Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis.
To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin. Nested case-control study. 367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland. 9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice. Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants. A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease. These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.


Single-Molecule Dynamics of SARS-CoV-2 5' Cap Recognition by Human eIF4F.
Coronaviruses initiate translation through recognition of the viral RNA 5' m 7 GpppA m cap by translation factor eIF4F. eIF4F is a heterotrimeric protein complex with cap-binding, RNA-binding, and RNA helicase activities. Modulating eIF4F function through cellular regulation or small-molecule inhibition impacts coronavirus replication, including for SARS-CoV-2. Translation initiation involves highly coordinated dynamics of translation factors with messenger or viral RNA. However, how the eIF4F subunits coordinate on the initiation timescale to define cap-binding efficiency remains incompletely understood. Here we report that translation supported by the SARS-CoV-2 5'-UTR is highly sensitive to eIF4A inhibition by rocaglamide. Through a single-molecule fluorescence approach that reports on eIF4E-cap interaction, we dissect how eIF4F subunits contribute to cap-recognition efficiency on the SARS-CoV-2 5' UTR. We find that free eIF4A enhances cap accessibility for eIF4E binding, but eIF4G alone does not change the kinetics of eIF4E-RNA interaction. Conversely, formation of the full eIF4F complex significantly alters eIF4E-cap interaction, suggesting that coordinated eIF4E and eIF4A activities establish the net eIF4F-cap recognition efficiency. Moreover, the eIF4F complex formed with phosphomimetic eIF4E(S209D) binds the viral UTR more efficiently than with wild-type eIF4E. These results highlight a dynamic interplay of eIF4F subunits and mRNA that determines cap-recognition efficiency.


The Association of Dietary Patterns with High-Risk Human Papillomavirus Infection and Cervical Cancer: A Cross-Sectional Study in Italy.
Specific foods and nutrients help prevent the progression of persistent high-risk human papillomavirus (hrHPV) infection to cervical cancer (CC). The aim of this study was to investigate dietary patterns which may be associated with hrHPV status and the risk of high-grade cervical intraepithelial neoplasia (CIN2+). Overall, 539 eligible women, including 127 with CIN2+, were enrolled in a cross-sectional study, and tested for hrHPV infection. Food intake was estimated using a food frequency questionnaire. Logistic regression models were applied. Using the Mediterranean Diet Score, we demonstrated that, among 252 women with a normal cervical epithelium, medium adherence to the Mediterranean diet decreased the odds of hrHPV infection when compared to low adherence (adjOR = 0.40, 95%CI = 0.22-0.73). Using the principal component analysis, we also identified two dietary patterns which explained 14.31% of the variance in food groups intake. Women in the third and fourth quartiles of the "Western pattern" had higher odds of hrHPV infection when compared with first quartile (adjOR = 1.77, 95% CI = 1.04-3.54 and adjOR = 1.97, 95%CI = 1.14-4.18, respectively). Adjusting for hrHPV status and age, women in the third quartile of the "prudent pattern" had lower odds of CIN2+ when compared with those in the first quartile (OR = 0.50, 95%CI = 0.26-0.98). Our study is the first to demonstrate the association of dietary patterns with hrHPV infection and CC and discourages unhealthy habits in favour of a Mediterranean-like diet.


Prehospital randomised assessment of a mechanical compression device in out-of-hospital cardiac arrest (PARAMEDIC): a pragmatic, cluster randomised trial and economic evaluation.
Mechanical chest compression devices may help to maintain high-quality cardiopulmonary resuscitation (CPR), but little evidence exists for their effectiveness. We evaluated whether or not the introduction of Lund University Cardiopulmonary Assistance System-2 (LUCAS-2; Jolife AB, Lund, Sweden) mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest (OHCA). Evaluation of the LUCAS-2 device as a routine ambulance service treatment for OHCA. Pragmatic, cluster randomised trial including adults with non-traumatic OHCA. Ambulance dispatch staff and those collecting the primary outcome were blind to treatment allocation. Blinding of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. We also conducted a health economic evaluation and a systematic review of all trials of out-of-hospital mechanical chest compression. Four UK ambulance services (West Midlands, North East England, Wales and South Central), comprising 91 urban and semiurban ambulance stations. Clusters were ambulance service vehicles, which were randomly assigned (approximately 1 : 2) to the LUCAS-2 device or manual CPR. Patients were included if they were in cardiac arrest in the out-of-hospital environment. Exclusions were patients with cardiac arrest as a result of trauma, with known or clinically apparent pregnancy, or aged < 18 years. Patients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene. Survival at 30 days following cardiac arrest; survival without significant neurological impairment [Cerebral Performance Category (CPC) score of 1 or 2]. We enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 device and 2819 assigned to control) between 15 April 2010 and 10 June 2013. A total of 985 (60%) patients in the LUCAS-2 group received mechanical chest compression and 11 (< 1%) patients in the control group received LUCAS-2. In the intention-to-treat analysis, 30-day survival was similar in the LUCAS-2 (104/1652, 6.3%) and manual CPR groups [193/2819, 6.8%; adjusted odds ratio (OR) 0.86, 95% confidence interval (CI) 0.64 to 1.15]. Survival with a CPC score of 1 or 2 may have been worse in the LUCAS-2 group (adjusted OR 0.72, 95% CI 0.52 to 0.99). No serious adverse events were noted. The systematic review found no evidence of a survival advantage if mechanical chest compression was used. The health economic analysis showed that LUCAS-2 was dominated by manual chest compression. There was substantial non-compliance in the LUCAS-2 arm. For 272 out of 1652 patients (16.5%), mechanical chest compression was not used for reasons that would not occur in clinical practice. We addressed this issue by using complier average causal effect analyses. We attempted to measure CPR quality during the resuscitation attempts of trial participants, but were unable to do so. There was no evidence of improvement in 30-day survival with LUCAS-2 compared with manual compressions. Our systematic review of recent randomised trials did not suggest that survival or survival without significant disability may be improved by the use of mechanical chest compression. The use of mechanical chest compression for in-hospital cardiac arrest, and in specific circumstances (e.g. transport), has not yet been evaluated. Current Controlled Trials ISRCTN08233942. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 11. See the NIHR Journals Library website for further project information.


Triplet state formation in photoexcited slip-stacked perylene-3,4:9,10-bis(dicarboximide) dimers on a xanthene scaffold.
Two covalent perylene-3,4:9,10-bis(dicarboximide) (PDI) dimers in which the PDI molecules are attached to a xanthene (Xan) scaffold in which the long axes of the two π-π stacked PDI molecules are slipped by 4.3 and 7.9 Å were prepared. These dimers are designed to mimic J-aggregates and provide insights into the photophysics of triplet state formation in PDI aggregates that target organic electronics. Using ultrafast transient absorption and stimulated Raman spectroscopy, the mechanism of (3)*PDI formation was found to depend strongly on a competition between the rate of Xan(•+)-PDI(•-) formation involving the spacer group and the rate of excimer-like state formation. Which mechanism is favored depends on the degree of electronic coupling between the two PDI molecules and/or solvent polarity. Singlet exciton fission to produce (3)*PDI does not compete kinetically with these processes. The excimer-like state decays relatively slowly with τ = 28 ns to produce (3)*PDI, while charge recombination of Xan(•+)-PDI(•-) yields (3)*PDI more than an order of magnitude faster. The perpendicular orientation between the π orbitals of PDI and the Xan bridge provides a large enough orbital angular momentum change to greatly increase the intersystem crossing rate via Xan(•+)-PDI(•-) → (3)*PDI charge recombination. These results highlight the importance of understanding inter-chromophore electronic coupling in a wide range of geometries as well as the active role that molecular spacers can play in the photophysics of covalent models for self-assembled chromophore aggregates.


The Alzheimer's disease beta-secretase enzyme, BACE1.
The pathogenesis of Alzheimer's disease is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the beta-amyloid peptide are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that beta-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE1 enzyme is essential for the generation of beta-amyloid. BACE1 knockout mice do not produce beta-amyloid and are free from Alzheimer's associated pathologies including neuronal loss and certain memory deficits. The fact that BACE1 initiates the formation of beta-amyloid, and the observation that BACE1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE1 inhibition thus reducing beta-amyloid and its associated toxicities. However, new data indicates that complete abolishment of BACE1 may be associated with specific behavioral and physiological alterations. Recently a number of non-APP BACE1 substrates have been identified. It is plausible that failure to process certain BACE1 substrates may underlie some of the reported abnormalities in the BACE1-deficient mice. Here we review BACE1 biology, covering aspects ranging from the initial identification and characterization of this enzyme to recent data detailing the apparent dysregulation of BACE1 in Alzheimer's disease. We pay special attention to the putative function of BACE1 during healthy conditions and discuss in detail the relationship that exists between key risk factors for AD, such as vascular disease (and downstream cellular consequences), and the pathogenic alterations in BACE1 that are observed in the diseased state.


