Nurses' responses to severity dependent errors: a study of the causal attributions made by nurses following an error.
Attribution theory attempts to understand how people explain events and their own role in them, particularly events which are unusual or unpleasant. Based on previous studies on attributions, it was suggested that nurses would make more external attributions (i.e. blaming others or the environment) following an error with a serious outcome than one with a non-serious outcome. This would in turn suggest that they might be less likely to respond constructively and learn from serious errors. Sixty nurses were approached for this study. They were divided into two groups. One group (30 subjects) completed a questionnaire on the responses to a description of an error with a non-serious outcome and the second group (also 30 subjects) responded to questions to an identical error but with a serious outcome. The findings from this study indicated that nurses behaved in an atypical manner in response to making an error. Although both groups of nurses tended to make slightly more internal attributions for the error, indicating that they are likely to take responsibility for their error, those nurses in the serious outcome condition blamed themselves more for the error. This may be due to the strong professional ethos which exists amongst nurses that expects them to take responsibility for their actions. This would inevitably include any error that they may make in the course of giving care. The conclusion that can be drawn is that nurses might be quite receptive to making constructive changes in their practice following an error, provided this situation is managed properly.


Trends in HIV counseling and testing uptake among married individuals in Rakai, Uganda.
Despite efforts to promote HIV counseling and testing (HCT) among couples, few couples know their own or their partners' HIV status. We assessed trends in HCT uptake among married individuals in Rakai district, southwestern Uganda. We analysed data for 11,268 married individuals aged 15-49 years who were enrolled into the Rakai Community Cohort Study (RCCS) between 2003 and 2009. Married individuals were interviewed separately but were retrospectively linked to their partners at analysis. All participants had serologic samples obtained for HIV testing, and had the option of receiving HCT together (couples' HCT) or separately (individual HCT). Individuals were categorized as concordant HIV-positive if both partners had HIV; concordant HIV-negative if both did not have HIV; or HIV-discordant if only one of the partners had HIV. We used χ2 tests to assess linear trends in individual and couples' HCT uptake in the entire sample and conducted multinomial logistic regression on a sub-sample of 10,712 individuals to assess relative risk ratios (RRR) and 95% Confidence Intervals (95% CI) associated with individual and couples' HCT uptake. Analysis was done using STATA version 11.0. Uptake of couples' HCT was 27.2% in 2003/04, 25.1% in 2005/06, 28.5% in 2006/08 and 27.8% in 2008/09 (χ2 for trend = 2.38; P = 0.12). Uptake of individual HCT was 57.9% in 2003/04, 60.2% in 2005/06, 54.0% in 2006/08 and 54.4% in 2008/09 (χ2 for trend = 8.72; P = 0.003). The proportion of couples who had never tested increased from 14.9% in 2003/04 to 17.8% in 2008/09 (χ2 for trend = 18.16; P < 0.0001). Uptake of couples' HCT was significantly associated with prior HCT (Adjusted [Adj.] RRR = 6.80; 95% CI: 5.44, 8.51) and being 25-34 years of age (Adj. RRR = 1.81; 95% CI: 1.32, 2.50). Uptake of individual HCT was significantly associated with prior HCT (Adj. RRR = 6.26; 95% CI: 4.24, 9.24) and the female partner being HIV-positive (Adj. RRR = 2.46; 95% CI: 1.26, 4.80). Uptake of couples' HCT remained consistently low (below 30%) over the years, while uptake of individual HCT declined over time. These findings call for innovative strategies to increase demand for couples' HCT, particularly among younger couples and those with no prior HCT.


Associations of arterial stiffness and cognitive function with physical fitness in patients with chronic stroke.
To determine whether arterial stiffness is associated with cognitive function after adjustment for physical fitness in patients with chronic stroke. Cross-sectional analyses were conducted in 102 patients with chronic stroke who participated in an exercise rehabilitation programme. Carotid femoral pulse wave velocity and augmentation index were measured as indices of arterial stiffness and central systolic loading. Cognitive function was assessed with the Mini Mental State Examination. Parameters of physical fitness included the 6-min walk test, flexibility, balance, and muscle strength tests. Carotid femoral pulse wave velocity was significantly associated with Mini Mental State Examination (r = -0.45, p < 0.01) and parameters of physical fitness (r = -0.45~ -0.55, p < 0.01, all). Mini Mental State Examination was significantly associated with parameters of physical fitness (r = 0.32~0.46, p < 0.01, all). In multivariable linear regression models, carotid femoral pulse wave velocity was inversely associated with Mini Mental State Examination after adjustment for multiple risk factors (beta = -0.33, p = 0.01). However, the association was attenuated and became non-significant after additional adjustment for physical fitness (beta = -0.11, p = 0.39). Arterial stiffness measured by carotid femoral pulse wave velocity is associated with cognitive function in patients with chronic stroke, but not after adjustment for physical fitness. Maintaining appropriate levels of physical fitness may have a favourable effect on both vascular and cognitive function in patients with stroke.


Arbuscular mycorrhizal trees influence the latitudinal beta-diversity gradient of tree communities in forests worldwide.
Arbuscular mycorrhizal (AM) and ectomycorrhizal (EcM) associations are critical for host-tree performance. However, how mycorrhizal associations correlate with the latitudinal tree beta-diversity remains untested. Using a global dataset of 45 forest plots representing 2,804,270 trees across 3840 species, we test how AM and EcM trees contribute to total beta-diversity and its components (turnover and nestedness) of all trees. We find AM rather than EcM trees predominantly contribute to decreasing total beta-diversity and turnover and increasing nestedness with increasing latitude, probably because wide distributions of EcM trees do not generate strong compositional differences among localities. Environmental variables, especially temperature and precipitation, are strongly correlated with beta-diversity patterns for both AM trees and all trees rather than EcM trees. Results support our hypotheses that latitudinal beta-diversity patterns and environmental effects on these patterns are highly dependent on mycorrhizal types. Our findings highlight the importance of AM-dominated forests for conserving global forest biodiversity.


Compliance with inhaled asthma medication in preschool children.
Previous studies have shown poor compliance with regular drug therapy in children and adults with asthma. In preschool children the parents supervise and are responsible for drug administration, but little is known of compliance in this group. In addition, there are few data on the patterns of drug use of inhaled prophylactic asthma therapy or of the relation between compliance and symptom control. A study was undertaken to address these issues with the hypothesis that parental supervision would result in good compliance. The subjects were 29 asthmatic children aged 15 months to five years already established on inhaled prophylactic medication delivered through a large volume spacer. The prescribed drug regimens varied between subjects. This was an observational study using an electronic inhaler timer device to record the date and time of each actuation of the aerosol canister. Diary cards were used for parallel recording of symptoms and parentally reported compliance with a drug regimen. Variable and generally poor compliance was demonstrated with a median of 50% of study days with full compliance (subject range 0-94%) and an overall median of 77% of prescribed doses of therapy taken during the study period. No relation was found between frequency of prescribed regimen and good compliance. Day care was associated with poorer compliance. No relation between good compliance and low symptom scores was found. Compliance with inhaled prophylactic therapy is poor in preschool children with asthma whose medication is administered under parental supervision.


Effect of soybean oil and fish oil on individual molecular species of Atlantic salmon head kidney phospholipids determined by normal-phase liquid chromatography coupled to negative ion electrospray tandem mass spectrometry.
The effect of soybean oil (SO) and fish oil (FO) on the relative molecular species distribution of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylserine (PS) in Atlantic salmon head kidney was studied using normal-phase liquid chromatography coupled with negative ion electrospray tandem mass spectrometry. The conformation of identity of the phospholipid species was based on retention time, the mass of the [M-H]- ([M-15]- for PC) molecular ions and the carboxylate anion fragments in the product ion spectrum. The intensity ratio of sn-1/sn-2 fragment ions increased with increasing number of double bonds in the sn-2 acyl chain but was not affected by increasing number of double bonds in the sn-1 acyl chain of the species examined. The relative distribution of the molecular species was determined by multiple reaction monitoring of the carboxylate anion fragment from the sn-1 position. A total of 68 different phospholipid species were determined in the head kidney and the largest amount was found in PE (22 species). Depending on the diet, the main species identified in the different phospholipid classes were; PC 16:0/18:1, PE 16:0/22:6, PI 18:0/20:4 and PS 16:0/22:6. The SO diet significantly increased the 18:2, 20:3 and most 20:4 containing species and significantly reduced the 14:0 and most 20:5 and 22:6 fatty acid containing species. The increase of the 20:4 and the decrease of the 20:5 and 22:6 containing species were dependent on the fatty acid combination of the species.


Platelet sodium kinetics, blood pressure and serum urate: aberrations in non-obese men at risk for type 2 diabetes mellitus.
The rate constants for the ouabain- and frusemide-sensitive 22Na+ efflux, the number of [3H]ouabain binding sites and the effect of plasma on [3H]ouabain binding were determined in platelets, as were blood pressure (BP) and serum urate concentrations, in 35 normoglycaemic men with family histories of type 2 diabetes (hereditary group), in 18 subjects with impaired glucose tolerance (IGT) and in 28 normoglycaemic controls. All subjects were non-obese males of comparable age. Earlier findings of increased BP both in normoglycaemic subjects with family histories of type 2 diabetes and in IGT subjects were confirmed. The mean serum urate concentration was significantly higher in the hereditary group than in controls, and intermediate in IGT subjects. The ouabain-sensitive 22Na+ efflux rate constant was significantly decreased in IGT subjects without any concomitant change in the number of [3H]ouabain binding sites. No differences in any of the rate constants for 22Na+ efflux, or in the number of [3H]ouabain binding sites, were noted between the hereditary group and controls. The ability of deproteinized plasma samples to interfere with [3H]ouabain binding to test platelets from one healthy individual was similar in all three groups. The present findings are not consistent with the hypothesis that the BP increase in normoglycaemic subjects with family histories of type 2 diabetes is linked to a disturbance in sodium transport. Our data suggest a decreased Na+/K+-ATPase activity in IGT, which may be of pathophysiological significance in relation to hypertension.


