patients at further risk for deterioration. The present study identified factors associated with a long ED stay for patients with a MHD. Linked ambulance, emergency, pathology, imaging and admission data for an 18-month period were analysed for ED presentations diagnosed with an MHD ICD-10 at a large teaching hospital. Admissions and discharges were considered separately; a long ED stay was defined as the 90th percentile length of stay. Multivariable generalised linear models were built, identifying predictors of a long ED stay for presentations diagnosed with a MHD. The sample comprised 1163 admissions and 2242 discharges. For admissions, significant predictors for long ED stay were investigations (pathology or imaging tests), a triage score of 1 or 2, arrival out-of-hours (18.00-05.59 hours) and arrival by ambulance. For discharges, significant predictors of a long ED stay were investigations (pathology or imaging tests), arrival out-of-hours, arrival by ambulance and increasing age. Some factors predictive of a long ED stay for patients presenting to the ED and diagnosed with a MHD varied based on their disposition. For admissions, the most urgent presentations were likely to stay longest. Strategies to reduce ED stay for both admissions and discharges should consider addressing modifiable aspects, including the need for certain investigations, and non-modifiable aspects, including the need for further access to after-hours mental health services in hospital and in the community.


Differential effects of monocular deprivation on glutamic acid decarboxylase and type II calcium-calmodulin-dependent protein kinase gene expression in the adult monkey visual cortex.
Increases in immunocytochemically detectable type II calcium-calmodulin-dependent protein kinase (CaM II kinase) and decreases in immunocytochemically detectable glutamic acid decarboxylase (GAD) are known to occur in the visual cortex of adult monkeys following brief periods of monocular visual deprivation. In the present study, GAD and CaM II kinase gene expression was investigated under these conditions. The polymerase chain reaction (PCR) was used to generate species-specific cDNA clones that were used to make antisense RNA probes. A second form of CaM II kinase alpha, CaM II kinase alpha-33, which contains an additional phosphorylation consensus sequence, was identified. In situ hybridization in normal visual cortex revealed a complex sublaminar organization of GAD-expressing cells within layers IVC and VI and a distribution of CaM II kinase alpha-expressing cells that was greatest in layers II, III, IVB, and VI. In situ hybridization in the cortex from animals that had been monocularly deprived revealed enhanced CaM II kinase mRNA levels in deprived-eye columns of layer IVC and, associated with the deprived eye, cytochrome oxidase-stained periodicities in other layers. In layer IV, the enhancement of labeling in deprived-eye stripes was, on average, 16% greater than in normal-eye stripes. By contrast, GAD, mRNA levels appeared unchanged in all layers, suggesting a posttranscriptional regulatory mechanism.


Novel treatment strategies and drugs in development for cryptosporidiosis.
Cryptosporidium is a protozoan pathogen that can cause diarrheal disease in healthy and immunosuppressed individuals, worldwide. Recent studies have highlighted the impact of cryptosporidiosis on children in resource-limited countries. Nitazoxanide is the only Food and Drug Administration approved treatment, but it is not consistently effective therapy for cryptosporidiosis in the most vulnerable populations. Areas covered: This review focused on recent published studies evaluating novel drugs and new compounds for the treatment of cryptosporidiosis. Expert commentary: Combinations of approved drugs have demonstrated some activity. Broad screens have demonstrated activity against Cryptosporidium for a number of available drugs, including statins and clofazimine, and the latter has advanced into clinical trials. Cryptosporidium calcium-dependent protein kinase 1 (CDPK1) has been identified as an attractive target for treatment, and bumped kinase inhibitors have been developed which inhibit CDPK1 and are active against Cryptosporidium growth both in vitro and in vivo. Inhibition of Plasmodium lipid kinase PI(4)K8 of Cryptosporidium by KDU731 greatly reduced oocyst shedding and improved diarrhea in calves with limited effects on the human PI(4)K. Another novel potent inhibitor MMV665917 was efficacious in mouse models with cidal activity against Cryptosporidium. Additional compounds have proved active in vitro. So far, only clofazimine has entered human trials.


Microbial Functional Responses to Cholesterol Catabolism in Denitrifying Sludge.
The 2,3-seco pathway, the pathway for anaerobic cholesterol degradation, has been established in the denitrifying betaproteobacterium Sterolibacterium denitrificans. However, knowledge of how microorganisms respond to cholesterol at the community level is elusive. Here, we applied mesocosm incubation and 16S rRNA sequencing to reveal that, in denitrifying sludge communities, three betaproteobacterial operational taxonomic units (OTUs) with low (94% to 95%) 16S rRNA sequence similarity to Stl. denitrificans are cholesterol degraders and members of the rare biosphere. Metatranscriptomic and metabolite analyses show that these degraders adopt the 2,3-seco pathway to sequentially catalyze the side chain and sterane of cholesterol and that two molybdoenzymes-steroid C25 dehydrogenase and 1-testosterone dehydrogenase/hydratase-are crucial for these bioprocesses, respectively. The metatranscriptome further suggests that these betaproteobacterial degraders display chemotaxis and motility toward cholesterol and that FadL-like transporters may be the key components for substrate uptake. Also, these betaproteobacteria are capable of transporting micronutrients and synthesizing cofactors essential for cellular metabolism and cholesterol degradation; however, the required cobalamin is possibly provided by cobalamin-de novo-synthesizing gamma-, delta-, and betaproteobacteria via the salvage pathway. Overall, our results indicate that the ability to degrade cholesterol in sludge communities is reserved for certain rare biosphere members and that C25 dehydrogenase can serve as a biomarker for sterol degradation in anoxic environments. IMPORTANCE Steroids are ubiquitous and abundant natural compounds that display recalcitrance. Biodegradation via sludge communities in wastewater treatment plants is the primary removal process for steroids. To date, compared to studies for aerobic steroid degradation, the knowledge of anaerobic degradation of steroids has been based on only a few model organisms. Due to the increase of anthropogenic impacts, steroid inputs may affect microbial diversity and functioning in ecosystems. Here, we first investigated microbial functional responses to cholesterol, the most abundant steroid in sludge, at the community level. Our metagenomic and metatranscriptomic analyses revealed that the capacities for cholesterol approach, uptake, and degradation are unique traits of certain low-abundance betaproteobacteria, indicating the importance of the rare biosphere in bioremediation. Apparent expression of genes involved in cofactor de novo synthesis and salvage pathways suggests that these micronutrients play important roles for cholesterol degradation in sludge communities.