BMI and BMI SDS in childhood: annual increments and conditional change.
Background Early detection of abnormal weight gain in childhood may be important for preventive purposes. It is still debated which annual changes in BMI should warrant attention. Aim To analyse 1-year increments of Body Mass Index (BMI) and standardised BMI (BMI SDS) in childhood and explore conditional change in BMI SDS as an alternative method to evaluate 1-year changes in BMI. Subjects and methods The distributions of 1-year increments of BMI (kg/m2) and BMI SDS are summarised by percentiles. Differences according to sex, age, height, weight, initial BMI and weight status on the BMI and BMI SDS increments were assessed with multiple linear regression. Conditional change in BMI SDS was based on the correlation between annual BMI measurements converted to SDS. Results BMI increments depended significantly on sex, height, weight and initial BMI. Changes in BMI SDS depended significantly only on the initial BMI SDS. The distribution of conditional change in BMI SDS using a two-correlation model was close to normal (mean = 0.11, SD = 1.02, n = 1167), with 3.2% (2.3-4.4%) of the observations below -2 SD and 2.8% (2.0-4.0%) above +2 SD. Conclusion Conditional change in BMI SDS can be used to detect unexpected large changes in BMI SDS. Although this method requires the use of a computer, it may be clinically useful to detect aberrant weight development.


De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.
Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.


The effect of sodium fluoride at prophylactic and toxic doses on renal structure and function in the isolated perfused rat kidney.
To assess the renal effects of fluoride, isolated rat kidneys were perfused in single pass mode for 120 min. Five, 15 and 50, as well as 150, 500 and 1500 mumol NaF were administered 60, 80 and 100 min after starting the perfusion, respectively. Kidneys were perfused with constant pressure (100 mmHg). The perfusate consisted of a substrate supplemented Ringer solution containing hydroxy ethyl starch (HES) to produce isoncotic conditions. Concentrations below 500 mumol/l NaF did not induce major changes in the main parameters of renal function. Only upon admixture of the highest concentration of 1500 mumol/l NaF severe changes in renal function could be observed, resulting in complete anuria and a drastic reduction of renal perfusion to 5% of control, associated with a cessation of glomerular filtration. Due to the lack in tubular load, tubular reabsorptive processes inevitably declined to zero. The morphological analysis of kidneys exhibited to 500 mumol/l NaF revealed the occurrence of vesicular material within the urinary space. These vesicles could electron microscopically be identified as membrane enclosed material of podocytic origin. The interstitium was widened. Upon admixture of 1500 mumol/l NaF, kidneys responded with a decrease of the interstitial space. Moreover, epithelial cell swelling, hydropic degeneration of all proximal and distal tubular segments, bleb formation and intraluminal casts were observed frequently. Glomerular capillaries were filled with fine precipitates and their endothelium was severely damaged. The results of our studies in the isolated perfused rat kidney (IPRK) model clearly demonstrate a direct dose dependent acute nephrotoxic effect of NaF only for extremely high doses, which, however, may be reached in human cases of severe fluoride intoxication. On the contrary, for low fluoride doses, especially for those concentrations occurring in human plasma upon cariesprophylactic intake of fluorides, no signs of direct acute nephrotoxic action could be observed in the IPRK model.


Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging.
Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 °C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.


Variability in the Treatment of Prehospital Hypoglycemia: A Structured Review of EMS Protocols in the United States.
In many industries, limiting variability in process has been associated with a reduction in errors. Hypoglycemia is a common prehospital diabetic emergency for which most EMS systems have a treatment protocol. To examine the treatment variability for prehospital hypoglycemia within EMS protocols in the U.S. EMS protocols were reviewed in a structured fashion from 2 sources: the website www.emsprotocols.org and through manual identification from the 50 largest populated cities in the U.S. Data was abstracted by trained investigators regarding the concentration of glucose recommended for the parenteral reversal of hypoglycemia, clinical treatment thresholds, dose recommendations, follow-up care, and non-transport policies. Descriptive statistics were used to summarize the findings. We also reviewed these EMS protocols for the protocol's effective date, the presence of a specific hypoglycemia patient non-transport policy, the use of dilutions of hypertonic dextrose for pediatric patients, glucagon use, and CBG or GCS for patient follow-up. Protocols were retrieved from 185 EMS agencies of a variety of sizes across the U.S. Seventy percent specified only D50 for the treatment of hypoglycemia in adult patients, 8% only D10, and 22% either D10 or D50. Most protocols (85%), which used D50, specified concentration dilutions for pediatric patients. The most frequently specified initial dose of glucose was 25 g of glucose for adults (73-78%), 0.5 g/kg for pediatric (70%), and 0.5 g/kg for neonates (45%). The median blood glucose level threshold for treatment was 60 mg/dl for patients of all ages, but the mean treatment threshold levels for adults, pediatric patients and neonates were statistically different (p < 0.0001). Nearly all protocols (97%) allowed for the use of glucagon in the absence of vascular access. Patient follow up with a repeat CBG was recommended in 32%, both CBG and GCS in 31%, GCS only in 4%, and no follow-up was specified in 33% of the protocols. A specific policy permitting the non-transport of select patients whose hypoglycemia had been corrected was noted in slightly less than half (49%) of the protocols. In the U.S., EMS protocols for the treatment of hypoglycemia vary significantly. Further studies are warranted to determine the factors underlying this variability and effects on patient outcomes.


Living in critical times: The impact of critical incidents on frontline ambulance personnel--a qualitative perspective.
Little is known about the impact of Critical Incidents (CIs) on the lives of ambulance personnel. One-to-one interviews were conducted with 27 participants who had experienced CIs during the previous 12 months in order to: assess the nature and impact of CIs on health and well-being; examine attitudes toward support services; and explore barriers to service use. The results showed that incidents involving children, suicides, and grotesque mutilation were the most distressing. Participants reported a wide range of physical and mental health problems including sleep difficulties, angry outbursts, irrationality and feelings of alienation. Key themes included: low support service uptake due to fears relating to confidentiality and machismo; a perceived lack of concern and support from management; and a need for professional counselling and stress awareness training. Emergency Medical Controllers (EMCs) also reported a number of difficulties unique to their role. The findings suggest that exposure to CIs has a significant impact on health and well-being; this has important implications for recognizing and appropriately addressing the health and training needs of ambulance personnel, including the effective management of Critical Incident Stress.


Fractional derivative Fourier plane filter for phase-change visualization.
Fractional derivatives of two-dimensional images have been discussed theoretically in terms of Fourier optics and computer simulated. Filters that realize the half-order differentiation can be either complex or real. We prove, in terms of fractional calculus, that the semiderivative filter is useful for the visualization of phase changes in a phase object in such a way that the output-image intensity is directly proportional to the first derivative of the input object. We give computer-simulated results of one-dimensional semidifferentiating.


E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy.
The distinction of self from non-self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma-b (Cbl-b) is a newly identified component in the ubiquitin-dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co-ordinated by Cbl-b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl-b and the suppressive signaling mechanisms of Cbl-b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.


Tuberculosis vaccine research: the impact of immunology.
A safe and effective vaccine to prevent tuberculosis is necessary to combat this ancient disease that kills millions worldwide. Recent advances in our understanding of the host immune response to Mycobacterium tuberculosis (Mtb) are facilitating the development of several novel vaccine approaches. New tools for measuring and characterizing cell-mediated immune responses to Mtb have furthered the assessment of these new vaccines in animal models and in human clinical studies including efficacy trials. Measurements of the relative contribution of CD4+ and CD8+ T cells, central and effector memory T cells, and regulatory T cells are being completed in these studies, as well as broad screening efforts utilizing bead array cytokine determination and microarray technology in an effort to determine the immunologic markers that predict vaccine-induced efficacy for different stages of TB infection and disease.


The variable hydroxamic acid siderophore metabolome of the marine actinomycete Salinispora tropica CNB-440.
The recently sequenced genome of the marine actinomycete Salinispora tropica CNB-440 revealed a high frequency of gene clusters which code for the biosynthesis of known and novel secondary metabolites. Of these metabolites, bioinformatics analysis predicted that S. tropica CNB-440 could potentially biosynthesize, as high affinity Fe(iii) ligands, siderophores from the hydroxamic acid desferrioxamine class (sid1 gene cluster) and the phenolate-thia(oxa)zoli(di)ne class (sid2 and sid4 gene clusters). In this work, we have used Ni(ii)-based immobilized metal ion affinity chromatography (IMAC) to pre-fractionate the hydroxamic acid siderophore metabolome of S. tropica CNB-440 from the secondary metabolome, to reveal low abundance siderophores. LC-MS measurements and electronic absorption spectra from purified extracts incubated with exogenous Fe(iii) revealed eight siderophores from the desferrioxamine class (DFOA2, DFOA1a, DFOA1b, DFOB, DFON, DFOD2, DFOE, DFOD1), which included two constitutional isomers (DFOA1a, DFOA1b), and one new siderophore (DFON), the latter which would require assembly from a combination of 1,5-diaminopentane and 1,6-diaminohexane as diamine substrates. Three additional species (m/zobs 496.14, 792.34 and 804.34) with electronic absorption spectra characteristic of complexes formed between Fe(iii) and hydroxamic acid-type siderophores were evident under some conditions. The signal at m/zobs 792.34 eluted in the hydrophobic region of the reverse-phase LC and correlated with a DFOD1 analogue with a C-terminal branched chain fatty acid ([M + K(+)](+)m/zcalc 792.35), which has been previously identified from marine sediment dwelling Micrococcus luteus KLE1011. The S. tropica CNB-440 hydroxamic acid siderophore metabolome was modulated by culture conditions (pH 7, 22 °C; pH 7, 28 °C; pH 9, 28 °C) designed to simulate the variable marine environment. An increase in temperature at constant pH value showed increased levels of DFOA2 and DFOA1, and decreased levels of DFOB and DFOE. An increase in pH value at constant temperature showed decreased levels of DFOA2 and DFOA1, and increased levels of DFOB, DFON and DFOE. These results indicate that the marine adaptation of S. tropica CNB-440 could involve its ability to select a suite of siderophores from a large number of candidates, which are optimized for the iron microenvironment.