The use of biomarkers as alternatives to current animal tests on food chemicals.
Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.


Psychodynamic techniques related to outcome for anxiety disorder patients at different points in treatment.
Although psychodynamic therapy has a well-articulated model of therapeutic change for anxiety, few empirical studies have examined specific treatment interventions related to symptom improvement. We examined the degree of adherence to a psychodynamic model of therapy (Blagys and Hilsenroth [Clin Psychol 7:167-188, 2000) related to changes in anxiety symptoms across early treatment process. Secondary analyses also examined the use of specific psychodynamic techniques across early treatment process in relation to symptom change. The current study sought to extend the findings of , who found a relationship between the use of psychodynamic techniques in the third session (independent clinical ratings) and reduction in anxiety symptoms at posttreatment (r = 0.46, p = 0.04). Using the same sample of anxiety disorder patients (N = 20), we found a significant relationship between psychodynamic technique and posttreatment change in anxiety symptoms at the ninth session (r = 0.49, p = 0.03) and the mean levels of psychodynamic technique across both third and ninth sessions (r = 0.53, p = 0.02). In addition, specific psychodynamic techniques demonstrated significant relationships or moderate to large effects with posttreatment changes in anxiety symptoms at the third and ninth sessions as well as mean ratings across early treatment (third and ninth sessions). These findings indicate that therapist focus on cyclical intrapersonal patterns in patient actions, feelings, or experience as well as suggestions of alternative ways to understand these experiences or events not previously recognized by the patient (i.e., interpretation) in the early treatment process were particularly helpful in reducing posttreatment anxiety symptoms. Clinical implications and areas for future research will be discussed.


Drosophila melanogaster glutamate-cysteine ligase activity is regulated by a modifier subunit with a mechanism of action similar to that of the mammalian form.
Glutamate-cysteine ligase (GCL) plays an important role in regulating glutathione homeostasis. In mammals, it comprises a catalytic (GCLC) and modifier (GCLM) subunit. The existence of a modifier subunit in invertebrates has not been described to date. We now demonstrate that GCL from Drosophila melanogaster has a functional modifier subunit (DmGCLM). A putative DmGCLM was obtained as an expressed sequence tag with 27% identity to human GCLM at the amino acid level. D. melanogaster GCLC (DmGCLC) and the candidate DmGCLM were expressed separately in Escherichia coli, purified, mixed, and then subjected to gel filtration, where they eluted as an approximately 140-kDa complex. DmGCLC co-immunoprecipitated with DmGCLM from S2 cell extracts, suggesting that they also associate in vivo. Enzyme kinetic analyses showed that DmGCLC has a K(m) for glutamate of 2.88 mm, but when complexed with DmGCLM, the K(m) for glutamate is 0.45 mm. Inhibition of DmGCLC activity by glutathione was found to be competitive with respect to glutamate (K(i) = 0.03 mm), whereas inhibition of the GCL complex was mixed (K(i) = 0.67 mm), suggesting allosteric effects. In accordance with this, DmGCLC and DmGCLM have the ability to form reversible intermolecular disulfide bridges. A further mechanism for control of D. melanogaster GCL was found to be induction of DmGCLC by tert-butylhydroquinone in S2 cells. DmGCLM levels were, however, unaffected by tert-butylhydroquinone.


Estrogenic activity of cosmetic components in reporter cell lines: parabens, UV screens, and musks.
In this work, the estrogenic effects of three classes of substances included in cosmetic formulations-parabens, ultraviolet (UV) screens, and musk fragrances-were studied. Their estrogenic activity was measured with the use of three reporter cell lines: HELN, HELN ERalpha, and HELN ERbeta. These three cell lines allowed for the measurement of estrogenic activity toward estrogen receptors alpha and beta (ERalpha and ERbeta, while taking nonspecific interactions into account. Eight of the 15 substances tested showed specific estrogenic activity with the following degree of potency on ERalpha butylparaben > propylparaben > homosalate = octyl-dimethyl-PABA = 4-methyl-benzylidenecamphor = octyl-methoxycinnamate > ethylparaben = galaxolide. Among these active substances, parabens activated ERalpha and ERbeta similarly, UV screens activated ERalpha moderately and had almost no effect on ERbeta, and fragrances did not activate ERbeta. Methylparaben, ethylparaben, musk moskene, celestolide, and cashmeran did not activate estrogenic responses up to 10(-5) M. Musk ketone and benzophenone-3 were not considered estrogenic at 10(-5) M.


Fluoride-induced alterations of synapse-related proteins in the cerebral cortex of ICR offspring mouse brain.
Fluoride (F) exposure causes cognitive dysfunction in humans and animals. However, the precise molecular mechanisms by which fluoride exerts its neurotoxic effects are poorly understood. In this study, an animal model of fluoride exposure was created by providing ICR mice were treated with vehicle F at a dose of 0 (control group), 50 (low-fluoride group) or 100 mg/L (high-fluoride group) in water for one month. After the mice mated, parents and offspring were treated and maintained under these conditions. The cognitive abilities of the mice were examined using a Morris water maze test. Results indicated that fluoride exposure significantly prolonged the escape latency period and decreased the number of crossings in a particular zone. Histopathologic analysis revealed the shrinkage and fragmentation of glial cells in the fluoride-treated groups. Pyramidal cells in the cerebral cortices of fluoride-treated groups were fewer than those of the control group. The expression of microtubule-associated protein 2 (MAP2) and synaptic proteins of the cerebral cortex in mouse offspring was assayed using RT-PCR and Western blot. Fluoride exposure possibly induced a significantly decreased expression of MAP2, synaptophysin (SYP) and developmentally regulated brain protein (Dbn) at protein and mRNA levels. Glutamate receptor (N-methyl-d-aspartate receptor, NMDAR) was also expressed, and this finding was consistent with the reduced MAP2, SYP and Dbn expression. Therefore, fluoride-mediated reduction in cognitive dysfunction is likely caused by the disruption of the expression of these synapse-associated proteins, resulting in attenuated neuronal functioning.


Erythropoietin: when liability becomes asset in neurovascular repair.
Erythropoietin (Epo) leads to the proliferation and differentiation of erythroid precursors, but is also involved in diverse nonhematopoietic biological functions. In this issue of the JCI, Chen, Smith, and colleagues demonstrate that the temporal expression of Epo is critical for determining whether physiological or pathological repair occurs following neurovascular retinal injury in the oxygen-induced retinopathy neonatal mouse model (see the related article beginning on page 526). The pleiotrophic properties of Epo make it a likely novel therapy for treatment of neurovascular damage, but the timing of its use must be carefully considered to prevent untoward effects.


Aortic arch recoarctation after the Norwood stage I palliation: the comparative accuracy of blood pressure cuff and echocardiographic Doppler gradients in detecting significant obstruction.
Aortic arch recoarctation is responsible for significant morbidity and mortality after the Norwood Stage I procedure. Cuff blood pressure (BP) gradients and echocardiographic Doppler gradients are routinely used as noninvasive screening tests for early detection, but accuracy has not been systematically tested. We sought to evaluate the ability of cuff BP and Doppler gradients, measured at routine outpatient clinic visits, to predict significant arch obstruction in single ventricle patients after the Norwood operation. Consecutive patients who underwent Norwood operation at our institution were identified retrospectively. Cuff and echocardiographic gradients measured prior to the pre-Glenn catheterization were compared to peak-to-peak systolic neoaortic arch gradients obtained at catheterization. Statistical analyses, including Receiver Operator Characteristic (ROC) curves, were performed using different cutpoints for cuff and echocardiographic gradients, evaluating their ability to predict a clinically significant catheter gradient. Data were obtained in 68 patients. Echocardiographic gradient cutpoints were more sensitive but less specific than cuff BP gradient cutpoints at detecting a catheter gradient > or = 10 mm Hg. Echo gradients > or = 20 mm Hg showed 85% sensitivity and 95% specificity in detecting a systolic catheter gradient > or = 10 mm Hg. chocardiographic Doppler outperforms cuff BP as a sensitive noninvasive screening tool for early detection of significant arch obstruction in infants after the Norwood operation.


Probing the Most Aromatic and Antiaromatic Pyrrolium Rings by Maximizing Hyperconjugation and Push-Pull Effect.
Hyperconjugation, a weak interaction in organic chemistry, can have a strong effect on aromaticity, leading to the concept of hyperconjugative aromaticity, which was first proposed by Mulliken in 1939. However, most studies are limited to main group chemistry. Here we report the most aromatic and antiaromatic pyrrolium ring by maximizing the hyperconjugation caused by transition metal fragments and the push-pull effect. Our calculations reveal that the origin of the outperformance of transition metal substituents over main group ones on hyperconjugative aromaticity could be attributed to their higher highest occupied molecular orbitals (HOMOs). Among the group 11 transition metals, a silver substituent results in the best performance. All these findings highlight the magic of the transition metal (silver) and could be particularly helpful for the design of other aromatic and antiaromatic counterparts based on a nonaromatic parent species.


Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1.
Obesity is associated with inflammation that can drive metabolic defects such as hyperlipidemia and insulin resistance. Specific metabolites can contribute to inflammation, but nutrient intake and obesity are also associated with altered bacterial load in metabolic tissues (i.e. metabolic endotoxemia). These bacterial cues can contribute to obesity-induced inflammation. The specific bacterial components and host receptors that underpin altered metabolic responses are emerging. We previously showed that Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) activation with bacterial peptidoglycan (PGN) caused insulin resistance in mice. We now show that PGN induces cell-autonomous lipolysis in adipocytes via NOD1. Specific bacterial PGN motifs stimulated lipolysis in white adipose tissue (WAT) explants from WT, but not NOD1⁻/⁻mice. NOD1-activating PGN stimulated mitogen activated protein kinases (MAPK),protein kinase A (PKA), and NF-κB in 3T3-L1 adipocytes. The NOD1-mediated lipolysis response was partially reduced by inhibition of ERK1/2 or PKA alone, but not c-Jun N-terminal kinase (JNK). NOD1-stimulated lipolysis was partially dependent on NF-κB and was completely suppressed by inhibiting ERK1/2 and PKA simultaneously or hormone sensitive lipase (HSL). Our results demonstrate that bacterial PGN stimulates lipolysis in adipocytes by engaging a stress kinase, PKA, NF-κB-dependent lipolytic program. Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes.


Early musical training and white-matter plasticity in the corpus callosum: evidence for a sensitive period.
Training during a sensitive period in development may have greater effects on brain structure and behavior than training later in life. Musicians are an excellent model for investigating sensitive periods because training starts early and can be quantified. Previous studies suggested that early training might be related to greater amounts of white matter in the corpus callosum, but did not control for length of training or identify behavioral correlates of structural change. The current study compared white-matter organization using diffusion tensor imaging in early- and late-trained musicians matched for years of training and experience. We found that early-trained musicians had greater connectivity in the posterior midbody/isthmus of the corpus callosum and that fractional anisotropy in this region was related to age of onset of training and sensorimotor synchronization performance. We propose that training before the age of 7 years results in changes in white-matter connectivity that may serve as a scaffold upon which ongoing experience can build.


Relationship between Pelvic Alignment and Weight-bearing Asymmetry in Community-dwelling Chronic Stroke Survivors.
Altered pelvic alignment and asymmetrical weight bearing on lower extremities are the most common findings observed in standing and walking after stroke. The purpose of this study was to find the relationship between pelvic alignment and weight-bearing asymmetry (WBA) in community-dwelling chronic stroke survivors. This cross-sectional study was conducted in tertiary care rehabilitation centers. In standing, the lateral and anterior pelvic tilt angle of chronic stroke survivors was assessed using palpation (PALM™) meter device. The percentage of WBA was measured with two standard weighing scales. Pearson correlation coefficient (r) was used to study the correlation between pelvic tilt and WBA. Of 112 study participants, the mean (standard deviation) age was 54.7 (11.7) years and the poststroke duration was 14 (11) months. The lateral pelvic tilt on the most affected side and bilateral anterior pelvic tilt were 2.47 (1.8) and 4.4 (1.8) degree, respectively. The percentage of WBA was 23.2 (18.94). There was a high correlation of lateral pelvic tilt with WBA (r = 0.631; P < 0.001) than anterior pelvic tilt (r = 0.44; P < 0.001). Excessive lateral pelvic tilt toward the most affected side in standing may influence the weight-bearing ability of the ipsilateral lower extremity in community-dwelling chronic stroke survivors.


Changes in health in the countries of the UK and 150 English Local Authority areas 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Previous studies have reported national and regional Global Burden of Disease (GBD) estimates for the UK. Because of substantial variation in health within the UK, action to improve it requires comparable estimates of disease burden and risks at country and local levels. The slowdown in the rate of improvement in life expectancy requires further investigation. We use GBD 2016 data on mortality, causes of death, and disability to analyse the burden of disease in the countries of the UK and within local authorities in England by deprivation quintile. We extracted data from the GBD 2016 to estimate years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and attributable risks from 1990 to 2016 for England, Scotland, Wales, Northern Ireland, the UK, and 150 English Upper-Tier Local Authorities. We estimated the burden of disease by cause of death, condition, year, and sex. We analysed the association between burden of disease and socioeconomic deprivation using the Index of Multiple Deprivation. We present results for all 264 GBD causes of death combined and the leading 20 specific causes, and all 84 GBD risks or risk clusters combined and 17 specific risks or risk clusters. The leading causes of age-adjusted YLLs in all UK countries in 2016 were ischaemic heart disease, lung cancers, cerebrovascular disease, and chronic obstructive pulmonary disease. Age-standardised rates of YLLs for all causes varied by two times between local areas in England according to levels of socioeconomic deprivation (from 14 274 per 100 000 population [95% uncertainty interval 12 791-15 875] in Blackpool to 6888 [6145-7739] in Wokingham). Some Upper-Tier Local Authorities, particularly those in London, did better than expected for their level of deprivation. Allowing for differences in age structure, more deprived Upper-Tier Local Authorities had higher attributable YLLs for most major risk factors in the GBD. The population attributable fractions for all-cause YLLs for individual major risk factors varied across Upper-Tier Local Authorities. Life expectancy and YLLs have improved more slowly since 2010 in all UK countries compared with 1990-2010. In nine of 150 Upper-Tier Local Authorities, YLLs increased after 2010. For attributable YLLs, the rate of improvement slowed most substantially for cardiovascular disease and breast, colorectal, and lung cancers, and showed little change for Alzheimer's disease and other dementias. Morbidity makes an increasing contribution to overall burden in the UK compared with mortality. The age-standardised UK DALY rate for low back and neck pain (1795 [1258-2356]) was higher than for ischaemic heart disease (1200 [1155-1246]) or lung cancer (660 [642-679]). The leading causes of ill health (measured through YLDs) in the UK in 2016 were low back and neck pain, skin and subcutaneous diseases, migraine, depressive disorders, and sense organ disease. Age-standardised YLD rates varied much less than equivalent YLL rates across the UK, which reflects the relative scarcity of local data on causes of ill health. These estimates at local, regional, and national level will allow policy makers to match resources and priorities to levels of burden and risk factors. Improvement in YLLs and life expectancy slowed notably after 2010, particularly in cardiovascular disease and cancer, and targeted actions are needed if the rate of improvement is to recover. A targeted policy response is also required to address the increasing proportion of burden due to morbidity, such as musculoskeletal problems and depression. Improving the quality and completeness of available data on these causes is an essential component of this response. Bill & Melinda Gates Foundation and Public Health England.


Genetic linkage between resistance to quaternary ammonium compounds and beta-lactam antibiotics in food-related Staphylococcus spp.
Little is known about the occurrence of antimicrobial resistance determinants in staphylococci isolated from food and food processing industries. Quaternary ammonium compound (QAC)-resistant coagulase-negative staphylococci (CNS) isolated from food and food-processing industries were investigated for the presence of genetic determinants (qacA/B and qacC/smr) encoding resistance to the QAC benzalkonium chloride (BC), several antibiotic resistance genes, and staphylococcal insertion sequences IS257 and IS256. Six qacA/B-harboring strains were resistant to penicillin and hybridized to a blaZ probe. The qacA/B and blaZ probes hybridized to plasmids of similar size in three isolates. Molecular and genetic characterization of the 23-kb plasmid (pST6) of Staphylococcus epidermidis St.6 revealed the presence of qacB adjacent to an incomplete beta-lactamase transposon Tn552 encoding the gene cluster blaZ, blaR, and blaI. Sequence analysis of flanking regions and the intergenic region between blaZ and qacB revealed the presence of IS257 downstream of blaZ as well as sin and binR between blaZ and qacB. In the three other BC and penicillin-resistant strains, the qacA/B and blaZ genes were located on separate plasmids. A qacC harboring S. epidermidis strain (St.17) also hybridized to tetK (tetracycline resistance) and ermB (erythromycin resistance) genes. The individual genes were located on separate plasmids, suggesting no linkage between QAC and antibiotic resistance determinants. Plasmid-free Staphylococcus aureus RN4220 allowed uptake of the pST6 plasmid DNA, indicating that the resistance genes could potentially be transferred to pathogens under selective stress. In conclusion, presence of both resistance determinants could lead to co-selection during antimicrobial therapy or disinfection in hospitals or in food industries.


Quantification of interaction strengths between chaperones and tetratricopeptide repeat domain-containing membrane proteins.
The three tetratricopeptide repeat domain-containing docking proteins Toc64, OM64, and AtTPR7 reside in the chloroplast, mitochondrion, and endoplasmic reticulum of Arabidopsis thaliana, respectively. They are suggested to act during post-translational protein import by association with chaperone-bound preprotein complexes. Here, we performed a detailed biochemical, biophysical, and computational analysis of the interaction between Toc64, OM64, and AtTPR7 and the five cytosolic chaperones HSP70.1, HSP90.1, HSP90.2, HSP90.3, and HSP90.4. We used surface plasmon resonance spectroscopy in combination with Interaction Map® analysis to distinguish between chaperone oligomerization and docking protein-chaperone interactions and to calculate binding affinities for all tested interactions. Complementary to this, we applied pulldown assays as well as microscale thermophoresis as surface immobilization independent techniques. The data revealed that OM64 prefers HSP70 over HSP90, whereas Toc64 binds all chaperones with comparable affinities. We could further show that AtTPR7 is able to bind HSP90 in addition to HSP70. Moreover, differences between the HSP90 isoforms were detected and revealed a weaker binding for HSP90.1 to AtTPR7 and OM64, showing that slight differences in the amino acid composition or structure of the chaperones influence binding to the tetratricopeptide repeat domain. The combinatory approach of several methods provided a powerful toolkit to determine binding affinities of similar interaction partners in a highly quantitative manner.


Genome-wide analysis of Atlantic salmon (Salmo salar) mucin genes and their role as biomarkers.
The aim of this study was to identify potential mucin genes in the Atlantic salmon genome and evaluate tissue-specific distribution and transcriptional regulation in response to aquaculture-relevant stress conditions in post-smolts. Seven secreted gel-forming mucin genes were identified based on several layers of evidence; annotation, transcription, phylogeny and domain structure. Two genes were annotated as muc2 and five genes as muc5. The muc2 genes were predominantly transcribed in the intestinal region while the different genes in the muc5 family were mainly transcribed in either skin, gill or pyloric caeca. In order to investigate transcriptional regulation of mucins during stress conditions, two controlled experiments were conducted. In the first experiment, handling stress induced mucin transcription in the gill, while transcription decreased in the skin and intestine. In the second experiment, long term intensive rearing conditions (fish biomass ~125 kg/m3) interrupted by additional confinement led to increased transcription of mucin genes in the skin at one, seven and fourteen days post-confinement.