Factors affecting the assay of urinary 3-hydroxy pyridinium crosslinks of collagen as markers of bone resorption.
The measurement of the 3-OH pyridinium compounds, pyridinoline (Pyr) and deoxypyridinoline (Dpyr), in urine by high performance liquid chromatography is potentially useful in clinical studies, since they are specific biochemical markers of bone resorption. The aims of the present study were to improve assay performance and optimize sample collection. An isocratic high performance liquid chromatogram (HPLC) separation with baseline resolution was accomplished within 4 min using heptafluorobutyric acid as an ion-pair. The sample preparation for HPLC, using CF1 cellulose, produced uncontaminated samples with a recovery higher than 90% for both crosslinks. An elastin-derived material, tentatively identified as isodesmosine (Ides), was also tested and proved to be a suitable internal standard. Use of this standard improved assay precision. The effect of an oral gelatin load on the excretion of Pyr and Dyr was investigated. The creatinine corrected excretion of Pyr and Dpyr was unchanged over a 6 h period, in contrast to the 10-fold increase in the excretion of urinary hydroxyproline with a peak 2-4 h after ingestion. In 20 postmenopausal women, 2 h fasting morning urine results correlated with results from 24-h urine collections Dpyr/Cr (r = 0.70, n = 20). There was a day-to-day variation of 26% in adults studied for 10 days.


Association of Central Noninvasive Brain Stimulation Interventions With Efficacy and Safety in Tinnitus Management: A Meta-analysis.
Tinnitus has a prevalence of 10% to 25% and is frequently associated with numerous complications, such as neuropsychiatric disease. Traditional treatments have failed to meet the needs of patients with tinnitus. Noninvasive brain stimulation (NIBS) can focally modify cortical functioning and has been proposed as a strategy for reducing tinnitus severity. However, the results have been inconclusive. To evaluate the association between different central NIBS therapies and efficacy and acceptability for treatment of tinnitus. ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, and Web of Science databases were searched from inception to August 4, 2019. No language restriction was applied. Manual searches were performed for potentially eligible articles selected from the reference lists of review articles and pairwise meta-analyses. Randomized clinical trials (RCTs) examining the central NIBS method used in patients with unilateral or bilateral tinnitus were included in the current network meta-analysis. The central NIBS method was compared with sham, waiting list, or active controls. Studies that were not clinical trials or RCTs and did not report the outcome of interest were excluded. Two authors independently screened the studies, extracted the relevant information, and evaluated the risk of bias in the included studies. In cases of discrepancy, a third author became involved. If manuscript data were not available, the corresponding authors or coauthors were approached to obtain the original data. This network meta-analysis was based on the frequentist model. The primary outcome was change in the severity of tinnitus. Secondary outcomes were changes in quality of life and the response rate related to the NIBS method in patients with tinnitus. Overall, 32 unique RCTs were included with 1458 unique participants (mean female proportion, 34.4% [range, 0%-81.2%]; mean age, 49.6 [range, 40.0-62.8] years; median age, 49.8 [interquartile range, 48.1-52.4] years). The results of the network meta-analysis revealed that cathodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex combined with transcranial random noise stimulation over the bilateral auditory cortex was associated with the greatest improvement in tinnitus severity (standardized mean difference [SMD], -1.89; 95% CI, -3.00 to -0.78) and quality of life (SMD, -1.24; 95% CI, -2.02 to -0.45) compared with the controls. Improvement in tinnitus severity ranked more favorably for continuous theta-burst stimulation (cTBS) over both auditory cortices (SMD, -0.79; 95% CI = -1.57 to -0.01) than cTBS over only the left auditory cortex (SMD, -0.30; 95% CI, -0.87 to 0.28), compared with controls. Repetitive transcranial magnetic stimulation with priming had a superior beneficial association with tinnitus severity compared with the strategies without priming. None of the investigated NIBS types had a significantly different dropout rate compared with that of the control group. This network meta-analysis suggests a potential role of NIBS interventions in tinnitus management. Future large-scale RCTs focusing on longer follow-up and different priming procedure NIBS are warranted to confirm these findings.


