Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial.
Growth-restricted preterm infants are at increased risk of developing necrotizing enterocolitis (NEC) and initiation of enteral feeding is frequently delayed. There is no evidence that this delay is beneficial and it might further compromise nutrition and growth. Infants with gestation below 35 weeks, birth weight below the 10th centile, and abnormal antenatal umbilical artery Doppler waveforms were randomly allocated to commence enteral feeds "early," on day 2 after birth, or "late," on day 6. Gradual increase in feeds was guided by a "feeding prescription" with rate of increase the same for both groups. Primary outcomes were time to achieve full enteral feeding sustained for 72 hours and NEC. Four hundred four infants were randomly assigned from 54 hospitals in the United Kingdom and Ireland (202 to each group). Median gestation was 31 weeks. Full, sustained, enteral feeding was achieved at an earlier age in the early group: median age was 18 days compared with 21 days (hazard ratio: 1.36 [95% confidence interval: 1.11-1.67]). There was no evidence of a difference in the incidence of NEC: 18% in the early group and 15% in the late group (relative risk: 1.2 [95% confidence interval: 0.77-1.87]). Early feeding resulted in shorter duration of parenteral nutrition and high-dependency care, lower incidence of cholestatic jaundice, and improved SD score for weight at discharge. Early introduction of enteral feeds in growth-restricted preterm infants results in earlier achievement of full enteral feeding and does not appear to increase the risk of NEC.


Lipopolysaccharide responsiveness in vocal fold fibroblasts.
Vocal fold fibroblast's (VFF) strategic location in the lamina propria and their ability to respond to external stimuli by producing inflammatory molecules suggest their possible direct involvement in innate immunity. Toll-like receptors (TLRs) are an essential signaling component to this response, as they allow for recognition of various microorganisms, leading to subsequent induction of pro-inflammatory genes. The objective of this study was to elucidate the role of VFF in the host immune response and subsequent influence on inflammatory cytokine secretion. VFF derived from polyp, scar, and normal tissue were treated with 5 μg/ml lipopolysaccharide (LPS). TLR1 through 9, CD14, and MD-2 were measured during stable conditions by polymerase chain reaction (PCR). Expression of TLR4 and IL-1R type-1 genes were quantified after 24 hrs LPS stimulation by reverse transcription-PCR. LPS responsiveness was determined by NF-κB nuclear translocation as measured by subunit p65 expression in nucleus with immunocytochemistry. Downstream effects were confirmed with immunoassay measuring IL-8 concentrations in supernatant after 8 hrs. All VFFs constitutively expressed TLR1 to 6, TLR9, CD14, and MD-2 mRNA. Polyp VFF exhibited significantly higher TLR4 transcript levels (p < 0.001) in comparison to scar and normal VFF. LPS stimulated scar and polyp VFF exhibited increased levels of p65 in the nucleus (p < 0.01) and secreted greater IL-8 protein (p < 0.0001) compared to normal VFF. VFF constitutively express genes for the receptors essential to the host immune response. Scar and polyp VFF produced greater LPS responsiveness resulting in over-activated inflammatory patterns. These findings support VFF role in the pathogenesis of inflammatory vocal fold disorders and suggests their presence in the wound bed could lead to chronic inflammation.


Multicolor spectral photon-counting computed tomography: in vivo dual contrast imaging with a high count rate scanner.
A new prototype spectral photon-counting computed tomography (SPCCT) based on a modified clinical CT system has been developed. SPCCT analysis of the energy composition of the transmitted x-ray spectrum potentially allows simultaneous dual contrast agent imaging, however, this has not yet been demonstrated with such a system. We investigated the feasibility of using this system to distinguish gold nanoparticles (AuNP) and an iodinated contrast agent. The contrast agents and calcium phosphate were imaged in phantoms. Conventional CT, gold K-edge, iodine and water images were produced and demonstrated accurate discrimination and quantification of gold and iodine concentrations in a phantom containing mixtures of the contrast agents. In vivo experiments were performed using New Zealand White rabbits at several times points after injections of AuNP and iodinated contrast agents. We found that the contrast material maps clearly differentiated the distributions of gold and iodine in the tissues allowing quantification of the contrast agents' concentrations, which matched their expected pharmacokinetics. Furthermore, rapid, repetitive scanning was done, which allowed measurement of contrast agent kinetics with high temporal resolution. In conclusion, a clinical scale, high count rate SPCCT system is able to discriminate gold and iodine contrast media in different organs in vivo.