Chinese Stroke Center Alliance: a national effort to improve healthcare quality for acute stroke and transient ischaemic attack: rationale, design and preliminary findings.
In June 2015, the Chinese Stroke Association (CSA) initiated the Chinese Stroke Center Alliance (CSCA) to establish the national hospital-based stroke care quality assessment and improvement platform. This article outlines its objectives, operational structure, patient population, quality improvement (QI) intervention tools, data elements, data collection methodology and current patient and hospital data. The CSCA is a national, hospital-based, multicentre, voluntary, multifaceted intervention and continuous QI initiative. This multifaceted intervention includes stroke centre development, written care protocols, workshops and a monitoring/feedback system of evidence-based performance measures. The data coordinating centre of the CSCA resides at the China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital. As of July 2017, 1576 hospitals in China have contributed detailed clinical information to serve as a benchmark for the stroke care quality of 433 264 patients with acute stroke/transient ischaemic attacks (TIA), including 352 572 (81.38%) acute ischaemic stroke, 30 362 (7.01%) TIA, 42 080 (9.71%) spontaneous intracranial haemorrhage, 5505 (1.27%) subarachnoid haemorrhage and 2745 (0.63%) not specified stroke. The CSCA programme is designed to establish a continuous national stroke registry and help healthcare providers develop stroke centres and treat patients in a consistent manner in accordance with accepted national guidelines and, ultimately, improve patient outcomes. It supports the CSA mission to reduce stroke burden in China.


A sensitive and selective chemiluminescence sensor for the determination of dopamine based on silanized magnetic graphene oxide-molecularly imprinted polymer.
Based on silanized magnetic graphene oxide-molecularly imprinted polymer (Si-MG-MIP), a sensitive and selective chemiluminescence sensor for dopamine measurement was developed. Si-MG-MIP, in which silanes was introduced to improve the mass transfer, graphene oxide was employed to improve absorption capacity, Fe3O4 nanoparticles were applied for separation easily and molecularly imprinted polymer was used to improve selectivity, demonstrated the advantages of the sensor. All the composites were confirmed by SEM, TEM, XRD and FTIR. Under the optimal conditions of chemiluminescence, dopamine could be assayed in the range of 8.0-200.0 ng/mL with a correlation coefficient of linear regression of 0.9970. The detection limit was 1.5 ng/mL (3δ) and the precision for 11 replicate detections of 80.0 ng/mL dopamine was 3.4% (RSD). When the sensor was applied in determining dopamine in actual samples, recovery ranged from 94% to 110%, which revealed that the results were satisfactory.


An unusual case of Creutzfeldt-Jakob disease.
A patient with histopathologically verified sporadic Creutzfeldt-Jakob disease (CJD) presented initially with diplopia, sleep disturbances, and L-dopa-responsive parkinsonism. After more than a year of slow progression, he did not become demented, and failed to fulfill the clinical criteria for possible CJD. No clinical examinations currently proposed to detect CJD showed the disease. CJD should be in the differential diagnosis of "parkinson plus" syndromes until a different etiology has been found or a histopathologic examination performed.


Measurement of the initial levels of DNA damage in human lymphocytes induced by 29 kV X rays (mammography X rays) relative to 220 kV X rays and gamma rays.
Experiments using the alkaline comet assay, which measures all single-strand breaks regardless of their origin, were performed to evaluate the biological effectiveness of photons with different energies in causing these breaks. The aim was to measure human lymphocytes directly for DNA damage and subsequent repair kinetics induced by mammography 29 kV X rays relative to 220 kV X rays, 137Cs gamma rays and 60Co gamma rays. The level of DNA damage, predominantly due to single-strand breaks, was computed as the Olive tail moment or percentage DNA in the tail for different air kerma doses (0.5, 0.75, 1, 1.5, 2 and 3 Gy). Fifty cells were analyzed per slide with a semiautomatic imaging system. Data from five independent experiments were transformed to natural logarithms and fitted using a multiple linear regression analysis. Irradiations with the different photon energies were performed simultaneously for each experiment to minimize interexperimental variation. Blood from only one male and one female was used. The interexperimental variation and the influence of donor gender were negligible. In addition, repair kinetics and residual DNA damage after exposure to a dose of 3 Gy were evaluated in three independent experiments for different repair times (10, 20, 30 and 60 min). Data for the fraction of remaining damage were fitted to the simple function F(d) = A/(t + A), where F(d) is the fraction of remaining damage, t is the time allowed for repair, and A (the only fit parameter) is the repair half-time. It was found that the comet assay data did not indicate any difference in the initial radiation damage produced by 29 kV X rays relative to the reference radiation types, 220 kV X rays and the gamma rays of 137Cs and 60Co, either for the total dose range or in the low-dose range. These results are, with some restrictions, consistent with physical examinations and predictions concerning, for example, the assessment of the possible difference in effectiveness in causing strand breaks between mammography X rays and conventional (150-250 kV) X rays, indicating that differences in biological effects must arise through downstream processing of the damage.


Using high-resolution displays for high-resolution cardiac data.
The ability to perform fast, accurate, high-resolution visualization is fundamental to improving our understanding of anatomical data. As the volumes of data increase from improvements in scanning technology, the methods applied to visualization must evolve. In this paper, we address the interactive display of data from high-resolution magnetic resonance imaging scanning of a rabbit heart and subsequent histological imaging. We describe a visualization environment involving a tiled liquid crystal display panel display wall and associated software, which provides an interactive and intuitive user interface. The oView software is an OpenGL application that is written for the VR Juggler environment. This environment abstracts displays and devices away from the application itself, aiding portability between different systems, from desktop PCs to multi-tiled display walls. Portability between display walls has been demonstrated through its use on walls at the universities of both Leeds and Oxford. We discuss important factors to be considered for interactive two-dimensional display of large three-dimensional datasets, including the use of intuitive input devices and level of detail aspects.


Intracellular accumulation of mannopine, an opine produced by crown gall tumors, transiently inhibits growth of Agrobacterium tumefaciens.
pYDH208, a cosmid clone from the octopine-mannityl opine-type tumor-inducing (Ti) plasmid pTi15955 confers utilization of mannopine (MOP) and agropine (AGR) on Agrobacterium tumefaciens strain NT1. NT1 harboring pYDH208 with an insertion mutation in mocC, which codes for MOP oxidoreductase, not only fails to utilize MOP as a sole carbon source, but also was inhibited in its growth by MOP and AGR. In contrast, the growth of mutants with insertions in other tested moc genes was not inhibited by either opine. Growth of strains NT1 or UIA5, a derivative of C58 that lacks pAtC58, was not inhibited by MOP, but growth of NT1 or UIA5 harboring pRE10, which codes for the MOP transport system, was inhibited by the opine. When a clone expressing mocC was introduced, the growth of strain NT1(pRE10) was not inhibited by MOP, although UIA5(pRE10) was still weakly inhibited. In strain NT1(pRE10, mocC), santhopine (SOP), produced by the oxidation of MOP by MocC, was further degraded by functions encoded by pAtC58. These results suggest that MOP and, to a lesser extent, SOP are inhibitory when accumulated intracellularly. The growth of NT1(pRE10), as measured by turbidity and viable cell counts, ceased upon the addition of MOP but restarted in a few hours. Regrowth was partly the result of the outgrowth of spontaneous MOP-resistant mutants and partly the adaptation of cells to MOP in the medium. Chrysopine, isochrysopine, and analogs of MOP in which the glutamine residue is substituted with other amino acids were barely taken up by NT1(pRE10) and were not inhibitory to growth of the strain. Sugar analogs of MOP were inhibitory, and those containing sugars in the D form were more inhibitory than those containing sugars in the L form. MOP analogs containing hexose sugars were more inhibitory than those containing sugars with three, four, or five carbon atoms. Mutants of NT1(pRE10) that are resistant to MOP arose in the zone of growth inhibition. Genetic and physiological analyses indicate that the mutations are located on pRE10 and abolish uptake of the opine.


A fresh look at the definition of susceptibility of Streptococcus pneumoniae to beta-lactam antibiotics.
Definitions for susceptibility or resistance of Streptococcus pneumoniae to penicillin were not developed until penicillin-resistant pneumococci appeared in South Africa in the late 1970s. The definition that was accepted (which still remains in use) and later definitions of resistance to most other beta-lactam antibiotics were derived from laboratory and clinical data relating to the treatment of meningitis, not otitis media, sinusitis, or pneumonia. An understanding of the origin of these definitions helps to resolve the apparent paradox that infections of the respiratory tract due to seemingly beta-lactam-resistant pneumococci may still respond well to standard doses of these drugs. A recently sanctioned change in the definition of susceptibility to amoxicillin is helpful in eliminating the paradox for this drug, but it may create further confusion by implying that, on a microgram basis, amoxicillin is substantially more effective than penicillin or third-generation cephalosporins. This article examines definitions of susceptibility and resistance of pneumococci, highlighting areas that have led to confusion and proposing a new way of understanding them.