Do Not Attempt Cardiopulmonary Resuscitation orders in acute medical settings: a qualitative study.
Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) orders have been shown to be independently associated with patients receiving fewer treatments, reduced admission to intensive care and worse outcomes even after accounting for known confounders. The mechanisms by which they influence practice have not previously been studied. To present a rich qualitative description of the use of the DNACPR form in a hospital ward setting and explore what influence it has on the everyday care of patients. Multi-source qualitative study, primarily using direct observation and semi-structured interviews based on two acute wards in a typical middle-sized National Health Service hospital in UK. The study identified a range of ways in which DNACPR orders influence ward practice, beyond dictating whether or not cardiopulmonary resuscitation should be attempted. Five key themes encapsulate the range of potential impacts emerging from the data: the specific design and primacy of the form, matters relating to clinical decision making, staff reflections on how the form can affect care, staff concern over 'inappropriate' resuscitation, and discussions with patients/relatives about DNACPR decisions. Overall, it was found that while the DNACPR form is recognized as serving a useful purpose, its influence negatively permeated many aspects of clinical practice. DNACPR orders can act as unofficial 'stop' signs and can often signify the inappropriate end to clinical decision making and proactive care. Many clinicians were uncomfortable discussing DNACPR orders with patients and families. These findings help understand why patients with DNACPR orders have worse outcomes, as such they may inform improvements in resuscitation policies.


Negative priming and perceptual fluency: more than what meets the eye.
In two priming experiments, we manipulated the perceptual quality of the target or the distractor on the prime trial; the stimuli were repeated or novel. Negative priming was found to be contingent on stimulus repetition, because it was obtained with repeated items but not with novel items. Prime trial perceptual degradation modulated negative priming for repeated items but had no effect on priming in ignored repetition conditions using novel stimuli. These patterns were obtained even when the effect of perceptual degradation was (1) greater than the effect of stimulus repetition and (2) greater for novel words than for repeated words. Although stimulus repetition increases perceptual fluency, the activation of perceptual representations by itself is not sufficient to produce negative priming. Instead, we suggest that negative priming is a manifestation of an activation-sensitive inhibitory mechanism that functions to reduce response competition.


Statin-induced apoptosis and skeletal myopathy.
Over 100 million prescriptions were filled for statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) in 2004. Statins were originally developed to lower plasma cholesterol in patients with hypercholesterolemia and are the most effective drugs on the market in doing so. Because of the discovered pleiotropic effects of statins, the use has expanded to the treatment of many other conditions, including ventricular arrythmias, idiopathic dilated cardiomyopathy, cancer, osteoporosis, and diabetes. The elderly population is growing. Therefore, it is estimated that the number of statin users will also increase. Fortunately, the use of statins is relatively safe with few side effects. Myopathy is the most common side effect with symptoms ranging from fatigue, weakness, and pain to symptoms associated with rhabdomyolysis which is a life-threatening condition. The development of statin-induced rhabdomyolysis is rare occurring in approximately 0.1% of patients; however, the occurrence of less severe symptoms is underreported and may be 1-5% or more. Physical exercise appears to increase the likelihood for the development of myopathy in patients taking statins. It is thought that as many as 25% of statin users who exercise may experience muscle fatigue, weakness, aches, and cramping due to statin therapy and potentially dismissed by the patient and physician. The mechanisms causing statin-induced myopathy have not been elucidated; however, research efforts suggest that apoptosis of myofibers may contribute. The mitochondrion is considered a regulatory center of apoptosis, and therefore its role in the induction of apoptosis will be discussed as well as the mechanism of statin-induced apoptosis and myopathy.


The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer.
The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression. Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids. Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway. Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.


Limb salvage despite extensive tissue loss. Free tissue transfer combined with distal revascularization.
Extensive lower-extremity tissue loss may preclude limb salvage despite successful arterial reconstruction. We attempted to avoid limb loss in such patients by combining arterial bypass with microvascular free tissue transfer. Fourteen patient (12 diabetic), 33 to 74 years of age, presented with extensive tissue loss in 15 lower extremities, exposing bone or tendon on the heel, ankle, lower part of the leg, or hindfoot. Mean ulcer size was 5 X 8 cm. Four patients had had previous contralateral below-knee amputations. Femorodistal (seven), popliteal-distal (three), or femoropopliteal (four) bypass, or tibial angioplasty (one), was performed to provide sufficient inflow for free tissue transfer. Serratus anterior, scapular, latissimus dorsi, rectus abdominis, gracilis, ulnar, or temporalis free flaps were used. One free flap failed due to venous thrombosis and was corrected with a second flap. Limb salvage was achieved in 14 (93%) of 15 limbs during a mean follow-up of 24 months. The single amputation occurred due to severe foot ischemia in a patient whose femorodistal bypass remained patent only to the viable free flap. The remaining 13 patients (14 limbs) became ambulatory, including those with free flaps to weight-bearing regions.


RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis.
The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis.