Capsaicin effects on muscularis mucosa of opossum esophagus: substance P release from afferent nerves?
The effects of capsaicin on the function and structure of muscularis mucosa of opossum esophagus were studied. In this tissue there are numerous nerves containing a substance P-like immunoreactive substance (SPLS), and electrical field stimulation (EFS) leads to a phasic response that appears to be due to release of acetylcholine, followed by a tonic response at higher frequencies of stimulation that appears to be due to release of a SPLS. The acetylcholine released by EFS and exogenous muscarinic agonists inhibits release of this SPLS (8). In the present study capsaicin (5 X 10(-5) M) was shown to cause a tonic submaximal contraction in most cases. This was prevented by substance P tachyphylaxis and by pretreatment with the partial agonist [D-Pro2, D-Trp7,9]substance P, the antagonist [D-Arg1, D-Trp7, Leu11]substance P, and tetrodotoxin. This response to capsaicin could not be repeated even after 2 h. Capsaicin also abolished the tonic response to high-frequency EFS without affecting phasic responses and reduced markedly the enhanced tonic response after atropine had abolished the phasic response. This occurred with or without a preliminary contraction to capsaicin. This tonic response to high-frequency EFS recovered completely 1-2 h after washing out capsaicin. Then, a further administration of capsaicin had no direct effect but again abolished tonic responses to EFS. Capsaicin reduced responses to exogenous substance P or carbachol only partially. When tissues were fixed and studied after capsaicin had abolished tonic responses to EFS, specific damage to nerve varicosities or synaptic vesicles in nerve varicosities could not be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)


Characterization of non-equilibrium nanoparticle adsorption on a model biological substrate.
The kinetics of nanoparticle (NP) adsorption on a model biological interface (collagen) is measured in microfluidic channels using surface plasmon resonance (SPR) imaging over a range of CdSe/ZnS quantum dot concentrations to investigate the underlying binding process. Spherical CdSe/ZnS core-shell NP, derivatized with 3-mercaptopropionic acid (3-MPA), were considered to be model NPs because of their widespread use in biological applications and their relatively monodisperse size. The kinetic adsorption data suggests that the binding between the NP and the collagen substrate is irreversible at room temperature (pH approximately 7.4), and this type of adsorption process was further characterized in the context of a surface absorption model. Specifically, diffusion-limited adsorption was found to predominate the adsorption process at lower concentrations (<0.4 micromol/L), and NP adsorption was reaction-limited at higher concentration (>0.4 micromol/L). A limited pH study of our system indicates that NPs desorb from collagen under acidic conditions (pH 5.5); no significant desorption was observed under neutral and basic pH conditions. These observations are consistent with electrostatic interactions being the dominant force governing NP desorption from collagen substrates. Our present methodology for characterizing the seemingly irreversible NP adsorption complements our earlier study where NP adsorption onto weakly adsorbing surfaces (self-assembled monolayers) was characterized by Langmuir NP adsorption measurements.


The Memory Aid study: protocol for a randomized controlled clinical trial evaluating the effect of computer-based working memory training in elderly patients with mild cognitive impairment (MCI).
Mild cognitive impairment (MCI) is a condition characterized by memory problems that are more severe than the normal cognitive changes due to aging, but less severe than dementia. Reduced working memory (WM) is regarded as one of the core symptoms of an MCI condition. Recent studies have indicated that WM can be improved through computer-based training. The objective of this study is to evaluate if WM training is effective in improving cognitive function in elderly patients with MCI, and if cognitive training induces structural changes in the white and gray matter of the brain, as assessed by structural MRI. The proposed study is a blinded, randomized, controlled trail that will include 90 elderly patients diagnosed with MCI at a hospital-based memory clinic. The participants will be randomized to either a training program or a placebo version of the program. The intervention is computerized WM training performed for 45 minutes of 25 sessions over 5 weeks. The placebo version is identical in duration but is non-adaptive in the difficulty level of the tasks. Neuropsychological assessment and structural MRI will be performed before and 1 month after training, and at a 5-month folllow-up. If computer-based training results in positive changes to memory functions in patients with MCI this may represent a new, cost-effective treatment for MCI. Secondly, evaluation of any training-induced structural changes to gray or white matter will improve the current understanding of the mechanisms behind effective cognitive interventions in patients with MCI. ClinicalTrials.gov NCT01991405. November 18, 2013.