Juvenile Justice Anger Management (JJAM) Treatment for Girls: Results of a randomized controlled trial.
This study examined the efficacy of the Juvenile Justice Anger Management (JJAM) Treatment for Girls, an anger management and aggression reduction treatment designed to meet the unique needs of adolescent girls in residential juvenile justice facilities. This randomized controlled trial of JJAM compared changes in levels of anger and aggression among girls who participated in the JJAM treatment with those of girls who participated in treatment as usual (TAU) at the facilities. This study also investigated the theoretical model underlying the JJAM treatment, which proposed that reductions in hostile attribution biases, development of emotion regulation skills, and improvement in social problem solving would serve as mechanisms of action in JJAM. Participants were 70 female youth who ranged in age from 14 to 20 years (M = 17.45, SD = 1.24) and were placed at 1 of 3 participating juvenile justice facilities; 57 youth completed the study and were included in analyses. Results revealed greater reductions in anger, reactive physical aggression, and reactive relational aggression among girls in the JJAM treatment condition when compared to girls in the TAU control condition. The proposed theoretical model was partially supported via significant mediation findings; changes in hostile attribution bias were identified as a significant mechanism of action in the JJAM treatment. Results suggest that JJAM is a promising treatment to effectively reduce anger and reactive aggression among adolescent girls in juvenile justice placements. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


In vitro grown human ovarian follicles from cancer patients support oocyte growth.
Young female adult and adolescent cancer patients facing life-preserving but fertility-threatening chemo- or radiation-therapy are increasingly seeking options to protect their reproductive potential. Ovarian tissue cryopreservation with transplantation is a promising technique to safeguard fertility in cancer patients. However, this method may risk re-introduction of the original cancer to the survivor of the disease. Thus, developing a method for in vitro growth of immature follicles may provide a method for fertility restoration in the future. Human secondary follicles were isolated from ovarian tissues obtained from cancer patients and grown in vitro within a bio-engineered culture system for 30 days. Human ovarian follicles became steroidogenically active, and developed from the early secondary to antral stage in vitro. The follicles contained healthy, growing oocytes that were connected by transzonal projections between the somatic cells and oocyte. Our data support the notion that human follicle development can be achieved in vitro in a bio-engineered culture system. More studies are required to investigate whether the fully sized oocytes obtained from in vitro grown follicle are competent to resume meiosis and be fertilized.


Research ethics for a globalised world: the revised CIOMS international guidelines.
On December 6, 2016, the Council of International Organisations of Medical Sciences published a new version of its guidelines with the title "International Ethical Guidelines for Health-related Research Involving Humans." In this article we briefly describe the revision process and the structure and content of these guidelines. We outline some of its main guidelines such as the ones on social value, post-trial access, and risk-benefit ratio. In our overall evaluation we come to the conclusion that the CIOMS guidelines manage to strike a balance between the protection of human participants in health-related research and the promotion of such research activities in an exemplary way. The guidelines combine key principles with a guide to their application based on the state of the art in research ethics. Thus they represent a timely and indispensable orientation for researchers, ethics committees, and other stakeholders in health-related research.


The relationship between nurses' religiosity and willingness to let patients control the conversation about end-of-life care.
The study attempts to examine the relationship between nurses' religious beliefs and how nurses communicate with patients. An online census survey was administered to graduate students in the School of Nursing at a Midwestern university. The survey was designed to measure: relational control, as measured by the subscales of dominance and task orientation in Burgoon and Hale's scale of relational communication; clinician empathy, as measured by the Jefferson scale of clinician empathy; and intrinsic and extrinsic religiosity, whether religious views are held for deep personal reasons or social reasons, as measured by the Maltby and Lewis scale. Data were analyzed using multiple regressions and one-way ANOVAs. Intrinsic religiosity and empathy were both associated with the willingness to relinquish relational control in certain, specific contexts, such as end-of-life care. Nurses who scored higher on a scale of intrinsic religious beliefs were more willing to let patients take control of conversations about end-of-life care. A nurse's religious beliefs can enhance the clinical experience without the nurse trying to impose his or her beliefs on the patient, as the nurse works to make sure the patient's religious beliefs are upheld.


Purinergic signaling: a common pathway for neural and mesenchymal stem cell maintenance and differentiation.
Extracellular ATP, related nucleotides and adenosine are among the earliest signaling molecules, operating in virtually all tissues and cells. Through their specific receptors, namely purinergic P1 for nucleosides and P2 for nucleotides, they are involved in a wide array of physiological effects ranging from neurotransmission and muscle contraction to endocrine secretion, vasodilation, immune response, and fertility. The purinergic system also participates in the proliferation and differentiation of stem cells from different niches. In particular, both mesenchymal stem cells (MSCs) and neural stem cells are endowed with several purinergic receptors and ecto-nucleotide metabolizing enzymes, and release extracellular purines that mediate autocrine and paracrine growth/proliferation, pro- or anti-apoptotic processes, differentiation-promoting effects and immunomodulatory actions. Here, we discuss the often opposing roles played by ATP and adenosine in adult neurogenesis in both physiological and pathological conditions, as well as in adipogenic and osteogenic MSC differentiation. We also focus on how purinergic ligands produced and released by transplanted stem cells can be regarded as ideal candidates to mediate the crosstalk with resident stem cell niches, promoting cell growth and survival, regulating inflammation and, therefore, contributing to local tissue homeostasis and repair.


Adverse drug reactions in an elderly hospitalised population: inappropriate prescription is a leading cause.
Adverse drug reactions (ADRs) represent a major public health problem in the aged. In order to better evaluate this problem in Brazil, this study was designed to assess the prevalence of ADRs in an elderly hospitalised population, identify the most common ADRs and the principal medications involved, evaluate the appropriateness of use of these drugs in elderly people and determine the risk factors implicated in the appearance of such ADRs. The study population was comprised of 186 elderly patients (> or =60 years of age) admitted to the internal medicine service of a teaching hospital. The patients were assessed by a single observer using an intensive drug surveillance method to identify and report ADRs. The degree of probability for each adverse reaction was determined using the Naranjo algorithm. The mean (+/- SD) age of the patients studied was 73.6 +/- 9.1 years. Up to 115 patients (61.8%) of the study population presented at least one ADR. A total of 199 ADRs were found, at an average of 1.7 per patient. The ADRs appeared during hospitalisation in 46.2% of the study population, were present at the time of the admission but did not cause hospitalisation in 17.2% of patients, and were the cause of admission in 11.3% of patients. The most frequent ADR that caused hospitalisation was digitalis toxicity (22.7% of such ADRs). Hypokalaemia as a result of diuretics was the most prevalent ADR both during hospitalisation (11.8%) and at the time of admission without being the cause (12.1%). Captopril was the most frequently prescribed drug (138 prescriptions), and led to an ADR in 18.1% of patients who received the drug. Almost a quarter of the patients presenting an ADR were prescribed drugs considered inappropriate for the elderly. By means of a multiple logistic regression model, the following were considered to be significant risk factors for the appearance of ADRs: number of diagnoses (odds ratio [OR] 1.40; 95% CI 1.06, 1.86), number of drugs (OR 1.07; 95% CI 1.01, 1.13) and use of drug that is inappropriate for the elderly (OR 2.32; 95% CI 1.17, 4.59). The main contribution of the present study was identification of use of drugs that are considered inappropriate for elderly populations as a major risk factor for presenting an ADR. This finding is useful for continuous education programmes, therapeutic committees and policy makers, because adverse effects complicate the course of diseases in aged patients, cause hospitalisation and/or require the prescription of additional drugs. In addition to contributing to a reduction in healthcare costs, continuous efforts to promote rational drug use could also benefit elderly patients by preventing some avoidable drug toxicity. A significant prevalence of ADRs was found among hospitalised elderly people. The risk factors associated with ADRs in this population included use of drugs considered to be inappropriate for that population, number of previous diagnoses and number of administered drugs. More appropriate drug prescription could avoid part of this burden of disease by minimising preventable ADRs.


Anterior short correction in thoracic adolescent idiopathic scoliosis with mini-open thoracotomy approach: prospective clinical, radiological and pulmonary function results.
This is a prospective study of adolescent patients in whom idiopathic thoracic scoliosis was corrected by short anterior fusion through a mini-open thoracotomy approach. Clinical, radiological and pulmonary function results of minimal 2-year (2-6) follow-up are presented. Consecutive 62 patients with Lenke 1 and 2 curves, having main thoracic scoliosis of up to 75°, were prospectively included. The shoulder imbalance in Lenke 2 patients was less than 20 mm. Thoracic scoliosis was corrected by short anterior fusion. The thoracic spine was exposed by an 8-cm mini-open thoracotomy incision. The operation technique and choosing of fusion levels are thoroughly described. Complete 360° discectomies and convex side vertebral endplates osteotomies are essential for deformity corrections with short fusions. Single-rod 5.5-mm titanium implants were used. The age at the time of operation was mean 15.2 years; 56 patients had a single thoracic curve and 6 patients had a double thoracic curve. There were almost equal numbers of patients with lumbar modifier A, B or C. The average length of fusion was 5.5 (4-7) vertebrae. The average length of fusion was 3.5 (2-6) vertebrae shorter than the average curve length. The instrumented thoracic curves improved by 58.3% at 6 weeks and 56.3% at the last follow-up. Apex thoracic vertebral rotation improved by 73.78% at 6 weeks and 76.24% at the last follow-up. The non-instrumented upper thoracic curve improved by 25% in double thoracic scoliosis, where the mid-thoracic curve was selectively fused, and the non-instrumented lumbar curves improved by 33.9% at the last follow-up. The radiological changes from 6 weeks to the last follow-up were statistically not significant. The clinical rib hump improved by 54% at the last follow-up. There were no significant changes in the pulmonary function. FVC% was 81.04% preoperatively, 76.41% at 6 months and 80.38% at the 2-year follow-up. The results of SRS 24 questionnaire improved from a total of 61.40 points preoperatively to 100.50 points at 6 months and 98.62 points at the 2-year follow-up. There were no neurological or thoracotomy related complications, no pseudarthrosis, no implant pullout or breakage. A good deformity correction without loss of correction or adding on, a good cosmetic result and good patient's satisfaction were achieved through shorter than end-to-end thoracic fusions. The radiological residual deformity is acceptable. Anterior correction of thoracic scoliosis with a short spinal fusion is recommended to keep the large part of the spine mobile. A very short fusion, small thoracotomy incision, low-profile implants and complete closure of parietal pleura are keys to prevent reduction in postoperative lung function.