Spectroscopic manifestations of the Kondo effect on single adatoms.
The present topical review focuses on recent advances concerning an intriguing phenomenon in condensed matter physics, the scattering of conduction electrons at the localized spin of a magnetic impurity: the Kondo effect. Spectroscopic signatures of this effect have been observed in the past by high-resolution photoemission which, however, has the drawback of averaging over a typical surface area of 1 mm(2). By combining the atomic-scale spatial resolution of the scanning tunneling microscope (STM) with an energy resolution of a few tens of µeV achievable nowadays in scanning tunneling spectroscopy (STS), and by exposing the magnetic adatom to external magnetic fields, our understanding of the interaction of a single magnetic impurity with the conduction electrons of the nonmagnetic host has been considerably deepened. New insight has emerged by taking advantage of quantum size effects in the metallic support and by decoupling the magnetic adatom from the supporting host metal, for instance by embedding it inside a molecule or by separating it by an ultrathin insulating film from the metal surface. In this way, Kondo resonances and Kondo temperatures can be tailored and manipulated by changing the local density of states of the environment. In the weak coupling limit between a Kondo impurity and a superconductor only a convolution of tip and sample DOS is observed while for strongly coupled systems midgap states appear, indicating superconducting pair breaking. Magnetic impurities with co-adsorbed hydrogen on metallic surfaces show pseudo-Kondo resonances owing to very low-energy vibrational excitations detected by inelastic tunneling spectroscopy. One of the most recent achievements in the field has been the clarification of the role of magnetic anisotropy in the Kondo effect for localized spin systems with a spin larger than S = 1/2.


Evaluation of the sustained effect of inpatient falls prevention education and predictors of falls after hospital discharge--follow-up to a randomized controlled trial.
This study aimed to determine (i) risk factors for postdischarge falls and (ii) the effect of inpatient falls prevention education on rates of falls after discharge. Participants (n = 343) were a prospective cohort nested within a randomized controlled trial (n = 1,206) of falls prevention patient education in hospital compared with usual care. Participants were followed up for 6 months after discharge and falls recorded via a falls diary and monthly telephone calls. Potential falls risk factors were assessed at point of discharge and at 6 months postdischarge using a telephone survey. There were 276 falls among 138 (40.2%) participants in the 6 months following discharge (4.52/1,000 person days) of which 150 were injurious falls (2.46/1,000 person days). Pairwise comparisons found no significant differences between groups in rates of falls after adjustment for confounding variables. Independent risk factors for all falls outcomes were male gender, history of falls prior to hospital admission, fall during hospital admission, depressed mood at discharge, using a walking aid at discharge, and receiving assistance with activities of daily living at 6 months following discharge. Receiving assistance with activities of daily living significantly reduced the risk of falls and injurious falls for high risk patients. Older patients are at increased risk of falls and falls injuries following discharge. Education that effectively reduced inpatient falls appears to have no ongoing protective effect after discharge. Independent risk factors for falls in this population differ from both hospital and general community settings.


Insulin suppresses rat growth hormone messenger ribonucleic acid levels in rat pituitary tumor cells.
Insulin has been shown to suppress growth hormone (GH) secretion by rat pituitary tumor cells (GH3) independently of glucose utilization. The effects of physiologic doses of insulin were therefore tested on cytoplasmic levels of GH messenger ribonucleic acid (mRNA) sequences. Insulin (3.5 nM) treatment of cells for 5 days suppressed the hybridization of cytoplasmic GH mRNA with 32P-cDNA for rGH by 50%. The three- to fourfold induction of cytoplasmic GH mRNA by hydrocortisone (1 microM) was also suppressed by insulin (3.5 nM) by 40%. The results show a direct suppression of cytoplasmic rGH mRNA concentration by physiologic doses of insulin. These findings may be due to either decreased rate of GH gene transcription, increased intracellular breakdown, or decreased nuclear-cytoplasmic transport of GH mRNA caused by insulin.


A Tutorial and Case Study in Propensity Score Analysis: An Application to Estimating the Effect of In-Hospital Smoking Cessation Counseling on Mortality.
Propensity score methods allow investigators to estimate causal treatment effects using observational or nonrandomized data. In this article we provide a practical illustration of the appropriate steps in conducting propensity score analyses. For illustrative purposes, we use a sample of current smokers who were discharged alive after being hospitalized with a diagnosis of acute myocardial infarction. The exposure of interest was receipt of smoking cessation counseling prior to hospital discharge and the outcome was mortality with 3 years of hospital discharge. We illustrate the following concepts: first, how to specify the propensity score model; second, how to match treated and untreated participants on the propensity score; third, how to compare the similarity of baseline characteristics between treated and untreated participants after stratifying on the propensity score, in a sample matched on the propensity score, or in a sample weighted by the inverse probability of treatment; fourth, how to estimate the effect of treatment on outcomes when using propensity score matching, stratification on the propensity score, inverse probability of treatment weighting using the propensity score, or covariate adjustment using the propensity score. Finally, we compare the results of the propensity score analyses with those obtained using conventional regression adjustment.