Coevolved Mutations Reveal Distinct Architectures for Two Core Proteins in the Bacterial Flagellar Motor.
Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.


Primary liver cancer among women in laundry and dry-cleaning work in Denmark.
Tetrachloroethylene has been the most commonly used solvent in dry cleaning in Denmark since the late 1950s. A cohort of laundry and dry-cleaning workers was identified from the Danish Occupational Cancer Register for the study of cancer incidence of persons exposed to tetrachloroethylene. The Register includes cancer incidence data for a 10-year period for 8567 women and 2033 men employed in laundry and dry-cleaning in 1970. A significant excess risk was found for primary liver cancer among the women, with 7 observed and 2.1 expected cases (standardized incidence ratio 3.4, 95% confidence interval 1.4-7.0). No case of primary liver cancer was observed among the men, for whom the expected value was 1.1. The excess risk of primary liver cancer among the women is unlikely to be explained exclusively by excess alcohol consumption.


Towards client-centered counseling: development and testing of the WHO Decision-Making Tool.
To describe development and testing of a counseling tool intended to inform family planning clients while helping the family planning provider facilitate the client's decision-making process; and to discuss challenges and requisites for shifting to shared decision-making from the extremes of decision-making dominated by the provider, on one hand, or unaided by the provider, on the other. DEVELOPMENT OF THE TOOL: The WHO Decision-Making Tool for Family Planning Clients and Providers is derived from evidence-based principles of client-centered care and counseling. This article discusses how these principles are manifested in the Tool and how the Tool aids both provider and client in improving counseling. Development of the Tool involved formative workshops with providers in Indonesia, Mexico, South Africa and Trinidad and Tobago and observational evaluation research in Indonesia, Mexico, and Nicaragua. Analysis of videotaped counseling sessions quantitatively assessed client-provider communication and decision-making. Also, focus-group discussions, interviews, and a questionnaire collected qualitative data from providers and clients. In general, use of the Tool improved providers' counseling performance: they engaged clients more and gave more and better tailored information. For clients, the Tool increased their communication and involvement. Both the Nicaraguan and Mexican studies found marked shifts toward the client in the locus of decision-making after introduction of the Tool. Use of the tool improves the performance of both providers and clients in family planning counseling and decision-making. There are challenges, however, at the levels of both the provider and the organization in sustaining these changes and scaling up such initiatives in quality of care.


Game intelligence in team sports.
We set up a game theoretic framework to analyze a wide range of situations from team sports. A fundamental idea is the concept of potential; the probability of the offense scoring the next goal minus the probability that the next goal is made by the defense. We develop categorical as well as continuous models, and obtain optimal strategies for both offense and defense. A main result is that the optimal defensive strategy is to minimize the maximum potential of all offensive strategies.


Encapsulation of labile trivalent lanthanides into a homobimetallic chromium(III)-containing triple-stranded helicate. Synthesis, characterization, and divergent intramolecular energy transfers.
The segmental bidentate-tridentate-bidentate ligand L2 reacts with M(II) (M = Cr, Zn) and Ln(III) (Ln = La, Eu, Gd, Tb, Lu) to give the heterotrimetallic triple-stranded helicates [MLnM(L2)3]7+. For M = Zn(II), the isolated complexes [ZnLnZn(L2)3](CF3SO3)7 (Ln = Eu, Tb) display only lanthanide-centred luminescence arising from the pseudo-tricapped trigonal prismatic LnN9 coordination site. For M = Cr(II), rapid air oxidation provides Cr(III) and leads to the isolation of inert [CrLnCr(L2)3](CF3SO3)9 (Ln = Eu, Tb) complexes, in which divergent intramolecular Ln --> Cr energy transfers can be evidenced. Taking [ZnEuZn(L2)3]7+ as a luminescent standard for Eu-centred emission, a quantitative treatment of the energy migration processes indicates that the rate constant characterizing the Eu --> Cr energy transfer is more efficient in the trimetallic system, than in the analogous simple bimetallic edifice. Particular attention is focused on potential control of directional energy transfer processes in Cr-Ln pairs.