Meat intake, heterocyclic amine exposure, and metabolizing enzyme polymorphisms in relation to colorectal polyp risk.
Most colorectal cancers arise from adenomatous polyps or certain hyperplastic polyps. Only a few studies have investigated potential genetic modifiers of the associations between meat intake and polyp risk, and results are inconsistent. Using data from the Tennessee Colorectal Polyp Study, a large colonoscopy-based study, including 1,002 polyp cases (557 adenoma only, 250 hyperplastic polyp only, 195 both polyps) and 1,493 polyp-free patients, we evaluated the association of colorectal polyp risk with carcinogen exposure from meat and genetic polymorphisms in enzymes involved in heterocyclic amine (HCA) metabolism, including N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP1A2), and aryl hydrocarbon receptor (AhR). Data on intake levels of meats by preparation methods, doneness preferences, and other lifestyle factors were obtained. Fourteen single nucleotide polymorphisms in the AhR, CYP1A2, NAT1, and NAT2 genes were evaluated. No clear association was found for any polymorphisms with polyp risk. However, apparent interactions were found for intake of meat and HCAs with AhR, NAT1, and NAT2 genotypes, and the interactions were statistically significant for the group with both adenomatous and hyperplastic polyps. Dose-response relationships with meat or HCA intake were found only among those with the AhR GA/AA (rs2066853) genotype, NAT1 rapid, or NAT2 rapid/intermediate acetylators but not among those with other genotypes of these genes. This dose-response relationship was more evident among those with both AhR GA/AA and the NAT1 rapid acetylator than those without this genotype combination. These results provide strong evidence for a modifying effect of metabolizing genes on the association of meat intake and HCA exposure with colorectal polyp risk.


Complementation of a Toxoplasma gondii ROP1 knock-out mutant using phleomycin selection.
The ROP1 gene of Toxoplasma gondii encodes a rhoptry protein that has been implicated in host cell invasion by this obligate intracellular protozoan. To further explore the function of this protein, we created a ROP1 deletion mutant by transfection with a plasmid encoding the bacterial chloramphenicol acetyltransferase (cat) gene flanked by ROP1 genomic sequences. Selection for chloramphenicol resistance yielded the desired ROP1-deleted or 'knock-out' mutant. Analysis of this mutant both in vitro and in vivo shows no significant alterations in growth rate, host specificity, invasiveness or virulence and thus the ROP1 gene is not obligatory for the RH strain, at least under the conditions tested. However, electron microscopy reveals that the mutant strain's rhoptries are altered in ultrastructure; they are thinner and homogeneously electron-dense compared with the thicker and normally mottled or honeycombed appearance of wild-type rhoptries. The knock-out mutant was rescued using co-transfection of a cosmid carrying the ROP1 gene together with a plasmid encoding a new selectable marker for T. gondii, the bleomycin resistance gene (ble) from Streptoalloteichus. Southern blot analysis showed that both DNAs were stably integrated into the Toxoplasma genome, although not into the ROPI locus. The resulting strain showed wild-type levels of ROP1 expression and rescue of the ultrastructural phenotype (i.e., the rhoptries returned to their normal, mottled appearance), thus establishing a cause/effect relationship between the absence of ROP1 and the electron-opacity. These results demonstrate the utility of the reverse genetic approach in the study of Toxoplasma gene function and provide a further selectable marker for such manipulations.


A new hypothesis of dinosaur relationships and early dinosaur evolution.
For 130 years, dinosaurs have been divided into two distinct clades-Ornithischia and Saurischia. Here we present a hypothesis for the phylogenetic relationships of the major dinosaurian groups that challenges the current consensus concerning early dinosaur evolution and highlights problematic aspects of current cladistic definitions. Our study has found a sister-group relationship between Ornithischia and Theropoda (united in the new clade Ornithoscelida), with Sauropodomorpha and Herrerasauridae (as the redefined Saurischia) forming its monophyletic outgroup. This new tree topology requires redefinition and rediagnosis of Dinosauria and the subsidiary dinosaurian clades. In addition, it forces re-evaluations of early dinosaur cladogenesis and character evolution, suggests that hypercarnivory was acquired independently in herrerasaurids and theropods, and offers an explanation for many of the anatomical features previously regarded as notable convergences between theropods and early ornithischians.


Universal patterns of long-distance commuting and social assortativity in cities.
Millions commute to work every day in cities and interact with colleagues, partners, friends, and strangers. Commuting facilitates the mixing of people from distant and diverse neighborhoods, but whether this has an imprint on social inclusion or instead, connections remain assortative is less explored. In this paper, we aim to better understand income sorting in social networks inside cities and investigate how commuting distance conditions the online social ties of Twitter users in the 50 largest metropolitan areas of the United States. An above-median commuting distance in cities is linked to more diverse individual networks, moreover, we find that longer commutes are associated with a nearly uniform, moderate reduction of overall social tie assortativity across all cities. This suggests a universal relation between long-distance commutes and the integration of social networks. Our results inform policy that facilitating access across distant neighborhoods can advance the social inclusion of low-income groups.


How reliable is a vasectomy? Long-term follow-up of vasectomised men.
Around 42 million couples worldwide rely on vasectomy as a method of family planning. It is well recognised that a vasectomy can fall at any stage, and therefore warning couples of risk of failure forms an important part of the consent procedure.


Leveraging population information in family-based rare variant association analyses of quantitative traits.
Confounding due to population substructure is always a concern in genetic association studies. Although methods have been proposed to adjust for population stratification in the context of common variation, it is unclear how well these approaches will work when interrogating rare variation. Family-based association tests can be constructed that are robust to population stratification. For example, when considering a quantitative trait, a linear model can be used that decomposes genetic effects into between- and within-family components and a test of the within-family component is robust to population stratification. However, this within-family test ignores between-family information potentially leading to a loss of power. Here, we propose a family-based two-stage rare-variant test for quantitative traits. We first construct a weight for each variant within a gene, or other genetic unit, based on score tests of between-family effect parameters. These weights are then used to combine variants using score tests of within-family effect parameters. Because the between-family and within-family tests are orthogonal under the null hypothesis, this two-stage approach can increase power while still maintaining validity. Using simulation, we show that this two-stage test can significantly improve power while correctly maintaining type I error. We further show that the two-stage approach maintains the robustness to population stratification of the within-family test and we illustrate this using simulations reflecting samples composed of continental and closely related subpopulations.


Mechanisms of Pinometostat (EPZ-5676) Treatment-Emergent Resistance in MLL-Rearranged Leukemia.
DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with well-characterized leukemic genes. Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment-emergent resistance (TER) in cell lines confirmed to have MLL-r. TER was achieved in five MLL-r cell lines, KOPN-8, MOLM-13, MV4-11, NOMO-1, and SEM. Two of the cell lines, KOPN-8 and NOMO-1, were thoroughly characterized to understand the mechanisms involved in pinometostat resistance. Unlike many other targeted therapies, resistance does not appear to be achieved through drug-induced selection of mutations of the target itself. Instead, we identified both drug efflux transporter dependent and independent mechanisms of resistance to pinometostat. In KOPN-8 TER cells, increased expression of the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the primary mechanism of drug resistance. In contrast, resistance in NOMO-1 cells occurs through a mechanism other than upregulation of a specific efflux pump. RNA-seq analysis performed on both parental and resistant KOPN-8 and NOMO-1 cell lines supported two unique candidate pathway mechanisms that may explain the pinometostat resistance observed in these cell lines. These results are the first demonstration of TER models of the DOT1L inhibitor pinometostat and may provide useful tools for investigating clinical resistance. Mol Cancer Ther; 16(8); 1669-79. ©2017 AACR.


Are digital interventions for smoking cessation in pregnancy effective? A systematic review protocol.
Behavioural support for smoking cessation in pregnancy can be effective; however, many pregnant women face barriers to seeking support to stop smoking. Some digital interventions have been found to be effective for smoking cessation in the general population and may be effective for supporting cessation in pregnancy due to their flexibility and the potential for personalisation. To date, there is limited evidence of the effectiveness of digital interventions for smoking cessation in pregnancy. This review aims to assess the following: (1) whether digital interventions are effective at promoting smoking cessation among pregnant women; (2) which behaviour change techniques (BCTs) or combinations of BCTs are associated with the effectiveness of digital interventions for smoking cessation in pregnancy; and (3) whether the number of BCTs used is associated with the effectiveness of digital interventions for smoking cessation in pregnancy. This review will include digital interventions delivered largely through computer (PC or laptop), video/DVD, mobile phone (including smartphones) or portable handheld device (e.g. tablet, iPad) and include websites, mobile or tablet applications and SMS text messages. Interventions must be randomised or quasi-randomised controlled trials aimed at women who smoke in pregnancy, with smoking cessation as a measured outcome (preferably the latest available point prevalence smoking status measure taken during pregnancy, biochemically verified if available). Electronic bibliographic databases will be searched to identify suitable studies indexed in the following: Academic Search Complete, ASSIA, CINAHL, The Cochrane Library, EMBASE, Medline, PsycINFO, Scopus, and Web of Science. The search strategy will include key words and database-specific subject headings relating to 'pregnancy' and 'smoking' and synonyms for the terms 'digital' and 'randomised controlled trial'. Where required and where possible, the first and second authors will independently code interventions and control groups for BCTs. If data allows, meta-analyses will be used to assess intervention effectiveness and the effectiveness of BCTs. This systematic review will provide a detailed synthesis of the effectiveness of current research using digital interventions for smoking cessation in pregnancy, to build on the evidence base and guide the development of future research in this area. PROSPERO CRD42016036201.