Marek's disease virus (MDV) encodes an interleukin-8 homolog (vIL-8): characterization of the vIL-8 protein and a vIL-8 deletion mutant MDV.
Chemokines induce chemotaxis, cell migration, and inflammatory responses. We report the identification of an interleukin-8 (IL-8) homolog, termed vIL-8, encoded within the genome of Marek's disease virus (MDV). The 134-amino-acid vIL-8 shares closest homology to mammalian and avian IL-8, molecules representing the prototype CXC chemokine. The gene for vIL-8 consists of three exons which map to the BamHI-L fragment within the repeats flanking the unique long region of the MDV genome. A 0.7-kb transcript encoding vIL-8 was detected in an n-butyrate-treated, MDV-transformed T-lymphoblastoid cell line, MSB-1. This induction is essentially abolished by cycloheximide and herpesvirus DNA polymerase inhibitor phosphonoacetate, indicating that vIL-8 is expressed with true late (gamma2) kinetics. Baculovirus-expressed vIL-8 was found to be secreted into the medium and shown to be functional as a chemoattractant for chicken peripheral blood mononuclear cells but not for heterophils. To characterize the function of vIL-8 with respect to MDV infection in vivo, a recombinant MDV was constructed with a deletion of all three exons and a soluble-modified green fluorescent protein (smGFP) expression cassette inserted at the site of deletion. In two in vivo experiments, the vIL-8 deletion mutant (RB1BvIL-8DeltasmGFP) showed a decreased level of lytic infection in comparison to its parent virus, an equal-passage-level parent virus, and to another recombinant MDV containing the insertion of a GFP expression cassette at the nonessential US2 gene. RB1BvIL-8DeltasmGFP retained oncogenicity, albeit at a greatly reduced level. Nonetheless, we have been able to establish a lymphoblastoid cell line from an RB1BvIL-8DeltasmGFP-induced ovarian lymphoma (MDCC-UA20) and verify the presence of a latent MDV genome lacking vIL-8. Taken together, these data describe the identification and characterization of a chemokine homolog encoded within the MDV genome that is dispensable for transformation but may affect the level of MDV in vivo lytic infection.


Predictions of hepatic disposition properties using a mechanistically realistic, physiologically based model.
Quantitative mappings were established between drug physicochemical properties (PCPs) and parameter values of a physiologically based, mechanistically realistic, in silico liver (ISL). The ISL plugs together autonomous software objects that represent hepatic components at different scales and levels of detail. Microarchitectural features are represented separately from the mechanisms that influence drug metabolism. The same ISL has been validated against liver perfusion data for sucrose and four cationic drugs: antipyrine, atenolol, labetalol, and diltiazem. Parameters sensitive to drug-specific PCPs were tuned so that ISL outflow profiles from a single ISL matched in situ perfused rat liver outflow profiles of all five compounds. Quantitative relationships were then established between the four sets of drug PCPs and the corresponding four sets of PCP-sensitive, ISL parameter values; those relationships were used to predict PCP-sensitive, ISL parameter values for prazosin and propranolol given only their PCPs. Relationships were established using three different methods: 1) a simple linear correlation method, 2) the fuzzy c-means algorithm, and 3) a simple artificial neural network. Each relationship was used separately to predict ISL parameter values for prazosin and propranolol, given their PCPs. Those values were applied in the ISL used earlier to predict the hepatic disposition details for each drug. Although we had only sparse data available, all predicted disposition profiles were judged reasonable (within a factor of 2 of referent profile data). The order of precision, based on a similarity measure, was 3 > 2 > 1.


Exploring genetic and environmental effects in dysphonia: a twin study.
To explore the existence of genetic effects as well as the interaction between potential genetic effects and a voice-demanding occupation on dysphonia. One thousand seven hundred and twenty-eight Finnish twins (555 male; 1,173 female) born between 1961 and 1989 completed a questionnaire concerning vocal symptoms and occupation. The zygosity determination resulted in 125 monozygotic and 108 dizygotic full twin pairs. A composite variable called dysphonia was formed by summing 6 vocal symptoms based on the results of a factor analysis. Twin model fitting was used to explore the contribution of genetic and environmental effects on the dysphonia variable. Individual differences in dysphonia were explained by genetic effects (35%) and nonshared environmental effects (65%). Shared environmental effects were estimated at 0%. Also, the authors found that for the participants who worked in voice-demanding occupations, the causes of dysphonia were more environmental, whereas the etiology of the symptoms was more strongly affected by genes in the participants with less voice-demanding occupations. However, this gene-environment interaction was not statistically significant. Both genetic and environmental factors have an impact on the etiology of voice problems. Environmental factors, either independently or interacting with genetic factors, seem to play the key role, especially if the person has a voice-demanding occupation.