Rapid quantification of free cholesterol in tears using direct insertion/electron ionization-mass spectrometry.
To establish a simple and rapid analytical method, based on direct insertion/electron ionization-mass spectrometry (DI/EI-MS), for measuring free cholesterol in tears from humans and rabbits. A stable-isotope dilution protocol employing DI/EI-MS in selected ion monitoring mode was developed and validated. It was used to quantify the free cholesterol content in human and rabbit tear extracts. Tears were collected from adult humans (n = 15) and rabbits (n = 10) and lipids extracted. Screening, full-scan (m/z 40-600) DI/EI-MS analysis of crude tear extracts showed that diagnostic ions located in the mass range m/z 350 to 400 were those derived from free cholesterol, with no contribution from cholesterol esters. DI/EI-MS data acquired using selected ion monitoring (SIM) were analyzed for the abundance ratios of diagnostic ions with their stable isotope-labeled analogues arising from the D6-cholesterol internal standard. Standard curves of good linearity were produced and an on-probe limit of detection of 3 ng (at 3:1 signal to noise) and limit of quantification of 8 ng (at 10:1 signal to noise). The concentration of free cholesterol in human tears was 15 ± 6 μg/g, which was higher than in rabbit tears (10 ± 5 μg/g). A stable-isotope dilution DI/EI-SIM method for free cholesterol quantification without prior chromatographic separation was established. Using this method demonstrated that humans have higher free cholesterol levels in their tears than rabbits. This is in agreement with previous reports. This paper provides a rapid and reliable method to measure free cholesterol in small-volume clinical samples.


Assembling the fungal tree of life: progress, classification, and evolution of subcellular traits.
Based on an overview of progress in molecular systematics of the true fungi (Fungi/Eumycota) since 1990, little overlap was found among single-locus data matrices, which explains why no large-scale multilocus phylogenetic analysis had been undertaken to reveal deep relationships among fungi. As part of the project "Assembling the Fungal Tree of Life" (AFTOL), results of four Bayesian analyses are reported with complementary bootstrap assessment of phylogenetic confidence based on (1) a combined two-locus data set (nucSSU and nucLSU rDNA) with 558 species representing all traditionally recognized fungal phyla (Ascomycota, Basidiomycota, Chytridiomycota, Zygomycota) and the Glomeromycota, (2) a combined three-locus data set (nucSSU, nucLSU, and mitSSU rDNA) with 236 species, (3) a combined three-locus data set (nucSSU, nucLSU rDNA, and RPB2) with 157 species, and (4) a combined four-locus data set (nucSSU, nucLSU, mitSSU rDNA, and RPB2) with 103 species. Because of the lack of complementarity among single-locus data sets, the last three analyses included only members of the Ascomycota and Basidiomycota. The four-locus analysis resolved multiple deep relationships within the Ascomycota and Basidiomycota that were not revealed previously or that received only weak support in previous studies. The impact of this newly discovered phylogenetic structure on supraordinal classifications is discussed. Based on these results and reanalysis of subcellular data, current knowledge of the evolution of septal features of fungal hyphae is synthesized, and a preliminary reassessment of ascomal evolution is presented. Based on previously unpublished data and sequences from GenBank, this study provides a phylogenetic synthesis for the Fungi and a framework for future phylogenetic studies on fungi.


