Revised description and classification of atypical isolates of Pasteurella multocida from bovine lungs based on genotypic characterization to include variants previously classified as biovar 2 of Pasteurella canis and Pasteurella avium.
Strains deviating in key phenotypic characters, mainly isolated from cases of bovine pneumonia in five European countries, were genotyped in order to examine their genotypic relationship with Pasteurella multocida. Twenty-two strains of Pasteurella avium biovar 2, including variants in indole, xylose and mannitol, 18 strains of Pasteurella canis biovar 2 and variants of this taxon, five strains of P. multocida subsp. septica showing variations in indole and ornithine decarboxylase, nine strains of P. multocida subsp. multocida showing variation in ornithine decarboxylase and mannitol, and type strains of the subspecies of P. multocida were included. Ribotyping was used to examine the relationship of the strains, and 13 types, each containing between one and 20 isolates, were observed. Identical ribotypes were observed in some cases for P. avium biovar 2 and either P. canis biovar 2 or P. multocida subsp. septica. ITS (16S-23S rRNA internal transcribed spacer) fragment-length profiling showed identity of the majority of strains (47 of 52), representing all four taxa, with only five divergent strains. A 16S rRNA sequence comparison of 11 strains representing the main ribotype clusters showed 99.9 % similarity to the type strain of P. multocida subsp. multocida, but only 97.4 % similarity was obtained to P. canis (biovar 1) and 93.7 % to P. avium (biovar 1). A species-specific PCR test for P. multocida gave a positive result with biovar 2 variants of P. avium and P. canis. DNA-DNA hybridizations between strains of P. multocida, biovar 2 variants of P. avium and P. canis, and P. multocida subsp. septica confirmed similarity at the species level. It is proposed, on the basis of genotypic similarity, that P. multocida be reclassified to include the biovar 2 variants of P. avium and P. canis and that the existence of the biovar 2 variants of P. avium and P. canis is highly questionable. It is concluded that the redefined P. multocida is genotypically homogeneous, although phenotypically diverse lineages exist with respect to ornithine decarboxylase, indole and mannitol, characters that have been regarded as essential for identification to the species level. A formal reclassification of the species is not possible, however, since too few strains have been found to vary in these key characters. Considering the phenotypic diversity of P. multocida, identification will have to depend partly on genotypic methods and the source host also seems important for safe diagnosis.


Generation of larger numbers of separated microbial populations by cultivation in segmented-flow microdevices.
The high speed production of fluid segments for the highly parallelized cultivation of monoclonal cell populations was carried out by the use of microchip segmentor modules. Aqueous fluid segments, embedded in a non-miscible carrier liquid, were produced with frequencies up to 30 s(-1) and showed a high homogeneity in size. This corresponds with the production of about 2.5 million samples per day. The segment volumes can be adapted between about 4 nl and 100 nl. The typical segment size for cultivation experiments is in the range between 40 nl and 80 nl. Nutrient medium can be applied instead of pure water. It is possible to aliquot a cell suspension in such a way that most of the aqueous fluid segments contain only one cell. In model experiments with four microbial species chip-produced aliquots of 60 nl, each containing one or a few cells, were incubated in Teflon capillary tubes. Rapid growth of the microcultures was observed. Cell densities were found to be as high as in conventional shake flask cultures.


Testing the ability of children with attention deficit hyperactivity disorder to accurately report the effects of medication on their behavior.
Children with attention deficit hyperactivity disorder (ADHD) are often treated with central nervous system stimulants, making the evaluation of medication effects an important topic for applied behavior analysts. Because assessment protocols emphasize informant reports and direct observations of child behavior, little is known about the extent to which children themselves can accurately report medication effects. Double-blind placebo-controlled procedures were used to examine whether 6 children with ADHD could recognize the effects of their medication. The children were given math worksheets to complete for 15 min during each of 14 sessions while on medication and placebo. Children completed a self-evaluation form at the end of each session, and ratings were compared to observed behavior and academic performance. Results indicated that 3 children were able to accurately report their medication status at levels greater than chance, whereas the accuracy of reports by all children was related to dosage level, differences in behavior, and the presence of adverse effects. The implications of these results for placebo-controlled research, self-monitoring of dosage levels, and accuracy training are discussed.


A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.
The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.


The Lamin-Like LITTLE NUCLEI 1 (LINC1) Regulates Pattern-Triggered Immunity and Jasmonic Acid Signaling.
Pathogen-associated molecular pattern (PAMP) recognition occurs by plasma membrane located receptors that induce among other processes nuclear gene expression. However, signaling to the nuclear compartment is restricted by the nuclear envelope and nuclear pore complexes. We show here that among the four Arabidopsis lamin homologs LITTLE NUCLEI/CROWDED NUCLEI (LINC/CRWN), LINC1 plays an important role in PTI and jasmonic acid (JA) signaling. We show that linc1 knock out mutants affect PAMP-triggered MAPK activation and growth inhibition, but not reactive oxygen species or callose accumulation. We also demonstrate that linc1 mutants are compromised in regulating PAMP-triggered pathogen-related genes, in particular encoding factors involved in JA signaling and responses. Expression of a number of JAZ domain proteins, the key JA-related transcription factor MYC2 as well as key MYB transcription factors and biosynthesis genes of both the indole and aliphatic glucosinolate pathways are changed in linc1 mutants. Moreover, PAMP triggers JA and JA-Ile accumulation in linc1 mutants, whereas salicylic acid levels are unchanged. Despite impairment in PAMP-triggered immunity, linc1 mutants still show basal immunity towards Pseudomonas syringae DC3000 strains. High JA levels usually render plants resistant to necrotrophic pathogen. Thus, linc1 mutants show enhanced resistance to Botrytis cinerea infection. In accordance with a general role of LINC1 in JA signaling, linc1 mutants are hypersensitive to growth inhibition to external JA. In summary, our findings show that the lamin-like LINC1 protein plays a key role in JA signaling and regulation of PTI responses in Arabidopsis.


Psychotherapy Is Chaotic-(Not Only) in a Computational World.
Objective: The aim of this article is to outline the role of chaotic dynamics in psychotherapy. Besides some empirical findings of chaos at different time scales, the focus is on theoretical modeling of change processes explaining and simulating chaotic dynamics. It will be illustrated how some common factors of psychotherapeutic change and psychological hypotheses on motivation, emotion regulation, and information processing of the client's functioning can be integrated into a comprehensive nonlinear model of human change processes. Methods: The model combines 5 variables (intensity of emotions, problem intensity, motivation to change, insight and new perspectives, therapeutic success) and 4 parameters into a set of 5 coupled nonlinear difference equations. The results of these simulations are presented as time series, as phase space embedding of these time series (i.e., attractors), and as bifurcation diagrams. Results: The model creates chaotic dynamics, phase transition-like phenomena, bi- or multi-stability, and sensibility of the dynamic patterns on parameter drift. These features are predicted by chaos theory and by Synergetics and correspond to empirical findings. The spectrum of these behaviors illustrates the complexity of psychotherapeutic processes. Conclusion: The model contributes to the development of an integrative conceptualization of psychotherapy. It is consistent with the state of scientific knowledge of common factors, as well as other psychological topics, such as: motivation, emotion regulation, and cognitive processing. The role of chaos theory is underpinned, not only in the world of computer simulations, but also in practice. In practice, chaos demands technologies capable of real-time monitoring and reporting on the nonlinear features of the ongoing process (e.g., its stability or instability). Based on this monitoring, a client-centered, continuous, and cooperative process of feedback and control becomes possible. By contrast, restricted predictability and spontaneous changes challenge the usefulness of prescriptive treatment manuals or other predefined programs of psychotherapy.


Cranial irradiation as an additional risk factor for anthracycline cardiotoxicity in childhood cancer survivors: an analysis from the cardiac risk factors in childhood cancer survivors study.
Anthracycline-treated childhood cancer survivors experience cardiac damage that results in decreased left ventricular (LV) mass, leading to increased LV wall stress, which underlies their greater risk of cardiomyopathy. Many of these survivors also are at risk of growth hormone (GH) abnormalities from cranial irradiation exposure, although it is unknown whether such exposure is associated with cardiotoxicity. Echocardiograms and insulin-like growth factor-1 (IGF-1), a marker of GH, were measured in 130 anthracycline-treated childhood cancer survivors, 59 of whom had been exposed to cranial irradiation, a mean 10 years after their cancer diagnosis. Echocardiographic parameters and IGF-1 were standardized relative to age or body surface area using data from sibling control subjects and expressed as the percentage difference from normal values. The results showed that after adjustment for other risk factors, survivors exposed to cranial irradiation had an additional 12 % decrease in LV mass compared with unexposed survivors (P < 0.01) and an additional 3.6 % decrease in LV dimension (P = 0.03). Survivors exposed to cranial irradiation also had a 30.8 % decrease in IGF-1 relative to normal values, which was greater than the 10.5 % decrease in unexposed survivors (P < 0.01). The above findings led us to conclude that in anthracycline-treated childhood cancer survivors a mean 10 years after their diagnosis, those with cranial irradiation exposure had significantly greater decreases in LV mass and dimension. Because cranial irradiation also was associated with decreased IGF-1, it is possible that GH deficiencies mediated this effect, suggesting that GH replacement therapy may help to prevent the development of cardiotoxicity.