Types of urethral catheter for reducing symptomatic urinary tract infections in hospitalised adults requiring short-term catheterisation: multicentre randomised controlled trial and economic evaluation of antimicrobial- and antiseptic-impregnated urethral catheters (the CATHETER trial).
Catheter-associated urinary tract infection (CAUTI) is a major preventable cause of harm for patients in hospital and incurs significant costs for health-care providers such as the UK NHS. Many preventative strategies and measures have been introduced to minimise CAUTI risk, including the use of antimicrobial catheters. However, there is considerable uncertainty regarding their usefulness in terms of reducing symptomatic CAUTI, and whether or not they are cost-effective. Do antimicrobial catheters reduce the rate of symptomatic urinary tract infection (UTI) during short-term hospital use and is their use cost-effective for the UK NHS? A pragmatic multicentre UK randomised controlled trial comparing three catheters as they would be used in the UK NHS: antimicrobial-impregnated (nitrofurazone) and antiseptic-coated (silver alloy) catheters with the standard polytetrafluoroethylene (PTFE)-coated catheters. Economic evaluation used a decision model populated with data from the trial. Sensitivity analysis was used to explore uncertainty. Relevant clinical departments in 24 NHS hospitals throughout the UK. Adults requiring temporary urethral catheterisation for a period of between 1 and 14 days as part of their care, predominantly as a result of elective surgery. Eligible participants were randomised 1 : 1 : 1 to one of three types of urethral catheter in order to make the following pragmatic comparisons: nitrofurazone-impregnated silicone catheter compared with standard PTFE-coated latex catheter; and silver alloy-coated hydrogel latex catheter compared with standard PTFE-coated latex catheter. The primary outcome for clinical effectiveness was the incidence of UTI at any time up to 6 weeks post randomisation. This was defined as any symptom reported during catheterisation, up to 3 days or 1 or 2 weeks post catheter removal or 6 weeks post randomisation combined with a prescription of antibiotics, at any of these times, for presumed symptomatic UTI. The primary economic outcome was incremental cost per quality-adjusted life-year (QALY). Health-care costs were estimated from NHS sources with QALYs calculated from participant completion of the European Quality of Life-5 Dimensions (EQ-5D). Outcome analyses encompassed 6394 (90%) of 7102 participants randomised. The rate of symptomatic UTI within 6 weeks of randomisation was 10.6% in the nitrofurazone group (n = 2153; -2.1% absolute risk difference), 12.5% in the silver alloy group (n = 2097; -0.1% absolute risk difference) and 12.6% in the PTFE group (n = 2144). The effect size {odds ratio (OR) [97.5% confidence interval (CI)]} was 0.82 (97.5% CI 0.66 to 1.01) for nitrofurazone (p = 0.037) and 0.99 (97.5% CI 0.81 to 1.22) for silver alloy (p = 0.92) catheters. The nitrofurazone catheters were more likely to cause discomfort during use and on removal. The primary economic analysis suggested that nitrofurazone-impregnated catheters would be, on average, the least costly (> £7 less than PTFE) and most effective option at current NHS prices. There was a 73% chance that nitrofurazone would be cost saving and an 84% chance that the incremental cost per QALY would be < £30,000. At the trial price (£6.46), silver alloy catheters were very unlikely to be cost-effective. These results were unchanged in sensitivity analyses, although when the length of stay cost was excluded the incremental cost per QALY for nitrofurazone against PTFE was £28,602. The trial estimate of clinical effectiveness for nitrofurazone-impregnated catheters was less than the pre-specified minimum absolute risk difference that we considered important (-3.3%), and the surrounding CI included zero, indicating that any reduction in catheter-associated UTI was uncertain. Economic analysis, although associated with uncertainty, suggested that nitrofurazone-impregnated catheters may be cost-effective for the NHS. The trial ruled out the possibility that silver alloy-coated catheters might reach the pre-set degree of clinical effectiveness and that their use was unlikely to be cost-effective. These findings should be considered by patients, clinicians and health-care policy-makers to determine whether or not a change in practice is worthwhile. Future research should be aimed at determining the minimum clinically important difference in terms of CAUTI prevention in comparative trials, and to identify reliable methods which can detect the impact of the intervention on quality of life and other drivers of cost, when the intervention is a subsidiary part of overall treatment plans.


Adding an App-Based Intervention to the Cognitive Behavioral Analysis System of Psychotherapy in Routine Outpatient Psychotherapy Treatment: Proof-of-Concept Study.
The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) is an empirically supported psychotherapeutic treatment developed specifically for persistent depressive disorder. However, given the high rates of nonresponse and relapse, there is a need for optimization. Studies suggest that outcomes can be improved by increasing the treatment dose via, for example, the continuous web-based application of therapy strategies between sessions. The strong emphasis in CBASP on the therapeutic relationship, combined with limited therapeutic availabilities, encourages the addition of web-based interventions to face-to-face therapy in terms of blended therapy. The aim of this study was to test an app-based intervention called CBASPath, which was designed to be used as a blended therapy tool. CBASPath offers 8 sequential modules with app-based exercises to facilitate additional engagement with the therapy content and a separate exercise to conduct situational analyses within the app at any time. CBASPath was tested in an open pilot study as part of routine outpatient CBASP treatment. Participating patients were asked to report their use patterns and blended use (integrated use of the app as part of therapy sessions) at 3 assessment points over the 6-month test period and rate the usability and quality of and their satisfaction with CBASPath. The results of the pilot trial showed that 93% (12/13) of participants used CBASPath as a blended tool during their therapy and maintained this throughout the study period. Overall, they reported good usability and quality ratings along with high user satisfaction. All participants showed favorable engagement with CBASPath; however, the frequency of use differed widely among the participants and assessment points. Situational analysis was used by all participants, and the number of completed modules ranged from 1 to 7. All participants reported blended use, although the frequency of integration in the face-to-face sessions varied widely. Our findings suggest that the digital augmentation of complex and highly interactive CBASP therapy in the form of blended therapy with CBASPath is feasible in routine outpatient care. Therapeutic guidance might contribute to high adherence and increase patient self-management. A few adjustments, such as saving entries directly in the app, could facilitate higher user engagement. A randomized controlled trial is now needed to investigate the efficacy and added value of this blended approach. In the long term, CBASPath could help optimize persistent depressive disorder treatment and reduce relapse by intensifying therapy and providing long-term patient support through the app.