Stable radio-frequency phase distribution over optical fiber by phase-drift auto-cancellation.
We report a new radio-frequency (RF) phase stabilization approach for long-haul optical fiber distribution. The phase drift of an RF signal induced by fiber-length variations can be canceled out automatically via RF mixing without using active phase discrimination and dynamic phase tracking. A key significance of our approach is that no assistant local oscillator (LO) signal is needed. Consequently, frequency estimation of the received RF signal, as well as frequency locking between the LO and the received RF signal, is no longer required, which simplifies the system. A proof-of-concept experiment shows that the phase drift of the received RF signal at 9.6 GHz is significantly reduced using the proposed method. The root mean square (RMS) timing jitter is 0.76 ps when a tunable optical delay line (TODL) inserted between the remote antenna unit (RAU) and local station is changed from 0 to 300 ps.


A study on community-based approaches to reduce leprosy stigma in India.
There is a global awareness that reduction of leprosy stigma is not at par with the technological developments and the resulting cognitive changes pertaining to leprosy, which can be attributed to lack of active community participation in the programmes. With a major aim of identifying the best methods using active participation of the society, the Leprosy Mission in India initiated a multi-state community-based interventional trial of leprosy stigma reduction in 2 similar rural blocks located beyond 25 km. from the three hospitals, from 3 states, at Faizabad in Uttar Pradesh, Purulia in West Bengal and Champa in Chhattisgarh of India during 2005. A baseline survey was done which confirmed a high level of leprosy stigma. A stigma reduction organizing committee (SROC) in each village, thus a total of 60 SROCs from 3 states @ 10 from each block were formed. One trained social worker appointed by the project as community organizer in each block acted as a facilitator for all the stigma reduction activities taken up by the committees. The outcome of the project shows, the SROCs' interventions are well accepted by the communities. Education and counseling through SROC members in local circumstances are very much feasible and effective.


Dietary Patterns, Asthma, and Lung Function in the Hispanic Community Health Study/Study of Latinos.
Rationale: Dietary patterns may alter immune responses and increase asthma risk or affect lung function.Objectives: To examine whether a proinflammatory diet (assessed by the energy-adjusted Dietary Inflammatory Index [E-DII]) or high dietary quality (assessed by the Alternative Healthy Eating Index [AHEI-2010]) are associated with current asthma, current asthma symptoms, and lung function in Hispanic adults.Methods: This was a cross-sectional study of 12,687 adults aged 18 to 76 years who participated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The E-DII and AHEI-2010 were calculated based on two 24-hour dietary recalls. Logistic or linear regression was used for the multivariable analysis of E-DII or AHEI-2010 scores and current asthma, asthma symptoms, and lung function measures, adjusting for age, sex, annual household income, study center, Hispanic/Latino background, smoking status, and other covariates.Results: A higher E-DII score was associated with current asthma (odds ratio [OR] for quartile 4 vs. 1, 1.35; 95% confidence interval [CI], 0.97-1.90) and asthma symptoms (OR for quartile 4 vs. 1, 1.42; 95% CI, 1.12-1.81). The AHEI-2010 score was not associated with current asthma or asthma symptoms. Among adults without asthma, a higher E-DII score was associated with lower forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and a higher AHEI-2010 score was associated with higher FEV1 and FVC.Conclusions: Our findings suggest that a proinflammatory diet increases the risk of asthma and asthma symptoms in Hispanic adults. An antiinflammatory diet (indicated by a lower E-DII or a higher AHEI-2010 score) may positively influence lung function in Hispanic adults without asthma.


Application of independent component analysis with adaptive density model to complex-valued fMRI data.
Independent component analysis (ICA) has proven quite useful for the analysis of real world datasets such as functional resonance magnetic imaging (fMRI) data, where the underlying nature of the data is hard to model. It is particularly useful for the analysis of fMRI data in its native complex form since very little is known about the nature of phase. Phase information has been discarded in most analyses as it is particularly noisy. In this paper, we show that a complex ICA approach using a flexible nonlinearity that adapts to the source density is the more desirable one for performing ICA of complex fMRI data compared to those that use fixed nonlinearity, especially when noise level is high. By adaptively matching the underlying fMRI density model, the analysis performance can be improved in terms of both the estimation of spatial maps and the task-related time courses, especially for the estimation of phase of the time course. We also define a procedure for analysis and visualization of complex-valued fMRI results, which includes the construction of bivariate t-maps for multiple subjects and a complex-valued ICASSO scheme for evaluating the consistency of ICA algorithms.