Exploration of water jet generated by Q-switched laser induced water breakdown with different depths beneath a flat free surface.
The dynamics of a water jet on a flat free surface are investigated using a nanosecond pulsed laser for creating an oscillating bubble with different depths beneath the free surface. A thin jet is shown to deform a crater surface resulted from surface depression and cause a circular ring-shaped crater on the connection surface between the crater of surface depression and the thin jet. The collapse of this circular ring-shaped crater is proposed to the crown-like formation around a thick jet. The evolution of the bubble depth suggests a classification of four distinctive ranges of the bubble depths: non-crown formation when the parameter of bubble depth over the maximum bubble radius γ ≤ 0.5, unstable crown formation when 0.5 ≤ γ ≤ 0.6, crown-like structure with a complete crown wall when 0.6 ≤ γ ≤ 1.1, and non-crown formation when 1.1 ≤ γ. Furthermore, the orientation of the crown wall gradually turns counterclockwise to vertical direction with increasing γ from 0.5 to 1.1, implying a high correlation between the orientation of the crown wall and the depth of the bubble. This correlation is explained and discussed by the directional change of the jet eruption from the collapse of circular ring-shaped crater.


Simulating the hallmarks of cancer.
Cancer can be viewed as the loss of cooperative cell behaviors that normally facilitate multicellularity, including the formation of tissues and organs. Hanahan and Weinberg describe the phenotypic differences between healthy and cancerous cells in an article titled "The Hallmarks of Cancer" (Cell, 100, 57-70, 2000). Here the authors propose six phenotypic changes at the cellular level as the essential hallmarks of cancer. They investigate the dynamics and interactions of these hallmarks in a model known as CancerSim. They describe how CancerSim implements the hallmarks in an agent-based simulation which can help test the hypotheses put forth by Hanahan and Weinberg. Experiments with CancerSim are described that study the interactions of cell phenotype alterations, and in particular, the likely sequences of precancerous mutations, known as pathways. The experiments show that sequencing is an important factor in tumorigenesis, as some mutations have preconditions--they are selectively advantageous only in combination with other mutations. CancerSim enables a modeler to study the dynamics of a developing tumor and simulate how progression can be altered by tuning model parameters.


Impact of fish oils on the outcomes of a mouse model of acute Pseudomonas aeruginosa pulmonary infection.
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium that causes pneumonia in immunocompromised humans and severe pulmonary damage in patients with cystic fibrosis. Imbalanced fatty acid incorporation in membranes, including increased arachidonic acid and decreased DHA concentrations, is known to play a critical role in chronic inflammation associated with bacterial infection. Other lipids, such as EPA and alkylglycerols, are also known to play a role in inflammation, particularly by stimulating the immune system, decreasing inflammation and inhibiting bacterial growth. In this context, the goal of the present study was to assess the effect of dietary DHA/EPA, in a 2:1 ratio, and alkylglycerols, as natural compounds extracted from oils of rays and chimeras, respectively, on the inflammatory reaction induced by P. aeruginosa pulmonary infection in mice. To this end, mice were fed with a control diet or isolipidic, isoenergetic diets prepared with oils enriched in DHA/EPA (2:1) or alkylglycerols for 5 weeks before the induction of acute P. aeruginosa lung infection by endotracheal instillation. In our model, DHA/EPA (2:1) significantly improved the survival of mice after infection, which was associated with the acceleration of bacterial clearance and the resolution of inflammation leading to the improvement of pulmonary injuries. By contrast, alkylglycerols did not affect the outcomes of P. aeruginosa infection. Our findings suggest that supplementation with ray oil enriched in DHA/EPA (2:1) can be considered as a preventive treatment for patients at risk for P. aeruginosa infection.


Maternal mortality in developing countries: challenges in scaling-up priority interventions.
Although maternal mortality is a significant global health issue, achievements in mortality decline to date have been inadequate. A review of the interventions targeted at maternal mortality reduction demonstrates that most developing countries face tremendous challenges in the implementation of these interventions, including the availability of unreliable data and the shortage in human and financial resources, as well as limited political commitment. Examples from developing countries, such as Sri Lanka, Malaysia and Honduras, demonstrate that maternal mortality will decline when appropriate strategies are in place. Such achievable strategies need to include redoubled commitments on the part of local, national and global political bodies, concrete investments in high-yield and cost-effective interventions and the delegation of some clinical tasks from higher-level healthcare providers to mid- or lower-level healthcare providers, as well as improved health-management information systems.


Insulin-like growth factor I induction of c-myc expression in bovine fibroblasts can be blocked by antecedent insulin receptor activation.
We previously reported that preexposure of cultured bovine fibroblasts to insulin at low concentrations inhibits subsequent insulin-like growth factor I (IGF-I)-stimulated DNA synthesis. This insulin-induced desensitization to IGF-I is mediated by specific insulin receptors on bovine fibroblasts and occurs distally to IGF-I receptor engagement and activation. In the present study, we use this model system to determine insulin and IGF-I receptor interplay in the regulation of proto-oncogenes involved in mitogenesis. Insulin (10 nM), IGF-I (10 nM), and 10% fetal bovine serum were each capable of stimulating rapid and transient c-fos and c-myc mRNA expression in bovine fibroblasts. Expression of c-myc was most responsive to mitogenic stimuli; IGF-I and serum had equivalent potency resulting in approximately 14-fold increases in c-myc mRNA expression, while insulin produced 3- to 5-fold increases. Max mRNA, which encodes the partner protein for Myc, was constitutively expressed and levels did not change with treatment or with time. When bovine fibroblasts were pretreated with 10 nM insulin for 48 h, washed, and then stimulated with 10 nM IGF-I, alterations in c-fos mRNA expression were moderate. In contrast, insulin pretreatment completely blocked IGF-I induction of c-myc expression. This block was averted if a specific inhibitor of intracellular signaling through the phosphatidylinositol 3-kinase pathway was present during the incubation period with insulin. These data indicate significant insulin/IGF-I receptor interplay in normal bovine fibroblasts and suggest that insulin receptor-initiated signaling can profoundly alter proto-oncogene expression induced by growth factors sharing components of a common intracellular signaling network.


Space versus Place in Complex Human-Natural Systems: Spatial and Multi-level Models of Tropical Land Use and Cover Change (LUCC) in Guatemala.
The relative role of space and place has long been debated in geography. Yet modeling efforts applied to coupled human-natural systems seemingly favor models assuming continuous spatial relationships. We examine the relative importance of placebased hierarchical versus spatial clustering influences in tropical land use/cover change (LUCC). Guatemala was chosen as our study site given its high rural population growth and deforestation in recent decades. We test predictors of 2009 forest cover and forest cover change from 2001-2009 across Guatemala's 331 municipalities and 22 departments using spatial and multi-level statistical models. Our results indicate the emergence of several socio-economic predictors of LUCC regardless of model choice. Hierarchical model results suggest that significant differences exist at the municipal and departmental levels but largely maintain the magnitude and direction of single-level model coefficient estimates. They are also intervention-relevant since policies tend to be applicable to distinct political units rather than to continuous space. Spatial models complement hierarchical approaches by indicating where and to what magnitude significant negative and positive clustering associations emerge. Appreciating the comparative advantages and limitations of spatial and nested models enhances a holistic approach to geographical analysis of tropical LUCC and human-environment interactions.