Predictors of caregiver unawareness and nontreatment of dementia among residents of assisted living facilities: the Maryland Assisted Living Study.
Assisted living (AL) is a rapidly expanding residential option for the senior population. With increased utilization, it becomes important to understand the detection and treatment of dementia in this setting, but little is known. The objective of this study was to identify and evaluate factors associated with caregiver unawareness of dementia and failure to treat dementia in AL. The setting was a cross-sectional study of a random sample of AL facilities in central Maryland (The Maryland Assisted Living Study). Geriatric psychiatrists evaluated 198 participants and assigned dementia diagnoses to 134 residents (67.7%). The extent to which dementia was recognized and treated in these facilities was estimated on the basis of caregiver interview and chart review data. Using logistic regression models, demographic, cognitive, and functional measures were evaluated as predictors of caregiver unawareness and nontreatment of dementia. Severity of cognitive and functional impairment, number of neuropsychiatric symptoms, and male gender were all independent predictors of caregiver unawareness of dementia. Family and caregiver unawareness of dementia and female gender were predictors of failure to treat dementia. Detection and treatment were not associated with race, age, or overall medical health. Caregivers were more likely to be unaware of dementia in residents who did not have severe cognitive impairment or obvious behavioral and functional problems. Caregiver and family unawareness were in turn associated with nontreatment. Observed gender differences in detection and treatment will require replication and further study. These observations suggest that systematic educational interventions for caregivers and families may improve detection and hence treatment in the AL setting.


'Cut down to quit' with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.
To examine the effectiveness and cost-effectiveness of nicotine replacement therapy (NRT) for 'cut down to quit' (CDTQ) smoking. Major electronic databases were searched up to July 2006. Data from studies meeting the criteria were reviewed and analysed. A decision analytical model was constructed to estimate the cost-effectiveness of CDTQ from the NHS perspective. No systematic reviews of the effectiveness of CDTQ and no randomised controlled trials (RCTs) specifically addressing CDTQ were identified. Seven randomised placebo-controlled trials satisfied the inclusion criteria; six of these were industry sponsored. However, sustained smoking cessation was only reported as a secondary outcome in these trials and required commencement of cessation within the first 6 weeks of treatment. Meta-analyses of the study level results demonstrated statistically significant superiority of NRT compared with placebo. Individual patient data from unpublished reports of five RCTs were used to calculate sustained abstinence of at least 6 months starting at any time during the treatment period (generally 12 months). From this the meta-analysis indicated statistically significant superiority of NRT versus placebo [relative risk 2.06, 95% confidence interval (CI) 1.34 to 3.15]. The proportions achieving this outcome across all five RCTs were 6.75% of participants in receipt of NRT and 3.29% of those receiving placebo. The number-needed-to-treat was 29. This measure of sustained abstinence was used for economic modelling. No existing economic analyses of CDTQ were identified. A de novo decision analytic model was constructed to estimate the cost-effectiveness of making CDTQ with NRT available for smokers unwilling or unable to attempt an abrupt quit. The outcome measure was expected quality-adjusted life-years (QALYs). The model results suggest that CDTQ with NRT delivers incremental cost-effectiveness ratios (ICERs) ranging from around 1500 pounds/QALY to 7700 pounds/QALY depending on the age at which smoking cessation was achieved and the modes of CDTQ delivery. Assuming applicability to a single population, CDTQ was not cost-effective compared with abrupt quitting. If CDTQ with NRT were to be offered on the NHS as a matter of policy, the base-case results suggest that it would only be effective and cost-effective if a substantial majority of the people attempting CDTQ with NRT were those who would otherwise make no attempt to quit. This result is robust to considerable variation in the forms of CDTQ with NRT offered, and to the assumptions about QALY gained per quit success. Meta-analysis of RCT evidence of quit rates in NRT-supported smoking reduction studies indicates that NRT is an effective intervention in achieving sustained smoking abstinence for smokers who declare unwillingness or inability to attempt an abrupt quit. The 12-month sustained abstinence success rate in this population (approximately 5.3% with NRT versus approximately 2.6% with placebo) is considerably less than that documented for an abrupt quit NRT regime in smokers willing to attempt an abrupt quit with NRT (which according to other systematic reviews is around 16% with NRT versus 10% with placebo). Most of the evidence of effectiveness of CDTQ came from trials that required considerable patient-investigator contact. Therefore, for CDTQ with NRT to generate similar abstinence rates for this recalcitrant population in a real-world setting would probably require a similar mode of delivery. The modelling undertaken, which was based on reasonable assumptions about costs, benefits and success rates, suggests that CDTQ is highly cost-effective compared with no quit attempt. CDTQ remains cost-effective if dilution from abrupt quitting forms a small proportion of CDTQ attempts. In an alternative analysis in which smokers who switch from an abrupt quit to CDTQ retain the success rate of abrupt quitters, all forms of CDTQ appear cost-effective. Randomised trials in recalcitrant smokers allowing head-to-head comparison of CDTQ delivered with various modalities would be informative.