Fruit Antioxidants during Vinegar Processing: Changes in Content and in Vitro Bio-Accessibility.
Vinegars based on fruit juices could conserve part of the health-associated compounds present in the fruits. However, in general very limited knowledge exists on the consequences of vinegar-making on different antioxidant compounds from fruit. In this study vinegars derived from apple and grape are studied. A number of steps, starting from the fermentation of the fruit juices to the formation of the final vinegars, were studied from an industrial vinegar process. The effect of each of the vinegar processing steps on content of antioxidants, phenolic compounds and flavonoids was studied, by spectroscopic methods and by high-performance liquid chromatography (HPLC). The major observation was that spectrophotometric methods indicate a strong loss of antioxidant phenolic compounds during the transition from fruit wine to fruit vinegar. A targeted HPLC analysis indicates that metabolites such as gallic acid are lost in later stages of the vinegar process. The major conclusion of this work is that major changes occur in phenolic compounds during vinegar making. An untargeted metabolite analysis should be used to reveal these changes in more detail. In addition, the effect of vinegar processing on bio-accessibility of phenolic compounds was investigated by mimicking the digestive tract in an in vitro set up. This study is meant to provide insight into the potential of vinegar as a source of health-related compounds from fruit.


JcLEA, a novel LEA-like protein from Jatropha curcas, confers a high level of tolerance to dehydration and salinity in Arabidopsis thaliana.
Jatropha curcas L. is a highly drought and salt tolerant plant species that is typically used as a traditional folk medicine and biofuel crop in many countries. Understanding the molecular mechanisms that underlie the response to various abiotic environmental stimuli, especially to drought and salt stresses, in J. curcas could be important to crop improvement efforts. In this study, we cloned and characterized the gene for a late embryogenesis abundant (LEA) protein from J. curcas that we designated JcLEA. Sequence analyses showed that the JcLEA protein belongs to group 5, a subgroup of the LEA protein family. In young seedlings, expression of JcLEA is significantly induced by abscisic acid (ABA), dehydration, and salt stress. Subcellular localization analysis shows that that JcLEA protein is distributed in both the nucleus and cytoplasm. Moreover, based on growth status and physiological indices, the overexpression of JcLEA in transgenic Arabidopsis plants conferred increased resistance to both drought and salt stresses compared to the WT. Our data suggests that the group 5 JcLEA protein contributes to drought and salt stress tolerance in plants. Thus, JcLEA is a potential candidate gene for plant genetic modification.


Psychological impact of news of genetic risk for Huntington disease.
A one-year longitudinal study was conducted investigating the psychological effects of the news of genetic testing for the Huntington disease (HD) gene. Participants were assessed at baseline (before obtaining news of test results) and at three, six, and 12 months after test results on stress-specific symptom measures. Among carriers of the HD gene, a considerable number (55%) showed evidence of neurological impairment at baseline, indicative of HD. Also noteworthy, these individuals had significantly higher psychological symptom scores at baseline than carriers without neurological impairment or noncarriers. Despite this, these individuals were no more aware of their carrier status at baseline than carriers without HD symptoms or noncarriers. Furthermore, the psychological symptom levels of HD carriers with neurological impairment remained elevated across the follow-up assessments. Results for noncarriers and carriers without HD neurological symptoms were consistent with the findings of previous studies indicating that news of genetic testing for the HD gene had limited detrimental impact. The clinical implications of the results are discussed.


Theoretical investigations toward the tandem reactions of N-aziridinyl imine compounds forming triquinanes via trimethylenemethane diyls: mechanisms and stereoselectivity.
In this paper, we have investigated the tandem reaction mechanism for the N-aziridinyl imine compounds forming triquinanes via trimethylenemethane (TMM) diyls in detail. Based on the calculated results, the reaction is initiated by the cleavage of the N-aziridinyl in the substrate, followed by an intramolecular 1,3-dipolar (3 + 2) cycloaddition preferentially leading to a linearly-fused tetrahydrocyclopentapyrazole intermediate. Next, the intermediate loses N2 to form the singlet TMM diyl M3S, which can then undergo another concerted (3 + 2) cycloaddition to generate the linearly-fused cis–trans or cis–syn triquinane products. In addition, M3S can also undergo intersystem crossing to the triplet TMM diyl M3T, and the six possible reaction pathways associated with M3T have also been identified. The calculated results reveal that the cis–trans fused pathway associated with M3S is energetically preferred with the highest free energy barrier of 25.0 kcal mol(−1). In comparison, the cyclization of M3T requires much higher activation free energies (ΔG(≠) = 34.4–57.8 kcal mol(−1)). At the experimental temperature 110 °C, only the linearly-fused cis–trans and cis–syn pathways associated with M3T (ΔG(≠) = 34.4 and 35.5 kcal mol(−1) respectively) are possible. The calculated results also indicate that for both M3S and M3T, the linearly-fused cis–trans triquinane should be the main product, which is consistent with the experimental observation. At last, conformational and NBO analyses on key transition states identified the cis–trans stereocontrol factors. Further calculations indicate that the methyl substituent on the allene group of the reactant substrate improves the stereoselectivity of the reaction but does not affect the rate-determining step.


Nitrogen remobilisation facilitates adventitious root formation on reversible dark-induced carbohydrate depletion in Petunia hybrida.
Adventitious root (AR) formation in axillary shoot tip cuttings is a crucial physiological process for ornamental propagation that is utilised in global production chains for young plants. In this process, the nitrogen and carbohydrate metabolisms of a cutting are regulated by its total nitrogen content (Nt), dark exposure during transport and irradiance levels at distinct production sites and phases through a specific plasticity to readjust metabolite pools. Here, we examined how elevated Nt contents with a combined dark exposure of cuttings influence their internal N-pools including free amino acids and considered early anatomic events of AR formation as well as further root development in Petunia hybrida cuttings. Enhanced Nt contents of unrooted cuttings resulted in elevated total free amino acid levels and in particular glutamate (glu) and glutamine (gln) in leaf and basal stem. N-allocation to mobile N-pools increased whereas the allocation to insoluble protein-N declined. A dark exposure of cuttings conserved initial Nt and nitrate-N, while it reduced insoluble protein-N and increased soluble protein, amino- and amide-N. The increase of amino acids mainly comprised asparagine (asn), aspartate (asp) and arginine (arg) in the leaves, with distinct tissue specific responses to an elevated N supply. Dark exposure induced an early transient rise of asp followed by a temporary increase of glu. A strong positive N effect of high Nt contents of cuttings on AR formation after 384 h was observed. Root meristematic cells developed at 72 h with a negligible difference for two Nt levels. After 168 h, an enhanced Nt accelerated AR formation and gave rise to first obvious fully developed roots while only meristems were formed with a low Nt. However, dark exposure for 168 h promoted AR formation particularly in cuttings with a low Nt to such an extent so that the benefit of the enhanced Nt was almost compensated. Combined dark exposure and low Nt of cuttings strongly reduced shoot growth during AR formation. The results indicate that both enhanced Nt content and dark exposure of cuttings reinforced N signals and mobile N resources in the stem base facilitated by senescence-related proteolysis in leaves. Based on our results, a model of N mobilisation concomitant with carbohydrate depletion and its significance for AR formation is postulated.


Likelihood-based classification of cryo-EM images using FREALIGN.
We describe an implementation of maximum likelihood classification for single particle electron cryo-microscopy that is based on the FREALIGN software. Particle alignment parameters are determined by maximizing a joint likelihood that can include hierarchical priors, while classification is performed by expectation maximization of a marginal likelihood. We test the FREALIGN implementation using a simulated dataset containing computer-generated projection images of three different 70S ribosome structures, as well as a publicly available dataset of 70S ribosomes. The results show that the mixed strategy of the new FREALIGN algorithm yields performance on par with other maximum likelihood implementations, while remaining computationally efficient.


Arbidol: a broad-spectrum antiviral that inhibits acute and chronic HCV infection.
Arbidol (ARB) is an antiviral compound that was originally proven effective for treatment of influenza and several other respiratory viral infections. The broad spectrum of ARB anti-viral activity led us to evaluate its effect on hepatitis C virus (HCV) infection and replication in cell culture. Long-term ARB treatment of Huh7 cells chronically replicating a genomic length genotype 1b replicon resulted in sustained reduction of viral RNA and protein expression, and eventually cured HCV infected cells. Pre-treatment of human hepatoma Huh7.5.1 cells with 15 microM ARB for 24 to 48 hours inhibited acute infection with JFH-1 virus by up to 1000-fold. The inhibitory effect of ARB on HCV was not due to generalized cytotoxicity, nor to augmentation of IFN antiviral signaling pathways, but involved impaired virus-mediated membrane fusion. ARB's affinity for membranes may inhibit several aspects of the HCV lifecycle that are membrane-dependent.


Physicians' responses to patient-requested cesarean delivery.
The issue about whether a woman's autonomy in childbirth should include the choice of cesarean delivery in the absence of medical indications has become a major source of debate. Our objective was to examine factors that determined physicians' responses to patient-requested cesarean delivery. Surveys were distributed to all obstetrician-gynecologists in the greater Portland, Oregon, metropolitan area in Spring, 2000. Physicians were asked to respond to scenarios involving a term patient with a singleton pregnancy requesting primary cesarean delivery. One hundred and seventy of 255 physicians (67%) responded, of whom 68 to 98 percent agreed to cesarean delivery in cases with clear medical indications. Without a clear medical indication, most practitioners would not perform a cesarean delivery. In cases where medical indications were unclear, responses were divided. Physician male gender and patient high socioeconomic status were associated with increased likelihood of physician agreement to patient-requested cesarean delivery. Age, years in practice, and practice type were not associated with agreement. Physicians are reluctant to agree to patient request for primary cesarean delivery without a clear medical indication. Male physicians were more likely to agree to a patient's request for cesarean delivery than female physicians.