The effect of soybean-derived phosphatidylserine on cognitive performance in elderly with subjective memory complaints: a pilot study.
To evaluate the efficacy and safety of soybean-derived phosphatidylserine (SB-PS) (300 mg/day) in improving cognitive performance in elderly with memory complaints, following a short duration of 12 weeks' SB-PS administration. SB-PS was administered daily for 12 weeks to 30 elderly volunteers with memory complaints (age range 50-90 years). Cognitive performance was determined by a computerized test battery and by the Rey Auditory Verbal Learning Test (Rey-AVLT). Physical examination and blood safety parameters were part of the extensive safety analysis of PS that was performed. The computerized test results showed that SB-PS supplementation significantly increased the following cognitive parameters: memory recognition (P = 0.004), memory recall (P = 0.006), executive functions (P = 0.004), and mental flexibility (P = 0.01). The Rey-AVLT indicated that, following SB-PS administration, total learning and immediate recall improved significantly (P = 0.013 and P = 0.007, respectively). Unexpected results from the safety tests suggested that SB-PS significantly reduces both systolic (P = 0.043) and diastolic (P = 0.003) blood pressure. SB-PS consumption was well tolerated and no serious adverse events were reported during the study. This exploratory study demonstrates that SB-PS may have favorable effects on cognitive function in elderly with memory complaints. In addition, the study suggests that SB-PS is safe for human consumption and may serve as a safe alternative to phosphatidylserine extracted from bovine cortex. These results encourage further extended studies in order to establish the safety and efficacy of SB-PS treatment.


Regulating proton-coupled electron transfer for efficient water splitting by manganese oxides at neutral pH.
Manganese oxides have been extensively investigated as model systems for the oxygen-evolving complex of photosystem II. However, most bioinspired catalysts are inefficient at neutral pH and functional similarity to the oxygen-evolving complex has been rarely achieved with manganese. Here we report the regulation of proton-coupled electron transfer involved in water oxidation by manganese oxides. Pyridine and its derivatives, which have pKa values intermediate to the water ligand bound to manganese(II) and manganese(III), are used as proton-coupled electron transfer induction reagents. The induction of concerted proton-coupled electron transfer is demonstrated by the detection of deuterium kinetic isotope effects and compliance of the reactions with the libido rule. Although proton-coupled electron transfer regulation is essential for the facial redox change of manganese in photosystem II, most manganese oxides impair these regulatory mechanisms. Thus, the present findings may provide a new design rationale for functional analogues of the oxygen-evolving complex for efficient water splitting at neutral pH.


Sagittal MR images of the knee: a low-signal band parallel to the posterior cruciate ligament caused by a displaced bucket-handle tear.
A low-signal band parallel and anterior to the posterior cruciate ligament has been noted on sagittal MR images of the knee in some patients with other evidence for medial meniscal tears. It was hypothesized that this low-signal band represented the mesially displaced fragment of a bucket-handle tear. To verify this, we retrospectively reviewed MR and arthroscopic findings in 54 consecutive patients. Arthroscopy showed a bucket-handle tear of the medial meniscus in seven patients and was considered diagnostic. Sagittal MR images were reviewed without knowledge of the arthroscopic results. The presence of a curvilinear low-signal band above the tibial cortex anterior, inferior, and parallel to the posterior cruciate ligament was identified on MR images in all seven of the patients in whom the presence of a bucket-handle medial meniscal tear was confirmed by arthroscopy. Our findings suggest that a low-signal band anterior and parallel to the posterior cruciate ligament on sagittal MR images of the knee is caused by a mesially displaced bucket-handle tear of the medial meniscus.


Hepatoid Variant of Yolk Sac Tumor of Both Ovaries with Widespread Intraabdominal and Lung Metastasis: A Case Report.
Hepatoid variant of yolk sac tumor of ovary is an unusual tumor with an aggressive behavior. It is usually observed in young females, presents with abdominal complaints and is associated with raised α-fetoprotein (AFP) levels. It should be differentiated from other hepatoid tumors involving the ovary. A complete patient evaluation with gross, microscopy, and immunohistochemistry can identify the site of origin to administer appropriate treatment. The current study reported the case of a 30-year-old married parous female presenting with abdominal distention and pain of two months duration. She had regular menstrual cycles. Based on lab investigations her serum AFP level was markedly raised to 34,244 ng/mL (normal range: 0-9 ng/mL). Computerized tomography (CT) scan showed large lobulated heterogeneous mass in both ovaries and omental, gall bladder, and lung metastasis. A CT guided biopsy of the ovarian mass was done. On histopathology, a differential diagnosis of hepatoid variant of yolk sac tumor, hepatoid carcinoma of ovary and hepatoid tumor arising from gall bladder metastasizing to the ovary were observed. Patient underwent surgery. Per operatively gross ascites with bilateral ovarian mass, extensive omental, pelvic, and gall bladder deposits were observed. Bilateral salpingo-oophorectomy with omental deposit biopsy was conducted. Histopathology along with immunohistochemistry confirmed a diagnosis of hepatoid variant of yolk sac tumor in both ovaries with widespread intra-abdominal metastasis.


Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review.
To summarise the evidence supporting the use of rapid d-dimer testing combined with estimation of clinical probability to exclude the diagnosis of deep venous thrombosis among outpatients. Medline (June 1993 to December 2003), the Database of Abstracts and Reviews (DARE), and reference lists of studies in English. We selected 12 studies from among 84 reviewed. The selected studies included more than 5000 patients and used a rapid D-dimer assay and explicit criteria to classify cases as having low, intermediate, or high clinical probability of deep vein thrombosis of the lower extremity among consecutive outpatients. Diagnosis required objective confirmation, and untreated patients had to have at least three months of follow up. The outcome was objectively documented venous thromboembolism. Two authors independently abstracted data by using a data collection form. When the less sensitive SimpliRED D-dimer assay was used the three month incidence of venous thromboembolism was 0.5% (95% confidence interval 0.07% to 1.1%) among patients with a low clinical probability of deep vein thrombosis and normal D-dimer concentrations. When a highly sensitive D-dimer assay was used, the three month incidence of venous thromboembolism was 0.4% (0.04% to 1.1%) among outpatients with low or moderate clinical probability of deep vein thrombosis and a normal D-dimer concentration. The combination of low clinical probability for deep vein thrombosis and a normal result from the SimpliRED D-dimer test safely excludes a diagnosis of acute venous thrombosis A normal result from a highly sensitive D-dimer test effectively rules out deep vein thrombosis among patients classified as having either low or moderate clinical probability of deep vein thrombosis.


Practice Patterns and Outcomes Associated With Procalcitonin Use in Critically Ill Patients With Sepsis.
Randomized trials support use of procalcitonin (PCT)-based algorithms to decrease duration of antibiotics for critically ill patients with sepsis. However, current use of PCT and associated outcomes in real-world clinical settings is unclear. We sought to determine PCT use in critically ill patients with sepsis in the United States and to examine associations between PCT use and clinical outcomes. This was a retrospective cohort study of approximately 20% of patients with sepsis hospitalized in US intensive care units. Hierarchical regression models were used to determine associations of PCT use with outcomes (antibiotic-days, incidence of Clostridium difficile infection, and in-hospital mortality). Sensitivity analyses were conducted to assess robustness of findings to different methods used to address unmeasured confounding (eg, instrumental variable, difference-in-differences analyses). Among 20750 critically ill patients with sepsis in 107 hospitals with PCT available, 3769 (18%) patients had PCT levels checked; 1119 (29.7%) had serial PCT measurements. PCT use was associated with increased antibiotic-days (adjusted relative risk, 1.1; 95% confidence interval [CI], 1.15-1.18) and incidence of C. difficile (adjusted odds ratio, 1.42; 95% CI, 1.09-1.85) without a change in mortality (adjusted hazard ratio, 1.05; 95% CI, 0.93-1.19). Analysis of PCT use by instrumental variable and difference-in-difference analyses showed similar lack of antibiotic or outcome improvements associated with PCT use. PCT use was not associated with improved antibiotic use or other clinical outcomes in real-world settings. Programs to improve implementation of PCT-based strategies are warranted prior to widespread adoption.


Effect of Fibrin Formulation on Initial Strength of Tendon Repair and Migration of Bone Marrow Stromal Cells in Vitro.
Cell-based tissue engineering techniques have been introduced to improve tendon repair outcomes. The purpose of this study was to determine optimal concentrations of fibrinogen and thrombin for use as a scaffold to deliver stromal cells to the tendon repair site. Lacerated flexor digitorum profundus tendons from forty canine forepaws underwent simulated repair with fibrin gel interposition. The tendons were divided into five groups with different ratios of fibrinogen (mg/mL) to thrombin (NIH units/mL) used to form the gels. These ratios, which ranged from those found in normal hemostasis to those used clinically as adhesives, were 5:25 (the physiological ratio, used as a control), 40:250 (a low adhesive concentration of fibrinogen and a low adhesive concentration of thrombin [low-low group]), 80:250 (high-low group), 40:500 (low-high group), and 80:500 (high-high group). The failure load and tensile stiffness at time zero, compressive stiffness of the fibrin gel, and cell viability and migration were evaluated. The failure loads of the high-low and high-high groups were significantly higher than that of the control group. The tensile stiffness of the high-high group was significantly higher than that of the control group. The high-low and high-high groups had significantly higher compressive stiffness than the other groups. While there was no significant difference among the groups regarding cell viability, the cells in the control, low-low, and low-high gels were spindle-shaped whereas those in the high-low and high-high groups were rounded. Cells migrated across scratch gaps within twenty-four hours in the control, low-low, and low-high groups, but not in the high-low and high-high groups. Higher concentrations of fibrinogen resulted in stronger and stiffer gels, but the strength was far less than that of a tendon suture and these gels were associated with a more rounded cell morphology and reduced cell migration. Therefore, lower concentrations of fibrinogen should be used if a fibrin gel is employed to deliver cells for tendon repair. Concentrations of fibrinogen lower than those used in fibrin glue may be more appropriate if fibrin is employed to create a cell delivery matrix for tendon repair.