Enamel defects and salivary methylmalonate in methylmalonic acidemia.
To characterize enamel defects in patients with methylmalonic acidemia (MMA) and cobalamin (cbl) metabolic disorders and to examine salivary methylmalonate levels in MMA. Teeth from patients (n = 32) were evaluated for enamel defects and compared with age- and gender-matched controls (n = 55). Complementation class (mut, cblA, cblB and cblC) and serum methylmalonate levels were examined. Primary teeth from two patients were examined by light and scanning electron microscopy and salivary methylmalonate levels from two patients were analyzed. Enamel defects were significantly more prevalent per tooth in the affected group than the control group, across complementation types (P < 0.0001). The mut MMA subgroup had a significantly higher prevalence per individual of severe enamel defects than controls (P = 0.021), and those with enamel defects exhibited higher serum methylmalonate levels than those without (P = 0.017). Salivary methylmalonate levels were extremely elevated and were significantly higher than controls (P = 0.002). Primary teeth were free of enamel defects except for two cblC patients who exhibited severe enamel hypoplasia. One primary tooth from a cblC patient manifested markedly altered crystal microstructure. Enamel anomalies represent a phenotypic manifestation of MMA and cbl metabolic disorders. These findings suggest an association between enamel developmental pathology and disordered metabolism.


Surface functionalization of polyoxovanadium clusters: generation of highly soluble charge carriers for nonaqueous energy storage.
Here, we demonstrate the effects of surface functionalization on a tunable series of nano-sized electron shuttles, toward improving their function in nonaqueous energy storage. The synthesis of a series of polyoxovanadium clusters featuring bridging ether functional groups is reported, revealing the influence of bridging "R" group identity on electrochemical stability in solution. Furthermore, the presence of bridging ether moeities yields enhanced solubility in acetonitrile (up to 1.2 M), highlighting synthetic strategies for the development of organofunctionalized polyoxometalate-derived charge carriers for nonaqueous, electrochemical energy storage.


Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration.
The role of dominant transforming p53 in carcinogenesis is poorly understood. Our previous data suggested that aberrant p53 proteins can enhance tumorigenesis and metastasis. Here, we examined potential mechanisms through which gain-of-function (GOF) p53 proteins can induce motility. Cells expressing GOF p53 -R175H, -R273H and -D281G showed enhanced migration, which was reversed by RNA interference (RNAi) or transactivation-deficient mutants. In cells with engineered or endogenous p53 mutants, enhanced migration was reduced by downregulation of nuclear factor-kappaB2, a GOF p53 target. We found that GOF p53 proteins upregulate CXC-chemokine expression, the inflammatory mediators that contribute to multiple aspects of tumorigenesis. Elevated expression of CXCL5, CXCL8 and CXCL12 was found in cells expressing oncogenic p53. Transcription was elevated as CXCL5 and CXCL8 promoter activity was higher in cells expressing GOF p53, whereas wild-type p53 repressed promoter activity. Chromatin immunoprecipitation assays revealed enhanced presence of acetylated histone H3 on the CXCL5 promoter in H1299/R273H cells, in agreement with increased transcriptional activity of the promoter, whereas RNAi-mediated repression of CXCL5 inhibited cell migration. Consistent with this, knockdown of the endogenous mutant p53 in lung cancer or melanoma cells reduced CXCL5 expression and cell migration. Furthermore, short hairpin RNA knockdown of mutant p53 in MDA-MB-231 cells reduced expression of a number of key targets, including several chemokines and other inflammatory mediators. Finally, CXCL5 expression was also elevated in lung tumor samples containing GOF p53, indicating relevance to human cancer. The data suggest a mechanistic link between GOF p53 proteins and chemokines in enhanced cell motility.


The fate of microcystins in the environment and challenges for monitoring.
Microcystins are secondary metabolites produced by cyanobacteria that act as hepatotoxins in higher organisms. These toxins can be altered through abiotic processes, such as photodegradation and adsorption, as well as through biological processes via metabolism and bacterial degradation. Some species of bacteria can degrade microcystins, and many other organisms metabolize microcystins into a series of conjugated products. There are toxicokinetic models used to examine microcystin uptake and elimination, which can be difficult to compare due to differences in compartmentalization and speciation. Metabolites of microcystins are formed as a detoxification mechanism, and little is known about how quickly these metabolites are formed. In summary, microcystins can undergo abiotic and biotic processes that alter the toxicity and structure of the microcystin molecule. The environmental impact and toxicity of these alterations and the metabolism of microcystins remains uncertain, making it difficult to establish guidelines for human health. Here, we present the current state of knowledge regarding the alterations microcystins can undergo in the environment.


Molecular dynamics of synthetic leucine-serine ion channels in a phospholipid membrane.
Molecular dynamics calculations were carried out on models of two synthetic leucine-serine ion channels: a tetrameric bundle with sequence (LSLLLSL)(3)NH(2) and a hexameric bundle with sequence (LSSLLSL)(3)NH(2). Each protein bundle is inserted in a palmitoyloleoylphosphatidylcholine bilayer membrane and solvated by simple point charge water molecules inside the pore and at both mouths. Both systems appear to be stable in the absence of an electric field during the 4 ns of molecular dynamics simulation. The water motion in the narrow pore of the four-helix bundle is highly restricted and may provide suitable conditions for proton transfer via a water wire mechanism. In the wider hexameric pore, the water diffuses much more slowly than in bulk but is still mobile. This, along with the dimensions of the pore, supports the observation that this peptide is selective for monovalent cations. Reasonable agreement of predicted conductances with experimentally determined values lends support to the validity of the simulations.