Circadian Potency Spectrum with Extended Exposure to Polychromatic White LED Light under Workplace Conditions.
Electric light has enabled humans to conquer the night, but light exposure at night can disrupt the circadian timing system and is associated with a diverse range of health disorders. To provide adequate lighting for visual tasks without disrupting the human circadian timing system, a precise definition of circadian spectral sensitivity is required. Prior attempts to define the circadian spectral sensitivity curve have used short (≤90-min) monochromatic light exposures in dark-adapted human subjects or in vitro dark-adapted isolated retina or melanopsin. Several lines of evidence suggest that these dark-adapted circadian spectral sensitivity curves, in addition to 430- to 499-nm (blue) wavelength sensitivity, may include transient 400- to 429-nm (violet) and 500- to 560-nm (green) components mediated by cone- and rod-originated extrinsic inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), which decay over the first 2 h of extended light exposure. To test the hypothesis that the human circadian spectral sensitivity in light-adapted conditions may have a narrower, predominantly blue, sensitivity, we used 12-h continuous exposures of light-adapted healthy human subjects to 6 polychromatic white light-emitting diode (LED) light sources with diverse spectral power distributions at recommended workplace levels of illumination (540 lux) to determine their effect on the area under curve of the overnight (2000-0800 h) salivary melatonin. We derived a narrow steady-state human Circadian Potency spectral sensitivity curve with a peak at 477 nm and a full-width half-maximum of 438 to 493 nm. This light-adapted Circadian Potency spectral sensitivity permits the development of spectrally engineered LED light sources to minimize circadian disruption and address the health risks of light exposure at night in our 24/7 society, by alternating between daytime circadian stimulatory white light spectra and nocturnal circadian protective white light spectra.


Pre-transplant immune factors may be associated with BK polyomavirus reactivation in kidney transplant recipients.
BK polyomavirus (BKPyV) reactivation in kidney transplant recipients can lead to allograft damage and loss. The elements of the adaptive immune system that are permissive of reactivation and responsible for viral control remain incompletely described. We performed a prospective study evaluating BKPyV-specific T-cell response, humoral response and overall T-cell phenotype beginning pre-transplant through one year post-transplant in 28 patients at two centers. We performed an exploratory analysis of risk factors for the development of viremia and viruria as well as compared the immune response to BKPyV in these groups and those who remained BK negative. 6 patients developed viruria and 3 developed viremia. BKPyV-specific CD8+ T-cells increased post-transplant in viremic and viruric but not BK negative patients. BKPyV-specific CD4+ T-cells increased in viremic, but not viruric or BK negative patients. Anti-BKPyV IgG antibodies increased in viruric and viremic patients but remained unchanged in BK negative patients. Viremic patients had a greater proportion of CD8+ effector cells pre-transplant and at 12 months post-transplant. Viremic patients had fewer CD4+ effector memory cells at 3 months post-transplant. Exploratory analysis demonstrated lower CD4 and higher total CD8 proportions, higher anti-BKPyV antibody titers and the cause of renal failure were associated BKPyV reactivation. In conclusion, low CD4, high CD8 and increased effector CD8 cells were found pre-transplant in patients who became viremic, a phenotype associated with immune senescence. This pre-transplant T-cell senescence phenotype could potentially be used to identify patients at increased risk of BKPyV reactivation.


Transmission potential of two chimeric Chikungunya vaccine candidates in the urban mosquito vectors, Aedes aegypti and Ae. albopictus.
Chikungunya virus (CHIKV) is an emerging, mosquito-borne alphavirus that has caused major epidemics in Africa and Asia. We developed chimeric vaccine candidates using the non-structural protein genes of either Venezuelan equine encephalitis virus (VEEV) attenuated vaccine strain TC-83 or a naturally attenuated strain of eastern equine encephalitis virus (EEEV) and the structural genes of CHIKV. Because the transmission of genetically modified live vaccine strains is undesirable because of the potentially unpredictable evolution of these viruses as well as the potential for reversion, we evaluated the ability of these vaccines to infect the urban CHIKV vectors, Aedes aegypti and Ae. albopictus. Both vaccine candidates exhibited significantly lower infection and dissemination rates compared with the parent alphaviruses. Intrathoracic inoculations indicated that reduced infectivity was mediated by midgut infection barriers in both species. These results indicate a low potential for transmission of these vaccine strains in the event that a vaccinee became viremic.


QYAG5 Q-switched Nd:YAG Laser Treatment of Nevus of Ota: An Indian Study of 50 Patients.
Nevus of Ota is very common in Asian patients. The condition is more common in females, with a male-female ratio of 1:4.8. Most patients seek treatment early in life due to the psychological trauma and cosmetic disfigurement. The Q-switched lasers have changed the way we approach the condition and have become the mainstay of therapy. To evaluate long-term safety and efficacy of pigmented lesion laser Palomar QYAG5 Q-switched Nd:YAG in 50 Indian patients. Fifty patients of nevus of Ota underwent multiple treatments (average 6 sessions) carried out over a period of 1year with a Q-switched Nd:YAG laser (QYAG5, Palomar, USA). Of the 50 patients, 2 were males; and the rest, females. Five patients had a bilateral involvement. Skin types treated included phototypes 4 and 5. The response after subsequent treatments was documented through serial photographs that were taken before and after the completion of treatments. Patients were followed up for a period of 1 year after the last session. Response to treatment was graded based on physician's global assessment. Excellent improvement was noted in a majority of the patients at the end of the treatments. Greater-than-60% improvement was seen in 66% of the patients. The remaining patients had moderate clearing of pigmentation (30%-60% improvement). No significant adverse effects were seen immediately after the treatments and on long-term follow-up. Transient post-inflammatory hyperpigmentation was observed in 5 (10%) patients, which cleared with use of sunscreens and bleaching agents within 2 months. No textural change or scarring was seen. Hypopigmentation (guttate type) was observed in 1 (2%) patient, which resolved within 3 months. No recurrence was observed after 1 year of follow-up. This study validates the superior efficacy of Q-switched Nd:YAG laser when compared to conventional methods for treatment of nevus of Ota.


Whole Genome Sequence Analysis Reveals Lower Diversity and Frequency of Acquired Antimicrobial Resistance (AMR) Genes in E. coli From Dairy Herds Compared With Human Isolates From the Same Region of Central Zambia.
Antibiotic treatment of sick dairy cattle is critical for the sustainability of this production system which is vital for food security and societal prosperity in many low and middle-income countries. Given the increasingly high levels of antibiotic resistance worldwide and the challenge this presents for the treatment of bacterial infections, the rational use of antibiotics in humans and animals has been emphatically recommended in the spirit of a "One Health" approach. The aim of this study was to characterize antimicrobial resistance (AMR) genes and their frequencies from whole genome sequences of Escherichia coli isolated from both dairy cattle and human patients in central Zambia. Whole genome sequences of E. coli isolates from dairy cattle (n = 224) and from patients at a local hospital (n = 73) were compared for the presence of acquired AMR genes. In addition we analyzed the publicly available genomes of 317 human E. coli isolates from over the wider African continent. Both acquired antibiotic resistance genes and phylogroups were identified from de novo assemblies and SNP based phylogenetic analyses were used to visualize the distribution of resistance genes in E. coli isolates from the two hosts. Greater acquired AMR gene diversity was detected in human compared to bovine E. coli isolates across multiple classes of antibiotics with particular resistance genes for extended-spectrum beta lactamases (ESBL), quinolones, macrolides and fosfomycin only detected in E. coli genomes of human origin. The striking difference was that the Zambian or wider African human isolates were significantly more likely to possess multiple acquired AMR genes compared to the Zambian dairy cattle isolates. The median number of resistance genes in the Zambian cattle cohort was 0 (0-1 interquartile range), while in the Zambian human and wider African cohorts the medians and interquartile ranges were 6 (4-9) and 6 (0-8), respectively. The lower frequency and reduced diversity of acquired AMR genes in the dairy cattle isolates is concordant with relatively limited antibiotic use that we have documented in this region, especially among smallholder farmers. The relatively distinct resistant profiles in the two host populations also indicates limited sharing of strains or genes.


Large-Scale Molecular Dynamics Simulations Reveal New Insights Into the Phase Transition Mechanisms in MIL-53(Al).
Soft porous crystals have the ability to undergo large structural transformations upon exposure to external stimuli while maintaining their long-range structural order, and the size of the crystal plays an important role in this flexible behavior. Computational modeling has the potential to unravel mechanistic details of these phase transitions, provided that the models are representative for experimental crystal sizes and allow for spatially disordered phenomena to occur. Here, we take a major step forward and enable simulations of metal-organic frameworks containing more than a million atoms. This is achieved by exploiting the massive parallelism of state-of-the-art GPUs using the OpenMM software package, for which we developed a new pressure control algorithm that allows for fully anisotropic unit cell fluctuations. As a proof of concept, we study the transition mechanism in MIL-53(Al) under various external pressures. In the lower pressure regime, a layer-by-layer mechanism is observed, while at higher pressures, the transition is initiated at discrete nucleation points and temporarily induces various domains in both the open and closed pore phases. The presented workflow opens the possibility to deduce transition mechanism diagrams for soft porous crystals in terms of the crystal size and the strength of the external stimulus.