The implementation of NICE guidance on venous thromboembolism risk assessment and prophylaxis: a before-after observational study to assess the impact on patient safety across four hospitals in England.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalised patients. VTE prevention has been identified as a major health need internationally to improve patient safety. A National Institute for Health and Clinical Excellence (NICE) guideline was issued in February 2010. Its key priorities were to assess patients for risk of VTE on admission to hospital, assess patients for bleeding risk and evaluate the risks and benefits of prescribing VTE prophylaxis. The aim of this study was to evaluate the implementation of NICE guidance and its impact on patient safety. A before-after observational design was used to investigate changes in VTE risk assessment documentation and inappropriate prescribing of prophylaxis between the year prior to (2009) and the year following (2010) the implementation of NICE guidance, using data from a 3-week period during each year. A total of 408 patients were sampled in each year across four hospitals in the NHS South region. Implementation strategies such as audit, education and training were used. The percentage of patients for whom a VTE risk assessment was documented increased from 51.5% (210/408) in 2009 to 79.2% (323/408) in 2010; difference 27.7% (95% CI: 21.4% to 33.9%; p < 0.001). There was little evidence of change in the percentage who were prescribed prophylaxis amongst patients without a risk assessment (71.7% (142/198) in 2009 and 68.2% (58/85) in 2010; difference -3.5% (95% CI: -15.2% to 8.2%; p =0.56) nor the percentage who were prescribed low molecular weight heparin amongst patients with a contraindication (14% (4/28) in 2009 and 15% (6/41) in 2010; RD = 0.3% (95% CI: -16.5% to 17.2%; p =0.97). The documentation of risk assessment improved following the implementation of NICE guidance; it is questionable, however, whether this led to improved patient safety with respect to prescribing appropriate prophylaxis.


The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours.
Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome. DOI: 10.1038/sj/bjc/6600041 www.bjcancer.comCopyright 2002 The Cancer Research Campaign


Understanding variation in transcription factor binding by modeling transcription factor genome-epigenome interactions.
Despite explosive growth in genomic datasets, the methods for studying epigenomic mechanisms of gene regulation remain primitive. Here we present a model-based approach to systematically analyze the epigenomic functions in modulating transcription factor-DNA binding. Based on the first principles of statistical mechanics, this model considers the interactions between epigenomic modifications and a cis-regulatory module, which contains multiple binding sites arranged in any configurations. We compiled a comprehensive epigenomic dataset in mouse embryonic stem (mES) cells, including DNA methylation (MeDIP-seq and MRE-seq), DNA hydroxymethylation (5-hmC-seq), and histone modifications (ChIP-seq). We discovered correlations of transcription factors (TFs) for specific combinations of epigenomic modifications, which we term epigenomic motifs. Epigenomic motifs explained why some TFs appeared to have different DNA binding motifs derived from in vivo (ChIP-seq) and in vitro experiments. Theoretical analyses suggested that the epigenome can modulate transcriptional noise and boost the cooperativity of weak TF binding sites. ChIP-seq data suggested that epigenomic boost of binding affinities in weak TF binding sites can function in mES cells. We showed in theory that the epigenome should suppress the TF binding differences on SNP-containing binding sites in two people. Using personal data, we identified strong associations between H3K4me2/H3K9ac and the degree of personal differences in NFκB binding in SNP-containing binding sites, which may explain why some SNPs introduce much smaller personal variations on TF binding than other SNPs. In summary, this model presents a powerful approach to analyze the functions of epigenomic modifications. This model was implemented into an open source program APEG (Affinity Prediction by Epigenome and Genome, http://systemsbio.ucsd.edu/apeg).


[Factors associated with the use of wheelchairs by institutionalized elderly people].
Due to the high prevalence of wheel-chair use by institutionalized elderly people, the scope of this research was to verify whether factors involving gender, age, education, length of institutionalization, comorbidities, cognition and functionality are associated with the use of such equipment, as well as ascertain the reasons for use according to the perceptions of the elderly. It is a cross-sectional descriptive study that included 55 elderly people subdivided into G1 (locomotion without assistance) and G2 (wheelchair users). Analysis of the profile in medical records, cognition and functionality by the Mini-Mental State Examination and Barthel index was conducted. Wheelchair users asked about the factors that lead to wheelchair use were recorded: 33 (60%) of the elderly were in G1 and 22 (40%) in G2. There were differences between the groups with respect to functionality (p = 0.005). The elderly who have not suffered a stroke are less likely to use a wheelchair (OR: 0.09; 95% CI: 0.02 to 0.36). Elderly wheelchair users reported: fear of falling, pain, tiredness, weakness in the legs, difficulty walking and lack of assistance in walking. Strokes and functionality are associated with wheelchair use. Knowledge of these factors and the reasons reported by the elderly may enable alternatives of prevention to be defined.


Predicting the presence of bacterial pathogens in the airways of primary care patients with acute cough.
Bacterial testing of all patients who present with acute cough is not feasible in primary care. Furthermore, the extent to which easily obtainable clinical information predicts bacterial infection is unknown. We evaluated the diagnostic value of clinical examination and testing for C-reactive protein and procalcitonin for bacterial lower respiratory tract infection. Through a European diagnostic study, we recruited 3104 adults with acute cough (≤ 28 days) in primary care settings. All of the patients underwent clinical examination, measurement of C-reactive protein and procalcitonin in blood, and chest radiography. Bacterial infection was determined by conventional culture, polymerase chain reaction and serology, and positive results were defined by the presence of Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Bordetella pertussis or Legionella pneumophila. Using multivariable regression analysis, we examined the association of diagnostic variables with the presence of bacterial infection. Overall, 539 patients (17%) had bacterial lower respiratory tract infection, and 38 (1%) had bacterial pneumonia. The only item with diagnostic value for lower respiratory tract infection was discoloured sputum (area under the receiver operating characteristic [ROC] curve 0.56, 95% confidence interval [CI] 0.54-0.59). Adding C-reactive protein above 30 mg/L increased the area under the ROC curve to 0.62 (95% CI 0.59-0.65). For bacterial pneumonia, comorbidity, fever and crackles on auscultation had diagnostic value (area under ROC curve 0.68, 95% CI 0.58-0.77). Adding C-reactive protein above 30 mg/L increased the area under the ROC curve to 0.79 (95% CI 0.71-0.87). Procalcitonin did not add diagnostic information for any bacterial lower respiratory tract infection, including bacterial pneumonia. In adults presenting with acute lower respiratory tract infection, signs, symptoms and C-reactive protein showed diagnostic value for a bacterial cause. However, the ability of these diagnostic indicators to exclude a bacterial cause was limited. Procalcitonin added no clinically relevant information.


Histone Methyltransferase SETDB1 Promotes the Progression of Colorectal Cancer by Inhibiting the Expression of TP53.
SETDB1 is a novel histone methyltransferase associated with the functional tri-methylation of histone H3K9. Although aberrant high expression of SETDB1 was experimentally obversed in a variety of solid tumors, its underlying mechanisms in human carcinogenesis are not well known. In this study, we investigated the expression of SETDB1 in a large cohort of colorectal cancer (CRC) samples and cell lines for the first time. Our findings showed that SETDB1 was highly expressed in majority CRC tissues and cell lines; moreover, up-regulation of SETDB1 was negatively correlated with the survival rate of CRC patients. Functionally, over-expression of SETDB1 significantly promoted the proliferation and migration of CRC cells in vitro and in vivo, while knocking down SETDB1 suppressed their growth. Mechanistically, we showed that over-expression of SETDB1 significantly inhibited the apoptosis induced by 5-Fluorouracil in CRC cells, which was closely related to the inhibition of TP53 and BAX expression. Furthermore, we confirmed that SETDB1 could be recruited to the promoter region of TP53, which might contribute its inhibition of apoptosis. For conclusion, our study indicated that SETDB1 is essential for colorectal carcinogenesis, and may be a newly target for treatment and prognostic evaluation in CRC.


Premature mortality in autism spectrum disorder.
Mortality has been suggested to be increased in autism spectrum disorder (ASD). To examine both all-cause and cause-specific mortality in ASD, as well as investigate moderating role of gender and intellectual ability. Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27,122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2,672,185). During the observed period, 24,358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38-2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability. Premature mortality was markedly increased in ASD owing to a multitude of medical conditions.