Value and application of trimodality therapy or definitive concurrent chemoradiotherapy in thoracic esophageal squamous cell carcinoma.
Few large, prospective, randomized studies have investigated the value and optimal application of neoadjuvant chemoradiotherapy followed by surgery (trimodality therapy) or definitive concurrent chemoradiotherapy (CCRT) for patients with thoracic esophageal squamous cell carcinoma (TESCC). The authors analyzed data from patients with TESCC in the Taiwan Cancer Registry database. To compare their outcomes, patients with TESCC were enrolled and categorized into the following groups according to treatment modality: group 1, those who underwent surgery alone; group 2, those who received trimodality therapy; and group 3, those who received definitive CCRT. Group 1 was used as the control arm for investigating the risk of mortality after treatment. In total, 3522 patients who had TESCC without distant metastasis were enrolled. Multivariate Cox regression analysis indicated that a Charlson comorbidity index score ≥3, American Joint Committee on Cancer stage ≥IIA, earlier year of diagnosis, alcohol consumption, cigarette smoking, and definitive CCRT were significant, independent predictors of a poor prognosis. After adjustment for confounders, adjusted hazard ratios and 95% confidence intervals (CIs) for overall mortality in patients with clinical stage I, IIA, IIB, IIIA, IIIB, and IIIC TESCC were 2.01 (95% CI, 0.44-6.18), 1.65 (95% CI, 0.99-2.70), 1.48 (95% CI, 0.91-2.42), 0.66 (95% CI, 1.08-1.14), 0.39 (95% CI, 0.26-0.57), and 0.44 (95% CI, 0.24-0.83), respectively, in group 2; and 2.06 (95% CI, 1.18-3.59), 2.65 (95% CI, 1.76-4.00), 2.25 (95% CI, 1.49-3.39), 1.34 (95% CI, 0.79-2.28), 0.82 (95% CI, 0.57-1.17), and 0.93 (95% CI, 0.51-1.71), respectively, in group 3. Trimodality therapy may be beneficial for the survival of patients with advanced-stage (IIIA-IIIC) TESCC, and CCRT might be an alternative to surgery alone in these patients. Cancer 2017;123:3904-15. © 2017 American Cancer Society.


Estimation of changes in volume of individual lower-limb muscles using magnetic resonance imaging (during bed-rest).
Muscle size in the lower limb is commonly assessed in neuromuscular research as it correlates with muscle function and some approaches have been assessed for their ability to provide valid estimates of muscle volume. Work to date has not examined the ability of different measurement approaches (such as cross-sectional area (CSA) measures on magnetic resonance (MR) imaging) to accurately track changes in muscle volume as a result of an intervention, such as exercise, injury or disuse. Here we assess whether (a) the percentage change in muscle CSA in 17 lower-limb muscles during 56 days bed-rest, as assessed by five different algorithms, lies within 0.5% of the muscle volume change and (b) the variability of the outcome measure is comparable to that of muscle volume. We find that an approach selecting the MR image with the highest muscle CSA and then a series of CSA measures, the number of which depended upon the muscle considered, immediately distal and proximal, provided an acceptable estimate of the muscle volume change. In the vastii, peroneal, sartorius and anterior tibial muscle groups, accurate results can be attained by increasing the spacing between CSA measures, thus reducing the total number of MR images and hence the measurement time. In the two heads of biceps femoris, semimembranosus and gracilis, it is not possible to reduce the number of CSA measures and the entire muscle volume must be evaluated. Using these approaches one can reduce the number of CSA measures required to estimate changes in muscle volume by ~60%. These findings help to attain more efficient means to track muscle volume changes in interventional studies.


A Randomized Trial Comparing the Effect of Nicotine Versus Placebo Electronic Cigarettes on Smoking Reduction Among Young Adult Smokers.
Electronic cigarette (EC) use is growing dramatically with use highest among young adults and current smokers. One of the most common reasons for using ECs is interest in quitting or reducing cigarettes per day (CPD); however there are few randomized controlled trials (RCT) on the effect of ECs on smoking abstinence and reduction. We conducted a two-arm; double-blind RCT. Subjects were randomized to receive 3-weeks of either disposable 4.5% nicotine EC (intervention) or placebo EC. The primary outcome was self-reported reduction of at least 50% in the number of CPDs smoked at week 3 (end of treatment) compared to baseline. Study subjects (n = 99) were young adult (21-35), current smokers (smoked ≥ 10 CPDs) living in NYC. Compared with baseline, a significant reduction in CPDs was observed at both study time periods (1 and 3 weeks) for intervention (P < .001) and placebo (P < .001) groups. Between-group analyses showed significantly fewer CPDs in the intervention group compared to the placebo group at week 3 (P = .03), but not at any other follow-up periods. The logistic regression analysis showed that using a greater number of ECs, treatment condition and higher baseline readiness to quit were significantly associated with achieving at least 50% reduction in CPDs at the end of treatment. A diverse young adult sample of current everyday smokers, who were not ready to quit, was able to reduce smoking with the help of ECs. Further study is needed to establish the role of both placebo and nicotine containing ECs in increasing both reduction and subsequent cessation. Despite the critical need for well-designed clinical trials on the effect of ECs on cessation and cigarette reduction, the majority of studies have been observational or noncomparative intervention designs. Only three RCTs studying ECs as a cessation or reduction intervention have been published, and none were conducted in the United States. The current study adds knowledge to current literature on the feasibility of using ECs to aid smoking reduction among young smokers in US urban populations.


Cytosine methylation at CpCpG sites triggers accumulation of non-CpG methylation in gene bodies.
Methylation of cytosine is an epigenetic mark involved in the regulation of transcription, usually associated with transcriptional repression. In mammals, methylated cytosines are found predominantly in CpGs but in plants non-CpG methylation (in the CpHpG or CpHpH contexts, where H is A, C or T) is also present and is associated with the transcriptional silencing of transposable elements. In addition, CpG methylation is found in coding regions of active genes. In the absence of the demethylase of lysine 9 of histone 3 (IBM1), a subset of body-methylated genes acquires non-CpG methylation. This was shown to alter their expression and affect plant development. It is not clear why only certain body-methylated genes gain non-CpG methylation in the absence of IBM1 and others do not. Here we describe a link between CpG methylation and the establishment of methylation in the CpHpG context that explains the two classes of body-methylated genes. We provide evidence that external cytosines of CpCpG sites can only be methylated when internal cytosines are methylated. CpCpG sites methylated in both cytosines promote spreading of methylation in the CpHpG context in genes protected by IBM1. In contrast, CpCpG sites remain unmethylated in IBM1-independent genes and do not promote spread of CpHpG methylation.


Depth moderates loss of marine foundation species after an extreme marine heatwave: could deep temperate reefs act as a refuge?
Marine heatwaves (MHWs) have been documented around the world, causing widespread mortality of numerous benthic species on shallow reefs (less than 15 m depth). Deeper habitats are hypothesized to be a potential refuge from environmental extremes, though we have little understanding of the response of deeper benthic communities to MHWs. Here, we show how increasing depth moderates the response of seaweed- and coral-dominated benthic communities to an extreme MHW across a subtropical-temperate biogeographical transition zone. Benthic community composition and key habitat-building species were characterized across three depths (15, 25 and 40 m) before and several times after the 2011 Western Australian MHW to assess resistance during and recovery after the heatwave. We found high natural variability in benthic community composition along the biogeographic transition zone and across depths with a clear shift in the composition after the MHW in shallow (15 m) sites but a lot less in deeper communities (40 m). Most importantly, key habitat-building seaweeds such as Ecklonia radiata and Syctothalia dorycarpa which had catastrophic losses on shallow reefs, remained and were less affected in deeper communities. Evidently, deep reefs have the potential to act as a refuge during MHWs for the foundation species of shallow reefs in this region.


Valproate, sexual health, and men: A narrative review.
This article explores current evidence about the effects of valproate (VPA) medicines on sexual health in men, how to monitor symptoms, communicate with patients, and improve clinical outcomes. There has been a lot of focus on VPA use in women of childbearing age following recent changes to prescribing regulations owing to the well-established and significant teratogenic risk. Concerns have been raised by patients and clinicians as to the risk of adverse sexual effects of VPA use in men. The evidence base for the effect of VPA on sexual function compared with other antiepileptic drugs (AEDs) in men is limited with no randomized controlled trials. Sexual function in men with epilepsy is complex, and there is no direct relationship between objective measures of sexual function and sexual satisfaction. Epilepsy, comorbidities, psychosocial factors, and most AEDs including VPA may cause sexual dysfunction in men, including reduced sexual desire, erectile dysfunction, and fertility problems. Sexual and reproductive function should be discussed with men prior to treatment with AEDs including VPA. Early and proactive discussion of sexual and reproductive functioning mitigates, rather than increases, the risk of sexual problems and potentially improves adherence. Sexual dysfunction in men with cognitive impairment [such as intellectual disability (ID) and dementia] may present with behavioral disturbance. Identification of sexual adverse effects of medication could significantly change treatment plans which is of particular importance for individuals with treatment resistance. We provide an information fact sheet for men to help guide prescribing discussions.