RAD sequencing resolves fine-scale population structure in a benthic invertebrate: implications for understanding phenotypic plasticity.
The field of molecular ecology is transitioning from the use of small panels of classical genetic markers such as microsatellites to much larger panels of single nucleotide polymorphisms (SNPs) generated by approaches like RAD sequencing. However, few empirical studies have directly compared the ability of these methods to resolve population structure. This could have implications for understanding phenotypic plasticity, as many previous studies of natural populations may have lacked the power to detect genetic differences, especially over micro-geographic scales. We therefore compared the ability of microsatellites and RAD sequencing to resolve fine-scale population structure in a commercially important benthic invertebrate by genotyping great scallops (Pecten maximus) from nine populations around Northern Ireland at 13 microsatellites and 10 539 SNPs. The shells were then subjected to morphometric and colour analysis in order to compare patterns of phenotypic and genetic variation. We found that RAD sequencing was superior at resolving population structure, yielding higher Fst values and support for two distinct genetic clusters, whereas only one cluster could be detected in a Bayesian analysis of the microsatellite dataset. Furthermore, appreciable phenotypic variation was observed in size-independent shell shape and coloration, including among localities that could not be distinguished from one another genetically, providing support for the notion that these traits are phenotypically plastic. Taken together, our results suggest that RAD sequencing is a powerful approach for studying population structure and phenotypic plasticity in natural populations.


Immunohistochemical expression of interlukin10 (IL10) and heat shock protein-90 (HSP-90) in prostatic carcinoma.
Specific cytokines are related to pathologically changed prostate, propose that the balance in cytokine differs in normal and pathological prostate. Of these cytokines the interleukins 10, due to its "pleiotropic" actions in inflammation and angiogenesis, and HSP-90 due to its expression in tumor cells at high levels, suggesting that it has an important role for growth and/or survival of tumor cells. Evaluation of HSP-90 and IL10 immunoreactivity in benign prostatic hyperplasia (BPH) and prostatic carcinoma and to correlate this expression with clinicopathological parameters. A retrospective study in which 83 Paraffin-embedded tissue specimens including (43) BPH, (40) prostatic carcinoma and (20) normal prostate as control were included between the period of January 2015 and January 2017. All the cases were evaluated histopathologically and stained immunohistochemically for IL10 and HSP-90. Only cytoplasmic staining was considered as positive. Immunoreactivity scoring for both markers expression was calculated based on both staining intensity and percentage. Was done using SPSS Version 21 statistical analysis software. P value of <0.05 was considered statistically significant. Statistical analysis of HSP-90 and IL10 expression revealed a highly significant correlation of expression of these two markers in advanced Gleason grading and tumor, node, and metastasis (TNM) staging cases of prostatic carcinoma. High expression of IL10 and HSP-90 is associated with high grade and stage of prostatic carcinoma. This provides a base for further studies and researches on the role of these investigated proteins as prognostic markers immunotherapy targets for carcinoma of the prostate.