Medical speciality choice: does personality matter?
There has been increasing interest in the personalities of doctors. This study examined whether personality differed based upon gender, level of training or medical speciality among 200 physicians and 134 medical students. Post-internship doctors scored significantly higher on conscientiousness (p = .001) than those pursuing basic medical training. Among those pursuing basic medical training, females scored significantly higher than males on agreeableness (p < .001) and conscientiousness (p = .001). Among post-internship respondents, females scored significantly higher on agreeableness (p = .004). There were no personality differences between post-internship doctors working in different specialities. However, among those pursuing basic medical training, those interested in person-focused medical specialities scored significantly higher on extraversion (p < .001), conscientiousness (p = .001), and lower on neuroticism (p = .01) than those who had no strong preference. These results suggest that there is no unique personality profile associated with medical practice, or medical speciality. Instead, it appears that medical school may shape personality.


Free heme and hemopexin in acute kidney injury after cardiopulmonary bypass and transient renal ischemia.
Free heme is released from hemoproteins during hemolysis or ischemia reperfusion injury and can be pro-inflammatory. Most studies on nephrotoxicity of hemolysis-derived proteins focus on free hemoglobin (fHb) with heme as a prosthetic group. Measurement of heme in its free, non-protein bound, form is challenging and not commonly used in clinical routine diagnostics. In contrast to fHb, the role of free heme in acute kidney injury (AKI) after cardiopulmonary bypass (CPB) surgery is unknown. Using an apo-horseradish peroxidase-based assay, we identified free heme during CPB surgery as predictor of AKI in patients undergoing cardiac valve replacement (n = 37). Free heme levels during CPB surgery correlated with depletion of hemopexin (Hx), a heme scavenger-protein. In mice, the impact of high levels of circulating free heme on the development of AKI following transient renal ischemia and the therapeutic potential of Hx were investigated. C57BL/6 mice were subjected to bilateral renal ischemia/reperfusion injury for 15 min which did not cause AKI. However, additional administration of free heme in this model promoted overt AKI with reduced renal function, increased renal inflammation, and reduced renal perfusion on functional magnetic resonance imaging. Hx treatment attenuated AKI. Free heme administration to sham operated control mice did not cause AKI. In conclusion, free heme is a predictor of AKI in CPB surgery patients and promotes AKI in transient renal ischemia. Depletion of Hx in CPB surgery patients and attenuation of AKI by Hx in the in vivo model encourage further research on Hx therapy in patients with increased free heme levels during CPB surgery.


Views of US Voters on Compensating Living Kidney Donors.
Patients in the United States waiting for kidney transplantation die in increasing numbers owing to the severe kidney shortage, which might be alleviated by compensating living kidney donors. To determine the willingness of voting US citizens to become living kidney donors and to ascertain the potential influence of compensation for donation. A professionally designed quantitative survey was administered by an international polling firm in June 2014. Information was collected on willingness to donate a kidney and the potential influence of compensation ($50 000); survey data included respondent age, income, education level, sex, US region, race/ethnicity, marital status, political affiliation, likelihood to vote, and employment status. The survey was performed via a random-digit dialing process that selected respondents via both landlines and mobile telephones to improve population representation. The survey included 1011 registered US voters likely to vote. The degree to which the US voting public is willing to donate a kidney and the perceptions of current voters toward paying living kidney donors. Of the 1011 respondents, 427 were male and 584 were female, with 43% of participants between ages 45 and 64 years. With respondents grouped by willingness to donate, we found that 689 (68%) would donate a kidney to anyone and 235 (23%) only to certain persons; 87 (9%) would not donate. Most (59%) indicated that payment of $50 000 would make them even more likely to donate a kidney, 32% were unmoved by compensation, and 9% were negatively influenced by payment. Most US voters view living kidney donation positively, and most would be motivated toward donor nephrectomy if offered a payment of $50 000. Because most registered voters favor such payments, and because thousands of lives might be saved should compensation increase the number of transplantable kidneys, laws and regulations prohibiting donor compensation should be modified to allow pilot studies of financial incentives for living kidney donors. Outcomes of such trials could then result in evidence-based policies, which would incorporate fair and just compensation to those persons willing to undergo donor nephrectomy.


Platform-switched implants vs platform-matched implants placed in different implant-abutment interface positions: A prospective randomized clinical and microbiological study.
Placement of the implant-abutment interface (IAI) away from the bone crest has been suggested to have positive impacts on maintenance of peri-implant tissues. To assess the effects of platform-switched and platform-matched implants, taking into consideration the IAI at different positions relative to the bone crest, on clinical, radiographic, and microbiological outcomes during 12 months following functional loading. The present prospective randomized study was performed upon 70 patients. Group I (n = 23) implants presenting a platform-switched implant-abutment connection design was inserted 1 mm subcrestally. Group II (n = 22) implants with similar properties were inserted crestally. Group III (n = 25) implants presenting a platform-matched approach with an internal hexagon connection design was inserted crestally. The periodontal parameters were assessed at baseline, and 3, 6, and 12 months postloading. Radiographic marginal bone level (MBL) changes were analyzed at the 12-month follow-up. The amount of DNA copies of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Provetalla intermedia and total bacterial mean load in peri-implant sulcus fluid (PISF) were assessed at the same periods. There were no significant differences among the groups with respect to the periodontal parameters for all time periods. At 12-month follow-up, the MBL changes were 0.16 ± 0.29 mm and 0.17 ± 0.23 mm for group I, 0.15 ± 0.25 mm and 0.17 ± 0.26 mm for group II, 0.17 ± 0.26 mm and for group III in mesial and distal sites, respectively. The mean total bacterial load was found significantly higher for group III compared to the other groups in the three interval times (P < .05). Implants restored with platform-switching and platform-matching performed equally regarding clinical and radiographic outcomes. Platform-matched implants inserted at the crestal level presented higher the mean bacterial total load in PISF.


Lateral epicondylalgia: a musculoskeletal physiotherapy perspective.
Tennis elbow or lateral epicondylalgia (LE) is a challenging musculoskeletal condition to treat. This is largely due to the lack of research-based evidence of the clinical efficacy of the myriad of treatment approaches espoused in the literature. In view of this, successful rehabilitation of LE is based on choosing treatments that address the physical impairments found during clinical examination. The primary physical impairment in LE is a deficit in grip strength predominately due to pain and its consequences on motor function. Hence the mainstay of successful management of this condition is therapeutic exercise, providing it is not pain provocative. Adjunctive procedures such as manipulative therapy and sports taping techniques have recently been shown to provide substantial initial pain relief. Early relief of pain in the rehabilitation program helps accelerate recovery and most importantly motivates the client to persist with the therapeutic exercise program. The manipulative therapy and taping treatments presented in this masterclass warrant consideration in the clinical best practice management of LE, and serve as a model for other similar musculoskeletal conditions.


Vegetable, fruit, and phytonutrient consumption patterns in Taiwan.
Phytonutrients may play important roles in human health and yet only recently a few studies have described phytonutrient consumption patterns, using data obtained from daily consumption methods. We aimed to estimate the phytonutrient content in Taiwanese diets and analyzed main food sources of 10 major phytonutrients. In this study, food items and dietary data gathered with the 24-hour dietary recall from 2908 participants in the 2005-2008 Nutrition and Health Survey in Taiwan were used to create a food phytonutrient database with 933 plant-based foods through integrating database, literature search, and chemical analysis and to appraise phytonutrient consumption status of participants. SUDAAN (Survey Data Analysis) was used for generating weighted phytonutrient intake estimates and for statistical testing. In Taiwanese adults, ∼20% met the recommended number of servings for fruits and 30% met that for vegetables from the Taiwan Food-Guide recommendations. However, only 7.4% consumed the recommended numbers for both fruits and vegetables. Those meeting the recommendations tended to be older and with more females compared with those who did not. Phytonutrient intake levels were higher in meeters than nonmeeters. More than 60% of α-carotene, lycopene, hesperetin, epigallocatechin 3-gallate, and isoflavones came from a single phytonutrient-specific food source. In addition, sweet potato leaf, spinach, and water spinach were among the top three sources of multiple phytonutrients. Cross-comparison between this study and two previous studies with similar methodology showed higher mean levels of lycopene and quercetin in the United States, anthocyanidins in Korea, and lutein and zeaxanthin in Taiwan. The Taiwanese phytonutrient pattern is different from that of the Korean and American. It would be interesting to relate phytonutrient patterns to health profiles in the future.