Fatal nocardiosis in a dog caused by multiresistant Nocardia veterana.
Among pathogenic Nocardia species in humans and animals, infections caused by Nocardia (N.) veterana have rarely been described and so far, all non-human cases are linked to bovine mastitis in Brazil. The aim of this study was to identify the causative microorganism involved in the death of a three-month-old dog suffering from dyspnea and neurological deficits ante mortem. Pathomorphological investigation revealed (pyo-)granulomatous lesions in various organs. Bacteriological examination was performed and the respective bacteria were subjected to matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), 16S rDNA sequencing, and antimicrobial susceptibility testing by broth microdilution. Gram-staining and colony morphology suggested the presence of an actinomycete which was identified as N. veterana by MALDI-TOF MS. This identification was confirmed by 16S rDNA sequence analysis. Distemper-associated immunosuppression may have played a role in the pathogenesis of systemic nocardiosis in this dog. Retrospective analysis of the antimicrobial susceptibility status showed that the N. veterana isolate was multiresistant and displayed high minimal inhibitory concentrations to all antimicrobial agents used for the dog's therapy. To the best of our knowledge, this is the first report of a systemic nocardiosis caused by N. veterana in a dog with a concurrent canine distemper virus infection.


Impact of the National Food Supplementary Program for Children on Household Food Security and Maternal Weight Status in Iran.
Food aid programs are strategies that aim to improve nutritional status and to tackle food insecurity. This study aimed to evaluate the effect of a National Food Supplementary Program for Children on households' food security. The study sample included 359 mothers of children aged 6-72 months under the coverage of the program in two provinces of Iran. Demographic and socioeconomic characteristics of the households and percentage of supplementary food items consumed by target child were assessed by a questionnaire and checklist. Data on household food security were collected by locally adapted Household Food Insecurity Access Scale at the baseline of the study and 6 months thereafter. At the baseline, only 4.7% of families were food secure, while 43.5% were severely food insecure, and these proportions were changed to 7.9% and 38%, respectively (P < 0.001), at the end of the study. Odds of having worse food insecurity in households with medium and high wealth index was 65% and 87% lower than those with low wealth index, respectively (odds ratio [OR] = 0.35, 95% confidence interval [CI]: 0.2-0.61, and OR = 0.23, 95% CI: 0.12-0.43). Food sharing was common among more than 95% of the studied households. Mean maternal body mass index (BMI) increased significantly after 6 months (P < 0.001). However, there was no significant association between mother's BMI and household food security in the baseline and at the end of the study (P > 0.05). Findings show that the food supplementary program for children can also improve the household food security status. Further research is needed to assess other factors that affect the effectiveness of this kind of programs.


CYP3A4/5 polymorphisms affect the blood level of cyclosporine and tacrolimus in Chinese renal transplant recipients.
Both cyclosporine and tacrolimus display a narrow therapeutic index as well as high interindividual pharmacokinetic variability. We approached the effect of the CYP3A4*18B and CYP3A5*3 polymorphisms and haplotypes on the whole blood cyclosporine or tacrolimus concentration in Chinese renal transplant patients during the first month after transplantation. A total of 83 recipients receiving tacrolimus or cyclosporine was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The whole blood concentration was measured by enzyme-multiplied immunoassay technique. Both CYP3A4*18B and CYP3A5*3 polymorphisms affected the tacrolimus dose-adjusted trough concentration (C0/D). The tacrolimus C0/D was higher in carriers of haplotype GG compared with the non-carriers. The cyclosporine dose-adjusted 2-hour post-dose concentrations (C2/D), dose-adjusted C0 + C2 ((C0 + C2)/D) and C2/C0 during Days 15 - 21 displayed significant difference among the three genotypes. Statistical difference was observed between CYP3A4*1/*1 and CYP3A4*18B/*18B groups and between CYP3A4*1/*18B and CYP3A4*18B/*18B groups, but no difference was detected between CYP3A4*1/*1 and CYP3A4*1/*18B groups. No difference was found in C0/D among the three genotypes of CYP3A4*18B polymorphism, and neither CYP3A5*3 polymorphisms nor CYP3A haplotype-derived genotypes affected the cyclosporine dose-adjusted concentration. Genetic polymorphisms of CYP3A5*3 and CYP3A4*18B may be partly responsible in large interindividual variability of cyclosporine and tacrolimus blood levels in Chinese renal transplant patients during the first month after transplantation. A patient carried combined genotype of CYP3A4*1/*1-CYP3A5* 3/*3 might require lower tacrolimus doses to achieve target concentration levels. Genotyping of CYP3A4*18B and CYP3A5*3 before transplantation is of benefit in determining a suitable initial dose for each patient.


Reducing video-quality fluctuations for streaming scalable video using unequal error protection, retransmission, and interleaving.
Forward error correction based multiple description (MD-FEC) transcoding for transmitting embedded bitstream over the packet erasure networks has been extensively studied in the past. In the existing work, a single embedded source bitstream, e.g., the bitstream of a group of pictures (GOP) encoded using three-dimensional set partitioning in hierarchical trees is optimally protected unequal error protection (UEP) in the rate-distortion sense. However, most of the previous work on transmitting embedded video using MD-FEC assumed that one GOP is transmitted only once, and did not consider the chance of retransmission. This may lead to noticeable video quality variations due to varying channel conditions. In this paper, a novel window-based packetization scheme is proposed, which combats bursty packet loss by combining the following three techniques: UEP, retransmission, and GOP-level interleaving. In particular, two retransmission mechanisms, namely segment-wise retransmission and byte-wise retransmission, are proposed based on different types of receiver feedback. Moreover, two levels of rate allocations are introduced: intra-GOP rate allocation minimizes the distortion of individual GOP; while inter-GOP rate allocation intends to reduce video quality fluctuations by adaptively allocating bandwidth according to video signal characteristics and client buffer status. In this way, more consistent video quality can be achieved under various packet loss probabilities, as demonstrated by our experimental results.


Paracrine modulation of CXCR4 by IGF-1 and VEGF: implications for choroidal neovascularization.
Modulators of angiogenesis typically work in an orchestrated manner. The authors examined the interaction between insulinlike growth factor (IGF)-1, vascular endothelial growth factor (VEGF), and stromal derived factor (SDF)-1 in vivo and in vitro using angiogenesis models. The angiogenic effect of SDF-1, alone or in combination with IGF-1 and VEGF, was assessed in human lung microvascular endothelial cells using capillary tube formation and thymidine incorporation. Immunohistochemical analysis for CD31, SDF-1, and CXCR4 was performed on mouse eyes 2 weeks after the initiation of laser rupture of Bruch's membrane, a choroidal neovascularization (CNV) model. CXCR4 antagonist and CXCR4 blocking antibody were tested on inhibition of CNV lesion size in this model. Real-time PCR was used to determine mRNA levels for SDF-1, VEGF, IGF-1, and their cognate receptors in the retinal pigment epithelium/choroid complex of mice that underwent this CNV model. IGF-1 and VEGF demonstrated an additive effect on SDF-1-induced in vitro angiogenesis. CXCR4 immunoreactivity was present in both normal and laser-injured mice at the laser burn site and at the ganglion cell layer, the anterior portion of the inner nuclear layer, photoreceptors, and choroidal stroma. SDF-1 was observed in identical locations but was not seen in photoreceptors. mRNA levels for SDF-1, VEGF, and IGF-1 and their receptors were increased after laser injury. CXCR4-neutralizing antibody reduced neovascularization when injected subretinally but not intraperitoneally or intravitreally. The potent proangiogenic factors IGF-1 and VEGF both stimulate SDF-1-induced angiogenesis. Local inhibition of CXCR4 is required for an antiangiogenic effect in CNV lesions.


The hepatitis C virus epidemic among injecting drug users.
Given the economic and health costs of hepatitis C virus (HCV) infection, and the ongoing transmission within the injecting drug user (IDU) population, there is a need for improved understanding of HCV epidemiology within this risk group. We employed a recently developed method based on phylogenetic analysis to infer HCV epidemic history and to provide the first estimates of the rate of spread of subtypes 1a and 3a circulating within injecting drug user populations. The data indicates that HCV subtype 1a entered the IDU population on at least three separate occasions. Both subtypes demonstrate exponential population growth during the 20th century, with a doubling time of 7-8 years. The results provide a baseline for prediction of the future course of the HCV epidemic, and its likely response to transmission control policies.


Prevalence of exposure to environmental tobacco smoke at work and at home--15-year trends in Finland.
This study describes the 15-year trends of exposure to environmental tobacco smoke at work and at home in Finland. A postal survey was made annually from 1985 to 2000. It included a random sample of 58,721 Finnish men and women aged 15 to 64 years. In the middle of the 1980s, about a quarter of employed nonsmoking men and 15% of nonsmoking women were exposed at least 1 hour daily to environmental tobacco smoke at work. In 2000, the proportions were 7.9% and 4.4%, respectively. Exposure to environmental tobacco smoke at home decreased also slightly. In 2000, 14.3% of the nonsmoking men and 13% of the nonsmoking women aged 15 to 64 years were exposed to environmental tobacco smoke either at work or at home. Exposure at work was about three times more common among smokers than among nonsmokers, but a decreasing trend was also found among smokers. In 2000, in 85% of workplaces smoking was permitted only in separate smoking rooms, or no one was smoking within the work environment. On the other hand, in 7.3% of workplaces smoking was permitted also in common areas. In the past 15 years, exposure to environmental tobacco smoke at work decreased significantly in Finland. Both legislative actions and the general decrease in smoking prevalence have contributed to this decline. However, despite the marked decrease, nearly 14% of nonsmokers aged 15 to 64 years are still exposed to environmental tobacco smoke, either at home or in the workplace.