Patterns of care for immediate and early delayed breast reconstruction following mastectomy.
The purpose of this study was to analyze factors associated with immediate or early (up to 4 months) postmastectomy reconstruction and to update and extend knowledge of patterns of care for reconstruction, using data from a large, population-based surveillance program. Procedures included analysis of data for 27,703 women diagnosed with breast carcinoma who underwent mastectomy in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program between 1998 and 2000. Descriptive, univariate, and multivariate logistic regression analyses were used to estimate the odds of selecting immediate or early reconstruction while simultaneously considering independent variables. Results of multivariate analyses showed that, for those women who underwent reconstruction, the proportion of black women was approximately one-third less than that of white women (odds ratio, 0.64; 95 percent CI, 0.55 to 0.74). Women who chose reconstruction were between two and four times more likely [odds ratio range, 2.27 (95 percent CI, 2.04 to 2.52) to 3.56 (95 percent CI, 2.53 to 4.58)] to be younger compared with those women aged 65 years and older, and were nearly 75 percent more likely to be diagnosed at the in situ stage compared with those diagnosed at later stages. Women choosing reconstruction were significantly less likely to live in Iowa and Seattle/Puget Sound and more likely to live in Detroit and Atlanta compared with women in San Francisco/Oakland, Connecticut, Hawaii, New Mexico, and Utah, and were significantly less likely to have never married or be widowed compared with married women. Women undergoing reconstruction were more than twice as likely to have had mastectomy with removal of the uninvolved contralateral breast. Results of this study updated previous research and showed that immediate or early reconstruction is used by a small but increasing proportion of women diagnosed with breast carcinoma who undergo mastectomy. Previous knowledge was extended by showing that use of reconstruction is most strongly associated with patient age and removal of the uninvolved contralateral breast and, to a lesser magnitude (but still significantly), with race, stage, marital status, and geographic location.


Emerging trends in antibiotic resistance: Implications for emergency medicine.
Many bacteria are demonstrating increasing levels of resistance to commonly used antibiotics. While this has implications for the healthcare system as a whole, many patients infected with these resistant organisms will initially present to the emergency department (ED). The purpose of this review is to provide a summary of current trends in infections caused by the most clinically relevant resistant organisms encountered in emergency medicine. Bacteria were selected based on the Centers for Disease Control and Prevention's National Action Plan for Combating Antibiotic Resistant Bacteria, and PubMed database. The following bacteria were included: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, Escherichia coli, carbapenem-resistant Enterobacteriaceae, Neisseria gonorrhoeae, and Pseudomonas aeruginosa. All have shown increasing rates of resistance to one or more of the antibiotics commonly used to treat them. Increasing rates of antibiotic resistance are associated with worse clinical outcomes and greater healthcare costs. Antibiotic resistance is increasing and poses significant a risk to both the patient and public health as a whole. Appropriate choice of initial antibiotic is important in improving clinical outcomes, which is often the role of the ED provider. On a broader level, the ED must also take part in institutional efforts such as Antibiotic Stewardship Programs, which have been shown to decrease costs and rates of infection with resistant organisms. Ultimately, a multifaceted approach will be required to curb the threat of antibiotic-resistant bacteria.


Stenotrophomonas maltophilia responds to exogenous AHL signals through the LuxR solo SmoR (Smlt1839).
Quorum Sensing (QS) mediated by Acyl Homoserine Lactone (AHL) molecules are probably the most widespread and studied among Gram-negative bacteria. Canonical AHL systems are composed by a synthase (LuxI family) and a regulator element (LuxR family), whose genes are usually adjacent in the genome. However, incomplete AHL-QS machinery lacking the synthase LuxI is frequently observed in Proteobacteria, and the regulator element is then referred as LuxR solo. It has been shown that certain LuxR solos participate in interspecific communication by detecting signals produced by different organisms. In the case of Stenotrophomonas maltophilia, a preliminary genome sequence analysis revealed numerous putative luxR genes, none of them associated to a luxI gene. From these, the hypothetical LuxR solo Smlt1839, here designated SmoR, presents a conserved AHL binding domain and a helix-turn-helix DNA binding motif. Its genomic organization-adjacent to hchA gene-indicate that SmoR belongs to the new family "LuxR regulator chaperone HchA-associated." AHL-binding assays revealed that SmoR binds to AHLs in-vitro, at least to oxo-C8-homoserine lactone, and it regulates operon transcription, likely by recognizing a conserved palindromic regulatory box in the hchA upstream region. Supplementation with concentrated supernatants from Pseudomonas aeruginosa, which contain significant amounts of AHLs, promoted swarming motility in S. maltophilia. Contrarily, no swarming stimulation was observed when the P. aeruginosa supernatant was treated with the lactonase AiiA from Bacillus subtilis, confirming that AHL contributes to enhance the swarming ability of S. maltophilia. Finally, mutation of smoR resulted in a swarming alteration and an apparent insensitivity to the exogenous AHLs provided by P. aeruginosa. In conclusion, our results demonstrate that S. maltophilia senses AHLs produced by neighboring bacteria through the LuxR solo SmoR, regulating population behaviors such as swarming motility.


Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder.
The efficacy of atomoxetine was assessed in school-age girls with attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. A total of 291 children who were 7 to 13 years of age and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD participated in 1 of 2 combined, double-blind, placebo-controlled, multisite, identical clinical trials. This intent-to-treat subset analysis examined the effects of atomoxetine versus placebo in 51 girls who were randomized to atomoxetine (n = 30) or placebo (n = 21) for 9 weeks. ADHD symptoms were assessed using parent- and investigator-rated scales. Atomoxetine was superior to placebo on the following measures: the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the Inattentive and Hyperactive/Impulsive subscales of the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the ADHD Index subscale of the Conners' Parent Rating Scale-Revised: Short Form; and the Clinical Global Impressions of Severity of ADHD. Statistically significant efficacy was seen 1 week after randomization and remained so for the duration of the study. One patient from each of the atomoxetine and placebo groups discontinued the study as a result of an adverse event. Atomoxetine was found to be effective and well tolerated for the treatment of ADHD in school-age girls.


Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress.
Chronic metabolic stress is related to diseases, whereas autophagy supplies nutrients by recycling the degradative products. Cyclosporin A (CsA), a frequently used immunosuppressant, induces metabolic stress via effects on mitochondrial respiration, and thereby, its chronic usage is often limited. Here we show that autophagy plays a protective role against CsA-induced metabolic stress in kidney proximal tubule epithelial cells. Autophagy deficiency leads to decreased mitochondrial membrane potential, which coincides with metabolic abnormalities as characterized by decreased levels of amino acids, increased tricarboxylic acid (TCA) ratio (the levels of intermediates of the latter part of the TCA cycle, over levels of intermediates in the earlier part), and decreased products of oxidative phosphorylation (ATP). In addition to the altered profile of amino acids, CsA decreased the hyperpolarization of mitochondria with the disturbance of mitochondrial energy metabolism in autophagy-competent cells, i.e., increased TCA ratio and worsening of the NAD(+)/NADH ratio, coupled with decreased energy status, which suggests that adaptation to CsA employs autophagy to supply electron donors from amino acids via intermediates of the latter part of the TCA cycle. The TCA ratio of autophagy-deficient cells was further worsened with decreased levels of amino acids in response to CsA, and, as a result, the deficiency of autophagy failed to adapt to the CsA-induced metabolic stress. Deterioration of the TCA ratio further worsened energy status. The CsA-induced metabolic stress also activated regulatory genes of metabolism and apoptotic signals, whose expressions were accelerated in autophagy-deficient cells. These data provide new perspectives on autophagy in conditions of chronic metabolic stress in disease.


Lung protective ventilation in ARDS: role of mediators, PEEP and surfactant.
Lung protective ventilation such as the ARDSnet low tidal volumes strategy can reduce mortality in ARDS patients. The knowledge that an essential therapy such as mechanical ventilation on the intensive care influences patient outcome has given rise to the re-evaluation of current ventilation practices. This review addresses the current state of lung protective strategies and their physiological rationale. Latest knowledge on the instigation and progression of lung injury by mechanical ventilation is explored, particularly the interaction between ventilation and the inflammatory response occurring in an ARDS lung. Furthermore, the role of tidal volume, PEEP, recruitment manoeuvres and surfactant on lung injury is discussed. Finally, we discuss results from clinical studies on mechanical ventilation and elucidate these results with data acquired in experimental studies. Guidelines for future strategies and/or investigations are presented.


[Effects of one cycle of inhalation crenotherapy with radioactive fluoridated oligomineral].
The objective of the study was to test the effects of inhalation crenotherapy using the radioactive, fluoridated oligomineral waters from the Merano Spa on both subjects with specific upper respiratory tract phlogosis and normal subjects. The double-blind study was performed on a population of 27 adults of both sexes treated with radioactive-fluoridated water (group A) and 20 subjects, suffering from the same chronic catarrh pathology, selected with the same criteria but treated with inhalation of steam and an aerosol using drinking water from the municipal water supply (group C). In addition, a group of 13 subjects--which in terms of age and sex were statistically comparable to groups A and C but who did not show any signs of acute or chronic upper respiratory tract pathologies (group B) were also treated with the radioactive-fluoridated waters. All subjects included in the study underwent the following tests before and after the cycle of crenotherapy: Objective E.N.T. examination. Computerized Active Anterior Rhinomanometry. Detection of the ciliary mucous transport (CMT) time. Nasal cytology. Physical and immunochemical examination of the nasal mucous. The results of this study--seen in the trend in some parameters monitored both before and after the cycle of crenotherapy using Merano Spa water--clearly show that that the crenotherapy studied had an effect on aspecific chronic phlogosis of the upper respiratory tract. In fact, among other things, group A showed decreased nasal resistance, increased nasal respiratory flow, normalized mucociliary transport, decreased bacterial flora and an increased number of plasma cells in the rhinocytogram. In addition there was an increase in the following values in the nasal mucous: Albumin, non-secretory Immunoglobulin and the secretory portion of secretory Immunoglobulin A. None of these variations are seen in the results from the control group treated with municipal drinking water. After treatment with Merano spa water, the pathology-free subjects showed variations in the parameters in line with those found for group A. This biological reality can most likely be attributed to the favorable response of the respiratory mucosa, promoting anti-infection defenses.