Are Partial Workplace Smoking Bans as Effective as Complete Smoking Bans? A National Population-Based Study of Smoke-Free Policy Among Japanese Employees.
Although complete workplace smoking bans are generally recommended rather than partial bans, the latter are widespread in many countries, especially Japan. Our objective was to compare complete workplace smoking bans and partial bans for associations with employee smoking and secondhand smoke (SHS)-related discomfort/ill-health. We also evaluated complete bans versus no ban and partial bans versus no ban. Eleven thousand ninety eligible employees (weighted number: 34 353 241) aged 20-64 years in 2011 (response rate: 62.5%) were analyzed using a nationally-representative, population-based cross-sectional study. Adjusted prevalence ratios for self-reported current smoking and SHS-related discomfort/ill-health according to workplace smoke-free policies were calculated, using conventional regression and propensity score (PS) weighting (targeting population of average treatment effect among both treated [TET] and untreated [TEU]). Both conventional regressions and PS weighting analyses showed complete bans were significantly associated with lower prevalence of current smoking and perceived SHS-related discomfort/ill-health among nonsmokers than partial or no ban. In contrast, partial bans were not significantly associated with either outcome compared with no ban. Using several PS trimming levels, we found interesting differences between TET and TEU in a comparison between partial and no ban: that is, significant associations in TET estimations, but none in TEU estimations. Although complete smoking bans were associated with lower levels of employee smoking and SHS-related discomfort/ill-health compared with no smoking ban, partial bans were not. Findings from PS weighting of TEU suggest that partial workplace bans may not be any more effective for Japanese employees than no ban. Therefore, complete bans may be strongly recommended for future implementation, but careful interpretation of the data is necessary because of the cross-sectional study design.


Three-dimensional MRI-linac intra-fraction guidance using multiple orthogonal cine-MRI planes.
The introduction of integrated MRI-radiation therapy systems will offer live intra-fraction imaging. We propose a feasible low-latency multi-plane MRI-linac guidance strategy. In this work we demonstrate how interleaved acquired, orthogonal cine-MRI planes can be used for low-latency tracking of the 3D trajectory of a soft-tissue target structure. The proposed strategy relies on acquiring a pre-treatment 3D breath-hold scan, extracting a 3D target template and performing template matching between this 3D template and pairs of orthogonal 2D cine-MRI planes intersecting the target motion path. For a 60 s free-breathing series of orthogonal cine-MRI planes, we demonstrate that the method was capable of accurately tracking the respiration related 3D motion of the left kidney. Quantitative evaluation of the method using a dataset designed for this purpose revealed a translational error of 1.15 mm for a translation of 39.9 mm. We have demonstrated how interleaved acquired, orthogonal cine-MRI planes can be used for online tracking of soft-tissue target volumes.


Communities in world input-output network: Robustness and rankings.
We introduce a method for assessing the robustness of community detection and apply it to a world input-output network (WION) to obtain economically plausible results. This method enabled us to rank communities in the WION in terms of their robustness and stability. The algorithmic assignment variability index proposed in this study is shown to have predictive power in terms of forthcoming community rearrangement. We also provide several new approaches for identifying key economic communities. These approaches are based on the application of several centrality measures to a synthetic network in which nodes represent WION communities. Using these methods, we show that in 2000-2014, United States and Japan-centered communities demonstrated decreasing trends, while the importance of the China-centered community predominantly increased. A notable feature of the Germany-centered community rank evolution is that its influence grew only as a result of the inclusion of the Netherlands and Belgium in 2013.


Use of multivariate statistics for 16S rRNA gene analysis of microbial communities.
Understanding dynamic processes and diversity in microbial communities is of key importance for combating pathogens and for stimulating beneficial bacteria. We have addressed these challenges utilising multivariate statistics for analyses of microbial community structures. We based our microbial community analyses on 16S rRNA gene data. This gene is by far the most widely applied genetic marker for phylogenetic and microbial community studies. Both probe and clone library data were analysed. We analysed the clone library data using a newly developed coordinate-based phylogenetic approach. By using coordinates, we avoid both DNA sequence alignments and the need for definition of operational taxonomic units (OTUs). The basic principle is to transform the sequence data to frequencies of multimers (short sequences of n=2 to 6), and then to use principal component analyses (PCA) for data compression into an orthogonal coordinate space. We used our coordinate method for global 16S rRNA gene analyses of prokaryotes. When comparing microbial communities, it is often important to determine the relationship between the microflora and knowledge about the samples analysed. We used partial least square regression (PLSR) to relate physical/chemical properties to microbial community composition. This was done by analysing both probe and clone library data using the effect of modified atmosphere packaging (MAP) on fish microflora as an example. We are currently investigating approaches to describe dynamic microbial community interactions. Our ultimate goal is to understand and model the main dynamic interactions in complete microbial communities.


Differences in the variability of cerebral proton magnetic resonance spectroscopy (1H-MRS) measurements within three HIV-infected cohorts.
Cerebral functional impairment remains prevalent in effectively treated HIV-infected subjects. As the results of formal cognitive testing are highly variable, surrogate markers to accurately measure cerebral function parameters are needed. Such markers include measurement of cerebral metabolite ratios (CMR) using proton magnetic resonance spectroscopy (1H-MRS). However, data on the inter-subject variability of CMR are sparse. Our aim was to assess inter-subject variability in CMRs within three different HIV-infected cohorts. Cerebral 1H-MRS was performed using a Phillips Achieva™ 1.5 Tesla magnetic resonance scanner in HIV-infected subjects as follows: 12 subjects before (group 1) and after intensification of antiretroviral therapy with maraviroc (group 2) and 13 subjects with acute viral hepatitis C (HCV) co-infection (group 3). The coefficients of variation (CV) for CMRs in each group were determined and compared using non-parametric tests to determine whether the inter-subject variability differed significantly. All baseline characteristics between the groups were similar. Overall CVs for all CMRs in groups 1, 2 and 3 were 32.3%, 33.2% and 23.4%, respectively (group 1 vs. 2, p=0.863; group 1 vs. 3, p=0.076). On testing for differences in variability between individual CMRs, two metabolites in the right basal ganglia (RBG) had statistically significantly different CVs when comparing group 1 with group 3: N-acetyl aspartate/creatine (NAA/Cr), p=0.029 and myo-Inositol/creatine (mI/Cr), p=0.016. The variability of 1H MRS-measurable CMRs in HIV-infected individuals was lower in those with acute HCV co-infection (group 3).We can conclude that the use of these CMRs in 1H MRS imaging in patients with HIV/acute HCV co-infection is more reliable to assess cerebral function than in patients with HIV infection alone. This has implications for future sample size estimations.


Prescribing pork in Israel.
Both Judaism and Islam have prohibited eating pork and its products for thousands of years. Scholars have proposed several reasons for the ban to which both religions almost totally adhere. Pork, and the refusal to eat it, possesses powerful cultural baggage for Jews. Israel has legislated two related laws: the Pork Law in 1962, that bans the rearing and slaughter of pigs across the country, and the Meat Law of 1994, prohibiting all imports of nonkosher meats into Israel. While not abounding, Israeli pork-eaters certainly exist, and a small number of pig-breeding farms operate in the country, mostly in Christian villages. The influx of Russian immigrants in the 1990s helped boost sales of pork, but the force of the taboo remains so powerful that many secular Israelis still eschew pork dishes, while willing to eat less charged nonkosher items such as shellfish. A porchetta feast recently held in the Muslim-Jewish town of Jaffa, defied the religious and cultural taboo. It was a celebration of a book by Dr. Eli Landau, The White Book, which is the first Hebrew-language collection of pork recipes. Fearing repercussions, Israeli publishers unanimously refused to publish it and the book chain stores declined to display it. As a result, Landau published it himself.


Current Status of Efforts on Standardizing Magnetic Resonance Imaging of Juvenile Idiopathic Arthritis: Report from the OMERACT MRI in JIA Working Group and Health-e-Child.
To report on the progress of an ongoing research collaboration on magnetic resonance imaging (MRI) in juvenile idiopathic arthritis (JIA) and describe the proceedings of a meeting, held prior to Outcome Measures in Rheumatology (OMERACT) 12, bringing together the OMERACT MRI in JIA working group and the Health-e-Child radiology group. The goal of the meeting was to establish agreement on scoring definitions, locations, and scales for the assessment of MRI of patients with JIA for both large and small joints. The collaborative work process included premeeting surveys, presentations, group discussions, consensus on scoring methods, pilot scoring, conjoint review, and discussion of a future research agenda. The meeting resulted in preliminary statements on the MR imaging protocol of the JIA knee and wrist and determination of the starting point for development of MRI scoring systems based on previous studies. It was also considered important to be descriptive rather than explanatory in the assessment of MRI in JIA (e.g., "thickening" instead of "hypertrophy"). Further, the group agreed that well-designed calibration sessions were warranted before any future scoring exercises were conducted. The combined efforts of the OMERACT MRI in JIA working group and Health-e-Child included the assessment of currently available material in the literature and determination of the basis from which to start the development of MRI scoring systems for both the knee and wrist. The future research agenda for the knee and wrist will include establishment of MRI scoring systems, an atlas of MR imaging in healthy children, and MRI protocol requisites.


Decadal-scale shifts in soil hydraulic properties as induced by altered precipitation.
Soil hydraulic properties influence the partitioning of rainfall into infiltration versus runoff, determine plant-available water, and constrain evapotranspiration. Although rapid changes in soil hydraulic properties from direct human disturbance are well documented, climate change may also induce such shifts on decadal time scales. Using soils from a 25-year precipitation manipulation experiment, we found that a 35% increase in water inputs substantially reduced infiltration rates and modestly increased water retention. We posit that these shifts were catalyzed by greater pore blockage by plant roots and reduced shrink-swell cycles. Given that precipitation regimes are expected to change at accelerating rates globally, shifts in soil structure could occur over broad regions more rapidly than expected and thus alter water storage and movement in numerous terrestrial ecosystems.