Automated Tracking of Biopolymer Growth and Network Deformation with TSOAX.
Studies of how individual semi-flexible biopolymers and their network assemblies change over time reveal dynamical and mechanical properties important to the understanding of their function in tissues and living cells. Automatic tracking of biopolymer networks from fluorescence microscopy time-lapse sequences facilitates such quantitative studies. We present an open source software tool that combines a global and local correspondence algorithm to track biopolymer networks in 2D and 3D, using stretching open active contours. We demonstrate its application in fully automated tracking of elongating and intersecting actin filaments, detection of loop formation and constriction of tilted contractile rings in live cells, and tracking of network deformation under shear deformation.


Phase I/II trial of radiation with chemotherapy "boost" for advanced squamous cell carcinomas of the head and neck: toxicities and responses.
Extrapolating from our experience delivering a "boost" field of radiation concurrently with fields treating both gross and subclinical disease at the end of a course of radiation therapy, we developed a regimen to deliver concurrent chemotherapy during the last 2 weeks of a conventionally fractionated course of radiation. Patients had stage III or IV biopsy-proven squamous cell carcinoma originating from a head and neck mucosal site. The regimen was 70 Gy delivered over 7 weeks with concurrent fluorouracil (5-FU) and cisplatin given daily with each radiation dose during the last 2 weeks. A phase I study was performed to determine the maximum-tolerated dose (MTD) before a phase II study was conducted. The MTD was 400 mg/m(2) per day for 5-FU and 10 mg/m(2) per day for cisplatin. Mucositis persisting more than 6 weeks after therapy was the dose-limiting toxicity. A total of 60 patients were treated on the two phases of the study. Eighteen patients (35%) treated at the MTD developed prolonged mucositis. There were two cases of neutropenic sepsis, including one fatality. The actuarial 2-year rates for overall survival, freedom from relapse, and local control were 62%, 59%, and 80%, respectively. Preliminary locoregional control rates seem to be higher than those reported for treatment with radiation alone. Toxicity was also greater than that seen with radiation alone, but the regimen was designed to deliver an intense treatment schedule, which could be completed without significant interruptions, and to obtain high control rates above the clavicles. These end points were achieved.


Genetic and biochemical characterization of mutations in the ATPase and helicase regions of the Upf1 protein.
mRNA degradation is an important control point in the regulation of gene expression and has been linked to the process of translation. One clear example of this linkage is the nonsense-mediated mRNA decay pathway, in which nonsense mutations in a gene can reduce the abundance of the mRNA transcribed from that gene. For the yeast Saccharomyces cerevisiae, the Upf1 protein (Upf1p), which contains a cysteine- and histidine-rich region and nucleoside triphosphate hydrolysis and helicase motifs, was shown to be a trans-acting factor in this decay pathway. Biochemical analysis of the wild-type Upf1p demonstrates that it has RNA-dependent ATPase, RNA helicase, and RNA binding activities. A UPF1 gene disruption results in stabilization of nonsense-containing mRNAs, leading to the production of enough functional product to overcome an auxotrophy resulting from a nonsense mutation. A genetic and biochemical study of the UPF1 gene was undertaken in order to understand the mechanism of Upf1p function in the nonsense-mediated mRNA decay pathway. Our analysis suggests that Upf1p is a multifunctional protein with separable activities that can affect mRNA turnover and nonsense suppression. Mutations in the conserved helicase motifs of Upf1p that inactivate its mRNA decay function while not allowing suppression of leu2-2 and tyr7-1 nonsense alleles have been identified. In particular, one mutation located in the ATP binding and hydrolysis motif of Upf1p that changed the aspartic and glutamic acid residues to alanine residues (DE572AA) lacked ATPase and helicase activities, and the mutant formed a Upf1p:RNA complex in the absence of ATP; surprisingly, however, the Upf1p:RNA complex dissociated as a consequence of ATP binding. This result suggests that ATP binding, independent of its hydrolysis, can modulate Upf1p:RNA complex formation for this mutant protein. The role of the RNA binding activity of Upf1p in modulating nonsense suppression is discussed.


Reduced Shh expression in TFF2-overexpressing lesions of the gastric fundus under hypochlorhydric conditions.
Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H(2) receptor-knockout (H(2)R-null) mice and an acid exposure model. Age-matched H(2)R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H(2)R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H(2)R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis.


Insulin sensitisation affects lipoprotein lipase transport in type 2 diabetes: role of adipose tissue and skeletal muscle in response to rosiglitazone.
Lipoprotein lipase (LPL) is produced by adipose tissue and skeletal muscle, but acts on plasma lipoproteins after being transported to endothelial binding sites. Insulin resistance is associated with decreased plasma LPL mass. We investigated the effects of insulin sensitisation on tissue-specific LPL expression and transport in patients with type 2 diabetes. Arterio-venous gradients of plasma LPL activity and mass across adipose tissue and skeletal muscle were measured in 16 type 2 diabetic patients in a double-blind, placebo-controlled, cross-over randomised trial of rosiglitazone. In vivo LPL rate of action was assessed by tissue-specific arterio-venous triglyceride concentration gradients. LPL mRNA was quantified in adipose tissue and skeletal muscle biopsies. Adipose tissue released large quantities of inactive LPL (p<0.001); skeletal muscle released small amounts of active LPL (p<0.01). Rosiglitazone increased adipose tissue release of LPL mass (+35%, p=0.04) and decreased the release of active LPL from skeletal muscle (-57%, p=0.03). Rosiglitazone increased adipose tissue and skeletal muscle LPL mRNA, but did not affect adipose tissue LPL rate of action or activity. Adipose tissue release of LPL mass correlated with systemic LPL mass concentrations (r=0.47, p=0.007), suggesting that the rate of adipose tissue release of LPL mass is a major determinant of systemic LPL mass concentrations. LPL transport from adipose tissue and skeletal muscle are regulated differently. In adipose tissue, rosiglitazone increases LPL mRNA abundance and LPL transport rate and possibly increases endothelial binding sites for LPL, but affects neither tissue LPL activity nor LPL rate of action.


Advantages of fast-track recovery after laparoscopic right hemicolectomy for colon cancer.
Fast-track (FT) recovery protocols have demonstrated advantages over historical recovery routines after open colectomy; however, their impact in recovery after laparoscopic colectomy is not clearly defined. This study was designed to determine whether patients who recover on FT protocol after laparoscopic colectomy have a shorter length of stay (LOS) and fewer complications compared with patients who recover on standard (non-FT) protocol. A cohort of consecutive patients with colon cancer who underwent completed laparoscopic-assisted right hemicolectomy from 2005-2007 was identified. Univariate and multivariate logistic analyses were performed to identify risk factors for increased LOS and postoperative complications with recovery protocol as the primary predictor. A total of 197 patients were included: 115 (58%) patients recovered on a non-FT protocol, and 82 (42%) patients on FT protocol. Univariate analysis showed no differences with respect to age, gender, body mass index, or American Society of Anesthesiologists (ASA) class between groups. The median (interquartile range) LOS was 4 (range, 3-6) days and 3 (range, 3-4) days for the non-FT and FT recovery patients, respectively (p < 0.001). On multivariate analysis, independent risk factors for increased LOS were complications (p < 0.001) and non-FT recovery (p = 0.007). Non-FT recovery also was associated with increased complications (56 vs. 29%, p = 0.0002); this remained significant on multivariate analysis (p < 0.001). Readmissions were similar (p = 1.0) between recovery groups. No mortalities were observed at 30 days. Fast-track recovery is independently associated with a shorter LOS and decreased morbidity after laparoscopic right hemicolectomy.


Classification of Tumor Histology via Morphometric Context.
Image-based classification of tissue histology, in terms of different components (e.g., normal signature, categories of aberrant signatures), provides a series of indices for tumor composition. Subsequently, aggregation of these indices in each whole slide image (WSI) from a large cohort can provide predictive models of clinical outcome. However, the performance of the existing techniques is hindered as a result of large technical and biological variations that are always present in a large cohort. In this paper, we propose two algorithms for classification of tissue histology based on robust representations of morphometric context, which are built upon nuclear level morphometric features at various locations and scales within the spatial pyramid matching (SPM) framework. These methods have been evaluated on two distinct datasets of different tumor types collected from The Cancer Genome Atlas (TCGA), and the experimental results indicate that our methods are (i) extensible to different tumor types; (ii) robust in the presence of wide technical and biological variations; (iii) invariant to different nuclear segmentation strategies; and (iv) scalable with varying training sample size. In addition, our experiments suggest that enforcing sparsity, during the construction of morphometric context, further improves the performance of the system.