Simulating the impact on health of internalising the cost of carbon in food prices combined with a tax on sugar-sweetened beverages.
Rising greenhouse gas emissions (GHGEs) have implications for health and up to 30 % of emissions globally are thought to arise from agriculture. Synergies exist between diets low in GHGEs and health however some foods have the opposite relationship, such as sugar production being a relatively low source of GHGEs. In order to address this and to further characterise a healthy sustainable diet, we model the effect on UK non-communicable disease mortality and GHGEs of internalising the social cost of carbon into the price of food alongside a 20 % tax on sugar sweetened beverages (SSBs). Developing previously published work, we simulate four tax scenarios: (A) a GHGEs tax of £2.86/tonne of CO2 equivalents (tCO2e)/100 g product on all products with emissions greater than the mean across all food groups (0.36 kgCO2e/100 g); (B) scenario A but with subsidies on foods with emissions lower than 0.36 kgCO2e/100 g such that the effect is revenue neutral; (C) scenario A but with a 20 % sales tax on SSBs; (D) scenario B but with a 20 % sales tax on SSBs. An almost ideal demand system is used to estimate price elasticities and a comparative risk assessment model is used to estimate changes to non-communicable disease mortality. We estimate that scenario A would lead to 300 deaths delayed or averted, 18,900 ktCO2e fewer GHGEs, and £3.0 billion tax revenue; scenario B, 90 deaths delayed or averted and 17,100 ktCO2e fewer GHGEs; scenario C, 1,200 deaths delayed or averted, 18,500 ktCO2e fewer GHGEs, and £3.4 billion revenue; and scenario D, 2,000 deaths delayed or averted and 16,500 ktCO2e fewer GHGEs. Deaths averted are mainly due to increased fibre and reduced fat consumption; a SSB tax reduces SSB and sugar consumption. Incorporating the social cost of carbon into the price of food has the potential to improve health, reduce GHGEs, and raise revenue. The simple addition of a tax on SSBs can mitigate negative health consequences arising from sugar being low in GHGEs. Further conflicts remain, including increased consumption of unhealthy foods such as cakes and nutrients such as salt.


A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate.
TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint-dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3-TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.


Minimally invasive treatments for benign prostatic enlargement: systematic review of randomised controlled trials.
To compare the effectiveness and risk profile of minimally invasive interventions against the current standard of transurethral resection of the prostate. Systematic review and meta-analysis of randomised controlled trials. Electronic and paper records up to March 2006. We searched for all relevant randomised controlled trials. Two reviewers independently extracted data and assessed quality. Meta-analyses of prespecified outcomes were performed with fixed and random effects models and reported using relative risks or weighted mean difference. 3794 abstracts were identified; 22 randomised controlled trials met the inclusion criteria. These provided data on 2434 participants. The studies evaluated were of moderate to poor quality with small sample sizes. Minimally invasive interventions were less effective than transurethral resection of the prostate in terms of improvement in symptom scores and increase in urine flow rate, with most comparisons showing significance despite wide confidence intervals. Rates of reoperation were significantly higher for minimally invasive treatments. The risk profile of minimally invasive interventions was better than that of transurethral resection, with fewer adverse events. The results, however, showed significant heterogeneity. Which minimally invasive intervention is the most promising remains unclear. Their place in the management of benign prostate enlargement will continue to remain controversial until well designed and well reported randomised controlled trials following CONSORT guidelines prove they are superior and more cost effective than drug treatment, or that strategies of sequential surgical treatments are preferred by patients and are more cost effective than the more invasive but more effective tissue ablative interventions such as transurethral resection.


Trends in antidepressant utilization from 2001 to 2004.
This study investigated whether the trend of increasing rates of antidepressant use in the 1990s continued into 2000-2004. Antidepressant treatment rates were examined by age group and by the class of antidepressant in order to identify whether any observed trends were being driven by a particular age group of patients or class of medication. Secondary analysis was performed on data from the 2000-2004 Medical Panel Expenditure Surveys, a nationally representative survey of U.S. households, to examine trends in antidepressant use by age group and medication class in the total sample (N=166,435). Trends in the rates of antidepressant use among individuals with self-reported depression (N=10,959) and self-reported anxiety disorders without comorbid depression (N=6,899) were also examined. Antidepressant use increased among all Americans, from 6.6% in 2000 to 8.1% in 2004 (p<.001). Rates of antidepressant use by individuals with anxiety disorders without comorbid depression increased from 30.8% in 2000 to 39.0% in 2002, before declining to 33.2% in 2004. However, antidepressant use decreased among individuals with self-reported depression, from 63.1% in 2000 to 56.7% in 2004 (p<.001). This downward trend in antidepressant use was largely driven by a decrease in use of selective serotonin reuptake inhibitors, especially among children and middle-aged adults with depression. Rates of adequate antidepressant treatment (defined as receiving at least four antidepressant prescriptions at the minimum adequate daily dosage) peaked in 2002 (36.9%), and there was a significant decline by 2004 (31.7%) (p=.003). After years of increased use of antidepressant therapy to treat depression, a trend reversal in the beginning of the 21st century was observed, including decreasing rates of adequate antidepressant treatment. This downward trend preceded the black-box warnings included on antidepressant labels beginning in 2004.