Physiological dynamics, reproduction-maintenance allocations, and life history evolution.
Allocation of resources to competing processes of growth, maintenance, or reproduction is arguably a key process driving the physiology of life history trade-offs and has been shown to affect immune defenses, the evolution of aging, and the evolutionary ecology of offspring quality. Here, we develop a framework to investigate the evolutionary consequences of physiological dynamics by developing theory linking reproductive cell dynamics and components of fitness associated with costly resource allocation decisions to broader life history consequences. We scale these reproductive cell allocation decisions to population-level survival and fecundity using a life history approach and explore the effects of investment in reproduction or tissue-specific repair (somatic or reproductive) on the force of selection, reproductive effort, and resource allocation decisions. At the cellular level, we show that investment in protecting reproductive cells increases fitness when reproductive cell maturation rate is high or reproductive cell death is high. At the population level, life history fitness measures show that cellular protection increases reproductive value by differential investment in somatic or reproductive cells and the optimal allocation of resources to reproduction is moulded by this level of investment. Our model provides a framework to understand the evolutionary consequences of physiological processes underlying trade-offs and highlights the insights to be gained from considering fitness at multiple levels, from cell dynamics through to population growth.


NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR.
Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.


Prevalence and risk factors of depression among community dwelling elderly.
Depression in the elderly is associated with increased morbidity and mortality. The purpose of this study was to determine the prevalence and risk factors of depression among community-dwelling older population in an urban setting in Turkey. This cross-sectional study was conducted among 482 elderly individuals 65 years and over in an urban area. Cluster sampling method was used for sample size. Depression in the elderly had been diagnosed by a clinical interview and Geriatric Depression Scale. Data were collected by door-to-door survey. Chi square test was used for statistical analysis. P value, which was calculated by the results of chi square test and coefficient of phi (φ), below 0.05 was included in the analysis of logistic regression. Depression was significantly associated with female gender, being single or divorced, lower educational status, low income, unemployment, and lack of health insurance. However, logistic regression analysis revealed higher depression rates in the elderly with chronic obstructive pulmonary disease, psychiatric disease, cerebrovascular disease, low income and being dependent. Depression is common among community-dwelling older people in an urban area of Izmir, Turkey. Older adults living in community should be cautiously screened to prevent or manage depression.


Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli.
Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.


Improvement of cardiac function in mouse myocardial infarction after transplantation of epigenetically-modified bone marrow progenitor cells.
To study usefulness of bone marrow progenitor cells (BPCs) epigenetically altered by chromatin modifying agents in mediating heart repair after myocardial infarction in mice. We tested the therapeutic efficacy of bone marrow progenitor cells treated with the clinically-used chromatin modifying agents Trichostatin A (TSA, histone deacetylase inhibitor) and 5Aza-2-deoxycytidine (Aza, DNA methylation inhibitor) in a mouse model of acute myocardial infarction (AMI). Treatment of BPCs with Aza and TSA induced expression of pluripotent genes Oct4, Nanog, Sox2, and thereafter culturing these cells in defined cardiac myocyte-conditioned medium resulted in their differentiation into cardiomyocyte progenitors and subsequently into cardiac myocytes. Their transition was deduced by expression of repertoire of markers: Nkx2.5, GATA4, cardiotroponin T, cardiotroponin I, α-sarcomeric actinin, Mef2c and MHC-α. We observed that the modified BPCs had greater AceH3K9 expression and reduced histone deacetylase1 (HDAC1) and lysine-specific demethylase1 (LSD1) expression compared to untreated BPCs, characteristic of epigenetic changes. Intra-myocardial injection of modified BPCs after AMI in mice significantly improved left ventricular function. These changes were ascribed to differentiation of the injected cells into cardiomyocytes and endothelial cells. Treatment of BPCs with Aza and TSA converts BPCs into multipotent cells, which can then be differentiated into myocyte progenitors. Transplantation of these modified progenitor cells into infarcted mouse hearts improved left ventricular function secondary to differentiation of cells in the niche into myocytes and endothelial cells.


Chlorproguanil-dapsone-artesunate versus artemether-lumefantrine: a randomized, double-blind phase III trial in African children and adolescents with uncomplicated Plasmodium falciparum malaria.
Chlorproguanil-dapsone-artesunate (CDA) was developed as an affordable, simple, fixed-dose artemisinin-based combination therapy for use in Africa. This trial was a randomized parallel-group, double-blind, double-dummy study to compare CDA and artemether-lumefantrine (AL) efficacy in uncomplicated Plasmodium falciparum malaria and further define the CDA safety profile, particularly its hematological safety in glucose-6-phosphate dehydrogenase (G6PD) -deficient patients. The trial was conducted at medical centers at 11 sites in five African countries between June 2006 and August 2007. 1372 patients (> or =1 to <15 years old, median age 3 years) with acute uncomplicated P. falciparum malaria were randomized (2:1) to receive CDA 2/2.5/4 mg/kg once daily for three days (N = 914) or six-doses of AL over three days (N = 458). Non-inferiority of CDA versus AL for efficacy was evaluated in the Day 28 per-protocol (PP) population using parasitological cure (polymerase chain reaction [PCR]-corrected). Cure rates were 94.1% (703/747) for CDA and 97.4% (369/379) for AL (treatment difference -3.3%, 95%CI -5.6, -0.9). CDA was non-inferior to AL, but there was simultaneous superiority of AL (upper 95%CI limit <0). Adequate clinical and parasitological response at Day 28 (uncorrected for reinfection) was 79% (604/765) with CDA and 83% (315/381) with AL. In patients with a G6PD-deficient genotype (94/603 [16%] hemizygous males, 22/598 [4%] homozygous females), CDA had the propensity to cause severe and clinically concerning hemoglobin decreases: the mean hemoglobin nadir was 75 g/L (95%CI 71, 79) at Day 7 versus 97 g/L (95%CI 91, 102) for AL. There were three deaths, unrelated to study medication (two with CDA, one with AL). Although parasitologically effective at Day 28, the hemolytic potential of CDA in G6PD-deficient patients makes it unsuitable for use in a public health setting in Africa. ClinicalTrials.Gov NCT00344006.


Inbreeding avoidance and female mate choice shape reproductive skew in capuchin monkeys (Cebus capucinus imitator).
Reproductive skew in multimale groups may be determined by the need for alpha males to offer reproductive opportunities as staying incentives to subordinate males (concessions), by the relative fighting ability of the alpha male (tug-of-war) or by how easily females can be monopolized (priority-of-access). These models have rarely been investigated in species with exceptionally long male tenures, such as white-faced capuchins, where female mate choice for novel unrelated males may be important in shaping reproductive skew. We investigated reproductive skew in white-faced capuchins at Sector Santa Rosa, Costa Rica, using 20 years of demographic, behavioural and genetic data. Infant survival and alpha male reproductive success were highest in small multimale groups, which suggests that the presence of subordinate males can be beneficial to the alpha male, in line with the concession model's assumptions. None of the skew models predicted the observed degree of reproductive sharing, and the probability of an alpha male producing offspring was not affected by his relatedness to subordinate males, whether he resided with older subordinate males, whether he was prime aged, the number of males or females in the group or the number of infants conceived within the same month. Instead, the alpha male's probability of producing offspring decreased when he was the sire of the mother, was weak and lacked a well-established position and had a longer tenure. Because our data best supported the inbreeding avoidance hypothesis and female choice for strong novel mates, these hypotheses should be taken into account in future skew models.


Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation.
Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth.


Optimal hematocrit for oxygenation of canine intestine.
To determine the direct effects of hematocrit on intestinal oxygen consumption and to determine whether an optimal hematocrit exists for intestinal oxygenation, we perfused isolated canine gut loops at a constant pressure (120 mm Hg) and varied hematocrit from 80% to 10%. As hematocrit fell, blood flow rose while arterial oxygen content fell. The regression of blood flow on hematocrit was linear, whereas the relationship between oxygen uptake and hematocrit was parabolic, showing a maximal oxygen uptake at an hematocrit of 48.7%. To determine whether the optimal hematocrit for intestinal oxygenation could be altered by changes in vasomotor tone, we performed two other series of experiments. Raising perfusion pressure to 180 mm Hg did not significantly alter the optimal hematocrit for oxygen uptake. However, when we increased the oxygen demands of the gut by placing transportable solutes within the intestinal lumen, the optimal hematocrit for oxygen uptake increased markedly. We conclude that the optimal hematocrit for intestinal oxygenation is slightly higher than the normal range, a finding that could possibly be explained by the plasma skimming known to occur in the intestinal mucosa. Our experimental design and method of data analysis could be used to determine the optimal hematocrit in other organs.