The current high prevalence of dietary zinc inadequacy among children and women in rural Bangladesh could be substantially ameliorated by zinc biofortification of rice.
Rural Bangladeshi populations have a high risk of zinc deficiency due to their consumption of a predominantly rice-based diet with few animal-source foods. Breeding rice for higher zinc content would offer a sustainable approach to increase the population's zinc intakes. The objectives of the study were to quantify usual rice and zinc intakes in young children and their adult female primary caregivers and to simulate the potential impact of zinc-biofortified rice on their zinc intakes. We measured dietary intake in a representative sample of 480 children (ages 24-48 mo) and their female caregivers residing in 2 rural districts of northern Bangladesh. Dietary intakes were estimated by 12-h weighed records and 12-h recall in homes on 2 nonconsecutive days. Serum zinc concentrations were determined in a subsample of children. The median (25th, 75th percentile) rice intakes of children and female caregivers were 134 (99, 172) and 420 (365, 476) g raw weight/d, respectively. The median zinc intakes were 2.5 (2.1, 2.9) and 5.4 (4.8, 6.1) mg/d in children and women, respectively. Twenty-four percent of children had low serum zinc concentrations ( < 9.9 micromol/L) after adjusting for elevated acute phase proteins. Rice was the main source of zinc intake, providing 49 and 69% of dietary zinc to children and women, respectively. The prevalence of inadequate zinc intakes was high in both the children (22%) and women (73-100%). Simulated increases in rice zinc content to levels currently achievable through selective breeding decreased the estimated prevalence of inadequacy to 9% in children and 20-85% in women, depending on the assumptions used to estimate absorption. Rural Bangladeshi children and women have inadequate intakes of zinc. Zinc biofortification of rice has the potential to markedly improve the zinc adequacy of their diets.


Inactivating CUX1 mutations promote tumorigenesis.
A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.


Does a bout of strength training affect 2,000 m rowing ergometer performance and rowing-specific maximal power 24 h later?
Rowers regularly undertake rowing training within 24 h of performing bouts of strength training; however, the effect of this practice has not been investigated. This study evaluated the impact of a bout of high-intensity strength training on 2,000 m rowing ergometer performance and rowing-specific maximal power. Eight highly trained male club rowers performed baseline measures of five separate, static squat jumps (SSJ) and countermovement jumps (CMJ), maximal rowing ergometer power strokes (PS) and a single 2,000 m rowing ergometer test (2,000 m). Subsequently, participants performed a high-intensity strength training session consisting of various multi-joint barbell exercises. The 2,000 m test was repeated at 24 and 48 h post-ST, in addition SSJ, CMJ and PS tests were performed at these time points and also at 2 h post-ST. Muscle soreness, serum creatine kinase (CK) and lactate dehydrogenase (LDH) were assessed pre-ST and 2, 24 and 48 h post-ST. Following the ST, there were significant elevations in muscle soreness (2 and 24 h, P < 0.01), CK (2, 24 and 48 h, P < 0.01), and LDH (2 h, P < 0.05) in comparison to baseline values. There were significant decrements across all time points for SSJ, CMJ and PS, which ranged between 3 and 10% (P < 0.05). However, 2,000 m performance and related measurements of heart rate and blood lactate were not significantly affected by ST. In summary, a bout of high-intensity strength training resulted in symptoms of muscle damage and decrements in rowing-specific maximal power, but this did not affect 2,000 m rowing ergometer performance in highly trained rowers.


Accuracy and validation of an automated electronic algorithm to identify patients with atrial fibrillation at risk for stroke.
There is no universally accepted algorithm for identifying atrial fibrillation (AF) patients and stroke risk using electronic data for use in performance measures. Patients with AF seen in clinic were identified based on International Classification of Diseases, Ninth Revision(ICD-9) codes. CHADS(2) and CHA(2)DS(s)-Vasc scores were derived from a broad, 10-year algorithm using IICD-9 codes dating back 10 years and a restrictive, 1-year algorithm that required a diagnosis within the past year. Accuracy of claims-based AF diagnoses and of each stroke risk classification algorithm were evaluated using chart reviews for 300 patients. These algorithms were applied to assess system-wide anticoagulation rates. Between 6/1/2011, and 5/31/2012, we identified 6,397 patients with AF. Chart reviews confirmed AF or atrial flutter in 95.7%. A 1-year algorithm using CHA(2)DS(2)-Vasc score ≥2 to identify patients at risk for stroke maximized positive predictive value (97.5% [negative predictive value 65.1%]). The PPV of the 10-year algorithm using CHADS(2) was 88.0%; 12% those identified as high-risk had CHADS(2) scores <2. Anticoagulation rates were identical using 1-year and 10-year algorithms for patients with CHADS(2) scores ≥2 (58.5% on anticoagulation) and CHA(2)DS(2)-Vasc scores ≥2 (56.0% on anticoagulation). Automated methods can be used to identify patients with prevalent AF indicated for anticoagulation but may have misclassification up to 12%, which limits the utility of relying on administrative data alone for quality assessment. Misclassification is minimized by requiring comorbidity diagnoses within the prior year and using a CHA(2)DS(2)-Vasc based algorithm. Despite differences in accuracy between algorithms, system-wide anticoagulation rates assessed were similar regardless of algorithm used.


CRITICAL CARE ECHO ROUNDS: Echo in cardiac arrest.
Management of medical cardiac arrest is challenging. The internationally agreed approach is highly protocolised with therapy and diagnosis occurring in parallel. Early identification of the precipitating cause increases the likelihood of favourable outcome. Echocardiography provides an invaluable diagnostic tool in this context. Acquisition of echo images can be challenging in cardiac arrest and should occur in a way that minimises disruption to cardiopulmonary resuscitation (CPR). In this article, the reversible causes of cardiac arrest are reviewed with associated echocardiography findings. A 71-year-old patient underwent right upper lobectomy for lung adenocarcinoma. On the 2nd post-operative day, he developed respiratory failure with rising oxygen requirement and right middle and lower lobe collapse and consolidation on chest X-ray. He was commenced on high-flow oxygen therapy and antibiotics. His condition continued to deteriorate and on the 3rd post-operative day he was intubated and mechanically ventilated. Six hours after intubation, he became suddenly hypotensive with a blood pressure of 50 systolic and then lost cardiac output. ECG monitoring showed pulseless electrical activity. CPR was commenced and return of circulation occurred after injection of 1 mg of adrenaline. Focused echocardiography was performed, which demonstrated signs of massive pulmonary embolism. Thrombolytic therapy with tissue plasminogen activator was given and his condition stabilised.


A complex barcode underlies the heterogeneous response of p53 to stress.
The tumour suppressor p53 is activated following stress and initiates a heterogeneous response in a cell-, tissue- and stress-dependent manner. This heterogeneity is reflected in the different physiological outcomes that follow p53 activation. One mechanism that may contribute to this variability is the promoter selectivity of p53 target genes. p53 is at the hub of numerous signalling pathways that are triggered in response to particular stresses, all of which can leave their mark on p53 by way of post-translational modifications and interactions with cofactors. The precise combination of these marks, much like the bars in a barcode, dictates the behaviour of p53 in any given situation.


Photoinduced work function changes by isomerization of a densely packed azobenzene-based SAM on Au: a joint experimental and theoretical study.
Responsive monolayers are key building blocks for future applications in organic and molecular electronics in particular because they hold potential for tuning the physico-chemical properties of interfaces, including their energetics. Here we study a photochromic SAM based on a conjugated azobenzene derivative and its influence on the gold work function (Φ(Au)) when chemisorbed on its surface. In particular we show that the Φ(Au) can be modulated with external stimuli by controlling the azobenzene trans/cis isomerization process. This phenomenon is characterized experimentally by four different techniques, kelvin probe, kelvin probe force microscopy, electroabsorption spectroscopy and ultraviolet photoelectron spectroscopy. The use of different techniques implies exposing the SAM to different measurement conditions and different preparation methods, which, remarkably, do not alter the observed work function change (Φ(trans)-Φ(cis)). Theoretical calculations provided a complementary insight crucial to attain a deeper knowledge on the origin of the work function photo-modulation.


Preparations for AIDS vaccine trials. Developing brief valid screening instruments for HIV-related sexual risk behavior among gay and bisexual men.
Enrolling and tracking cohorts for HIV vaccine efficacy trials requires that participants disclose behaviors that place them at risk for exposure to HIV. Brief screening procedures have been suggested for this purpose. In a previous study gay and bisexual men in three U.S. cities reported unprotected anal intercourse on a brief screening instrument. Screen reports were compared to subsequent in-depth, face-to-face interview data; 29% of the men who reported unprotected anal intercourse during the interview failed to disclose this behavior during screening. For recruitment into an HIV vaccine feasibility study at the same study sites, screening procedures were modified to encourage accurate reporting: to lessen stigma, low risk as well as high risk sexual behaviors were assessed, and screens were administered by trained study staff who presented it as a tool for understanding the gay community. Failures to disclose risk decreased to 18%, a rate that, while lower than in the previous study, remains high. Men less likely to disclose unprotected sex during the screen engaged in fewer high risk sexual behaviors, had more stringent norms regarding sexual safety, and were less identified with the gay community than were men who disclosed unprotected sex. Failure to disclose risk may have significant implications for participant selection and behavior tracking during vaccine trials. More systematic assessments that are sensitive to target communities may facilitate disclosure.


A voltammetric and mathematical analysis of histaminergic modulation of serotonin in the mouse hypothalamus.
Histamine and serotonin are neuromodulators which facilitate numerous, diverse neurological functions. Being co-localized in many brain regions, these two neurotransmitters are thought to modulate one another's chemistry and are often implicated in the etiology of disease. Thus, it is desirable to interpret the in vivo chemistry underlying neurotransmission of these two molecules to better define their roles in health and disease. In this work, we describe a voltammetric approach to monitoring serotonin and histamine simultaneously in real time. Via electrical stimulation of the axonal bundles in the medial forebrain bundle, histamine release was evoked in the mouse premammillary nucleus. We found that histamine release was accompanied by a rapid, potent inhibition of serotonin in a concentration-dependent manner. We developed mathematical models to capture the experimental time courses of histamine and serotonin, which necessitated incorporation of an inhibitory receptor on serotonin neurons. We employed pharmacological experiments to verify that this serotonin inhibition was mediated by H3 receptors. Our novel approach provides fundamental mechanistic insights that can be used to examine the full extent of interconnectivity between histamine and serotonin in the brain. Histamine and serotonin are co-implicated in many of the brain's functions. In this paper, we develop a novel voltammetric method for simultaneous real-time monitoring of histamine and serotonin in the mouse premammillary nucleus. Electrical stimulation of the medial forebrain bundle evokes histamine and inhibits serotonin release. We show voltammetrically, mathematically, and pharmacologically that this serotonin inhibition is H3 receptor mediated.


Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.
Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.


Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications.
Human indoleamine 2,3-dioxygenase catalyzes the oxidative cleavage of tryptophan to N-formyl kynurenine, the initial and rate-limiting step in the kynurenine pathway. Additionally, this enzyme has been identified as a possible target for cancer therapy. A 20-amino acid protein segment (the JK loop), which connects the J and K helices, was not resolved in the reported hIDO crystal structure. Previous studies have shown that this loop undergoes structural rearrangement upon substrate binding. In this work, we apply a combination of replica exchange molecular dynamics simulations and site-directed mutagenesis experiments to characterize the structure and dynamics of this protein region. Our simulations show that the JK loop can be divided into two regions: the first region (JK loop(C)) displays specific and well-defined conformations and is within hydrogen bonding distance of the substrate, while the second region (JK loop(N)) is highly disordered and exposed to the solvent. The peculiar flexible nature of JK loop(N) suggests that it may function as a target for post-translational modifications and/or a mediator for protein-protein interactions. In contrast, hydrogen bonding interactions are observed between the substrate and Thr379 in the highly conserved "GTGG" motif of JK loop(C), thereby anchoring JK loop(C) in a closed conformation, which secures the appropriate substrate binding mode for catalysis. Site-directed mutagenesis experiments confirm the key role of this residue, highlighting the importance of the JK loop(C) conformation in regulating the enzymatic activity. Furthermore, the existence of the partially and totally open conformations in the substrate-free form suggests a role of JK loop(C) in controlling substrate and product dynamics.


The suitcase packing activity: A new evaluation of hand function.
Prospective, repeated-measures study. Understanding individual hand function can assist therapists with the process of determining relevant treatment approaches and realistic therapeutic outcomes. At this point in time, a composite test that assesses both unilateral and bimanual hand function in relation to a functional activity is not available. To establish the reliability and validity of the suitcase packing activity (SPA). An expert panel established face and content validity. Eighty healthy, English-speaking volunteers aged between 18 and 45 years were randomly assigned to either 1 or 2 sessions (test-retest reliability). Relative agreement between 2 examiners using an intraclass correlation coefficient (ICC)3,1 determined interrater reliability. Test-retest reliability was determined by using a repeated-measures analysis of variance and an ICC3,2. Concurrent validity was evaluated against 2 well-established hand evaluations using separate tests of correlational coefficients. Face and content validity were established across 4 focus groups. Our results demonstrate good to excellent interrater reliability (ICC3,1 ≥ 0.93) and good to excellent test-retest reliability (ICC3,2 ≥ 0.83). SPA scores were moderately correlated with the 2-hand evaluations. Through evaluating hand function during participation in a goal-directed activity (eg, packing a suitcase), the SPA exhibits promise in usefulness as a future viable outcome measure that can be used to assess functional abilities following a hand injury. The SPA is a valid and reliable tool for assessing bimanual and unilateral hand function in healthy subjects. Diagnostic level II.


Controlling Foliar Blights of Wheat in the Rice-Wheat Systems of Asia.
Foliar blight caused by Cochliobolus sativus and Pyrenophora tritici-repentis is the main biotic stress of wheat in the rice-wheat systems of South Asia, where it causes, on average, up to 15% yield loss. Increases in food production have to come from higher and sustainable productivity. It requires a multidisciplinary approach combining novel resistance sources and adapted agronomic practices. Better host plant resistance has been achieved by crossing genetic resistance sources or wild relatives to high-yielding cultivars. Germ plasm improvement methods centered on regional partnerships are now more specifically addressing the needs of warmer areas. Observations in long-term trials underline the increasing role of soil fertility in reducing disease severity. Studies focusing on the effect of stress conditions on disease development increase knowledge about the stability of resistance. This makes breeding more efficient and helps recommend better-adapted crop management practices. The adoption of reduced tillage methods and soil conservation practices imply farmers' direct participation in the research process. Foliar fungicide treatments are not a viable alternative for small farmers, but seed treatment may prove useful as part of an integrated disease management approach based on improved genetic resistance and good agronomy.


New Approaches for Estimation of Effect Sizes and their Confidence Intervals for Treatment Effects from Randomized Controlled Trials.
Although Cohen's d and the growth modeling analysis (GMA) d from linear models are common standardized effect sizes used to convey treatment effects, popular statistical software packages do not include them in their standard outputs. This article demonstrated the use of statistical software with user-prescribed parameter functions (e.g., Mplus) to produce d for treatment effects from both classical analysis and GMA--along with their associated standard errors (SEs) and confidence intervals (CIs). A Monte Carlo study was conducted to examine bias in the SE and CI for GMA d obtained with Mplus and found that both estimates were more accurate when calculated by the software with the standard bootstrap than with the delta method, but the delta method estimates were less biased than respective estimates from extant post hoc equations. Thus, users of many statistical software packages (including SAS, R, and LISREL) should obtain d or GMA d and associated CIs directly. Researchers employing less versatile software--and meta-analysts including ds and GMA ds in their syntheses of treatment effects--should continue to use the conventional post hoc equations. Biases in SEs and CIs for effect sizes obtained with them are ignorable and point estimates of d and GMA d are the same whether obtained directly from the software or with post hoc equations.


What's wrong with cross-cultural comparisons of subjective Likert scales?: The reference-group effect.
Social comparison theory maintains that people think about themselves compared with similar others. Those in one culture, then, compare themselves with different others and standards than do those in another culture, thus potentially confounding cross-cultural comparisons. A pilot study and Study 1 demonstrated the problematic nature of this reference-group effect: Whereas cultural experts agreed that East Asians are more collectivistic than North Americans, cross-cultural comparisons of trait and attitude measures failed to reveal such a pattern. Study 2 found that manipulating reference groups enhanced the expected cultural differences, and Study 3 revealed that people from different cultural backgrounds within the same country exhibited larger differences than did people from different countries. Cross-cultural comparisons using subjective Likert scales are compromised because of different reference groups. Possible solutions are discussed.


Associations of pregnancy-related factors and birth characteristics with risk of endometrial cancer: A Nordic population-based case-control study.
Many pregnancy-related factors are associated with reduced endometrial cancer risk. However, it remains unclear whether pregnancy-related complications (e.g., hypertensive conditions) are associated with risk and whether these associations vary by endometrial cancer subtype. Thus, we evaluated the risk of endometrial cancer, overall and by subtype, in relation to pregnancy-related factors, pregnancy complications and birth characteristics. Utilizing population-based register data from four Nordic countries, we conducted a nested case-control analysis of endometrial cancer risk. We included 10,924 endometrial cancer cases and up to 10 matched controls per case. Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models. We further evaluated associations by individual histology (i.e., endometrioid, serous, etc.) or, for rare exposures (e.g., pregnancy complications), by dualistic type (Type I [n = 10,343] and Type II [n = 581]). Preexisting and pregnancy-related hypertensive conditions were associated with increased endometrial cancer risk (OR [95% CI]: preexisting hypertension 1.88 [1.39-2.55]; gestational hypertension 1.47 [1.33-1.63]; preeclampsia 1.43 [1.30-1.58]), with consistent associations across dualistic type. Increasing number of pregnancies (≥4 vs. 1 birth: 0.64 [0.59-0.69]) and shorter time since last birth (<10 vs. ≥30 years: 0.34 [0.29-0.40]) were associated with reduced endometrial cancer risk, with consistent associations across most subtypes. Our findings support the role for both hormonal exposures and cell clearance as well as immunologic/inflammatory etiologies for endometrial cancer. This research supports studying endometrial hyperplasia, a precursor condition of endometrial cancer, in the context of pregnancy-related exposures, as this may provide insight into the mechanisms by which pregnancy affects subsequent cancer risk.


Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies.
To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED). To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction. Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated. EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively. Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5. Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10. A total of 3581 randomized subjects were studied. Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata. In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001). Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement. Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction. Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD. Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction. Proportions of subjects reporting improved ejaculatory or orgasmic function were ≈ twofold higher with tadalafil than with placebo. These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).


Expression and coupling of human cytochrome P450 2E1 and NADPH-cytochrome P450 oxidoreductase in dual expression and co-infection systems with baculovirus in insect cells.
In order to study the interaction between human cytochrome P450 2E1 (h2E1) and NADPH-P450 oxidoreductase (hOR) in a native membrane environment, we used two approaches to express both h2E1 and hOR in a baculovirus expression system. For a dual-expression system, h2E1 and hOR were coexpressed in Spodoptera frugiperda (Sf9) insect cells using a recombinant baculovirus carrying both h2E1 and hOR cDNAs (v-h2E1-hOR). The h2E1 cDNA was expressed under the control of the polyhedrin promoter P(Polh), whereas hOR cDNA was expressed under the control of the P10 promoter. The expressed enzymes were catalytically active in the cell membrane preparations. The estimated molar expression ratio of h2E1 to hOR in the membranes was 1:5. The apparent Km and kcat for N-nitrosodimethylamine (NDMA) demethylase activity were 145 microM and 2.4 min-1, respectively. When Sf9 cells were co-infected with the dual-expression virus (v-h2E1-hOR) and human cytochrome b5 recombinant virus (v-hb5), a 9-fold decrease in the Km of NDMA demethylase activity (16 microM) was observed in the membrane preparations, whereas the kcat was increased to 4 min-1. In the second approach, recombinant viruses of h2E1 and hOR (v-h2E1 and v-hOR) were used to co-infect the Sf9 cells. In this double-expression system, with a fixed amount of v-h2E1, the expression of h2E1 in the Sf9 cells decreased as the amount of v-hOR increased. Western blot analysis of the membrane preparations showed that the level of hOR increased, but the level of h2E1 decreased with increasing amounts of v-hOR. A corresponding decrease in h2E1 mRNA, however, was not observed. In the presence of human cytochrome b5 (hb5), the optimal h2E1:hOR molar ratio for h2E1 catalytic activity was 1:1. In order to further investigate the hb5 effect on h2E1-catalyzed reactions in the native membranes, we co-infected Sf9 cells with v-h2E1, v-hOR, and v-hb5 and obtained a membrane preparation containing h2E1, hOR, and hb5. Stoichiometric analysis with membrane preparations from double-infection and triple-infection systems revealed that the presence of hb5 decreased NADPH oxidation and H202 formation by 72 and 80%, respectively, but increased product formation from NDMA 13-fold. These results suggest that hb5 enhances the coupling between h2E1 and hOR for product formation. These studies also demonstrate that the baculovirus-insect cell system can produce high levels of expression of functional h2E1, hOR, and hb5 for mechanistic studies.


Interventions to reduce harm from smoking with families in infancy and early childhood: a systematic review.
Exposure to adult smoking can have deleterious effects on children. Interventions that assist families with smoking cessation/reduction and environmental tobacco smoke (ETS) avoidance can improve child health outcomes and reduce the risk of smoking initiation. The purpose of this review was to describe the state of the science of interventions with families to promote smoke-free home environments for infants and young children, including parent smoking reduction and cessation interventions, ETS reduction, and anti-smoking socialisation interventions, using the socio-ecological framework as a guide. A systematic review of peer-reviewed articles identified from journal databases from 2000 to 2014 was undertaken. Of 921 articles identified, 28 were included in the review. Considerable heterogeneity characterised target populations, intervention types, complexity and intensity, precluding meta-analysis. Few studies used socio-ecological approaches, such as family theories or concepts. Studies in early parenthood (child age newborn to one year) tended to focus on parent smoking cessation, where studies of families with children aged 1-5 years were more likely to target household SHSe reduction. Results suggest that interventions for reduction in ETS may be more successful than for smoking cessation and relapse prevention in families of children aged less than 5 years. There is a need for a range of interventions to support families in creating a smoke free home environment that are both tailored and targeted to specific populations. Interventions that target the social and psychodynamics of the family should be considered further, particularly in reaching vulnerable populations. Consideration is also required for approaches to interventions that may further stigmatise families containing smokers. Further research is required to identify successful elements of interventions and the contexts in which they are most effective.


Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe.
An association between exposure to environmental tobacco smoke (ETS) and lung cancer risk has been suggested. To evaluate this possible association better, researchers need more precise estimates of risk, the relative contribution of different sources of ETS, and the effect of ETS exposure on different histologic types of lung cancer. To address these issues, we have conducted a case-control study of lung cancer and exposure to ETS in 12 centers from seven European countries. A total of 650 patients with lung cancer and 1542 control subjects up to 74 years of age were interviewed about exposure to ETS. Neither case subjects nor control subjects had smoked more than 400 cigarettes in their lifetime. ETS exposure during childhood was not associated with an increased risk of lung cancer (odds ratio [OR] for ever exposure = 0.78; 95% confidence interval [CI] = 0.64-0.96). The OR for ever exposure to spousal ETS was 1.16 (95% CI = 0.93-1.44). No clear dose-response relationship could be demonstrated for cumulative spousal ETS exposure. The OR for ever exposure to workplace ETS was 1.17 (95% CI = 0.94-1.45), with possible evidence of increasing risk for increasing duration of exposure. No increase in risk was detected in subjects whose exposure to spousal or workplace ETS ended more than 15 years earlier. Ever exposure to ETS from other sources was not associated with lung cancer risk. Risks from combined exposure to spousal and workplace ETS were higher for squamous cell carcinoma and small-cell carcinoma than for adenocarcinoma, but the differences were not statistically significant. Our results indicate no association between childhood exposure to ETS and lung cancer risk. We did find weak evidence of a dose-response relationship between risk of lung cancer and exposure to spousal and workplace ETS. There was no detectable risk after cessation of exposure.


Toward a social capital based framework for understanding the water-health nexus.
In recent years, there has been considerable interest in social capital theory in both research and policy arenas. Social capital has been associated with many aspects of improvements in health, environment and development. This paper assesses the theoretical support for a social capital based analysis of environment and health issues with a focus on the water-health nexus in low and middle income countries. We review conceptualisation of social capital by Pierre Bourdieu in relation to his concepts of "fields" and "habitus" as well as other conceptualisations of social capital by James Coleman and Robert Putnam. We integrate these authors' ideas with ecosocial analysis of social and geographical patterns of access to safe water, adequate sanitation and hygiene and the resulting health impacts. Further, we develop a conceptual framework for linking social capital and health through the water-health nexus. The framework focuses on the role of social capital in improving water-related knowledge, attitudes and practices as well as facilitating collective action towards improving access to water and sanitation. The proposed framework will facilitate critical engagement with the pathways through which social processes and interactions influence health within the context of access to water, sanitation and hygiene in low and middle income countries.


Emerging molecular targets for brain repair after stroke.
The field of neuroprotection generated consistent preclinical findings of mechanisms of cell death but these failed to be translated into clinics. The approaches that combine the modulation of the inhibitory environment together with the promotion of intrinsic axonal outgrowth needs further work before combined therapeutic strategies will be transferable to clinic trials. It is likely that only when some answers have been found to these issues will our therapeutic efforts meet our expectations. Stroke is a clinically heterogeneous disease and combinatorial treatments require much greater work in pharmacological and toxicological testing. Advances in genetics and results of the Whole Human Genome Project (HGP) provided new unknown information in relation to stroke. Genetic factors are not the only determinants of responses to some diseases. It was recognized early on that "epigenetic" factors were major players in the aetiology and progression of many diseases like stroke. The major players are microRNAs that represent the best-characterized subclass of noncoding RNAs. Epigenetic mechanisms convert environmental conditions and physiological stresses into long-term changes in gene expression and translation. Epigenetics in stroke are in their infancy but offer great promise for better understanding of stroke pathology and the potential viability of new strategies for its treatment.


What oncologists believe they said and what patients believe they heard: an analysis of phase I trial discussions.
PURPOSE; Evaluation of the communication and informed consent process in phase I clinical trial interviews to provide authentic, practice-based content for inclusion in a communication skills training intervention for health care professionals. Seventeen oncologists and 52 patients from five United Kingdom cancer centers consented to recording of phase I trial discussions. Following each consultation, clinicians completed questionnaires indicating areas they felt they had discussed, and researchers conducted semistructured interviews with patients examining their recall and understanding. Patients and oncologists also completed the Life Orientation Test-Revised questionnaire, measuring predisposition toward optimism. Independent researchers coded the consultations identifying discussion of key information areas and how well this was done. Observed levels of agreement were analyzed for each consultation between oncologist-coder, oncologist-patient, and patient-coder pairs. In several key areas, information was either missing or had been explained but was interpreted incorrectly by patients. Discussion of prognosis was a frequent omission, with patients and coders significantly more likely to agree that oncologists had not discussed it (odds, 4.8; P < .001). In contrast, coders and oncologists were more likely to agree that alternate care plans to phase I trial entry had been explained (odds, 2.5; P = .023). These data indicate that fundamental components of communication and information sharing about phase I trial participation are often missing from interviews. Important omissions included discussion of prognosis and ensuring patient understanding about supportive care. These findings will inform educational initiatives to assist communication about phase I trials.


The use of participatory appraisal by veterinarians in Africa.
The term 'participatory appraisal' refers to a range of methods for data collection, learning and facilitation, which enable local people to play an active role in defining, analysing and solving their problems. A questionnaire survey was used to obtain information on the use of participatory appraisal (PA) from veterinarians working in Africa. A low overall response rate of 28.6% was achieved. Within Africa, response rates varied from 15.6% from government veterinarians to 47.6% from veterinarians working with non-governmental organisations. Information is presented on preferred methods, specific uses, levels of training and perceived advantages and disadvantages of PA. While PA was considered by many informants to be a valuable approach to working with communities to analyse and solve local animal health problems, respondents also identified constraints to the wider use of PA. These constraints included lack of financial resources, low availability of relevant training courses and materials, lack of time to attend training courses, and negative attitudes among colleagues. The author concludes that greater institutional awareness of the role of PA in the development of Veterinary Services is required. Such awareness might be achieved by wider dissemination of experiences related to the use of PA and the development of veterinary-orientated training courses for centrally-based personnel and workers in the field. The latter should include attention to appropriate attitudes and behaviour for veterinary professionals who are attempting to develop services according to the priorities and capacity of the community.