The adherence of Staphylococcus aureus to human corneocytes.
Staphylococcus aureus has a peculiar ability to colonize the skin of patients with atopic dermatitis. We examined the possibility that this might be due to a specific ability of this pathogenic staphylococcus to adhere to atopic stratum corneum. We used an in vitro model to show that S aureus does have an unusual ability to adhere to atopic corneocytes when compared with corneocytes obtained from patients with other cutaneous diseases, including psoriasis. Protein A--a component of the staphylococcal cell wall--may be responsible in part for this adherence phenomenon. This trait did not extend to the other gram-positive bacteria tested.


Influence of yoga and aerobics exercise on fatigue, pain and psychosocial status in patients with multiple sclerosis: a randomized trial.
Multiple sclerosis (MS) is an autoimmune disease involving brain and spinal cord. Weakness, cognitive impairment, pain, depression and fatigue, as common symptoms of MS, may significantly affect on general health of MS patients. This study aimed to investigate the influence of yoga and aerobic exercise on fatigue, pain, and psychosocial status among these patients. In a randomized clinical trial study on 90 patients whom were randomly assigned to three equal groups of yoga exercises, aerobics exercises, and control group. The exercise program was performed as three sessions per week for 12 weeks. The exercise program included 40 minutes, including 5-10 minutes for warm-up, 25-30 minutes of exercise (walking), and 5 minutes for cooling down. Yoga exercises were scheduled three sessions a week for 12 weeks as well. There was no significant difference in fatigue, pain severity and psychological status among three groups prior to the study, but after the study, in yoga and exercise groups, fatigue physical function, physical and emotional role which patients play throughout daily life, social function, energy, mental status and overall hygiene increased, and the pain and fatigue were relieved in the patients. Yoga and aerobics exercise could decrease some of the MS symptoms, therapeutic costs, hospital stay, and days lost from work as well as increasing the patients' efficiency.


Syntheses, crystal structures and steady state and time-resolved fluorescence properties of a PET based macrocycle and its dinuclear ZnII/CdII/HgII complexes.
The work in the present investigation reports the syntheses, crystal structures, ESI-MS (positive) and steady state and time resolved photophysical properties of a tetraaminodiphenol macrocyclic ligand H2L (saturated analogue of a tetraiminodiphenol macrocycle obtained on 2 + 2 condensation of 4-ethyl-2,6-diformylphenol and 2,2-dimethyl-1,3-diaminopropane) and its three dinuclear d10 metal ion (ZnII, CdII and HgII) complexes having compositions [ZnLCl2]·2CH3OH (1), [CdL(μ-H2O)(H2O)2](NO3)2·4H2O (2) and [HgLCl2] (3). H2L is colorless and weakly fluorescent, Cd compound 2 is colorless and more weakly fluorescent, Zn compound 1 is colorless and highly fluorescent and Hg compound 3 is yellow and nonemissive. The order of the radiative rate constant (Kr), obtained from time-resolved studies, corroborates the order of quantum yields, obtained from steady state studies: 1 (φ = 0.12; Kr = 116.6 × 106 s-1) ≫ H2L (φ = 0.005; Kr = 7.726 × 106 s-1) > Cd compound 2 (φ = 0.0014; Kr = 0.675 × 106 s-1). Spectrophotometric and steady state/time-resolved spectrofluorimetric titrations of H2L with ZnII, CdII and HgII have been performed. The relative fluorescence efficiencies of H2L, H2L + various single metal ions (ZnII, CdII, HgII, CuII, NiII, CoII, FeII, MnII) and H2L + ZnII + another metal ion (metal ion competition study) have been studied. Relative fluorescence efficiency can be well rationalized in terms of photoinduced electron transfer (PET), perturbation of PET by metal coordination (chelation enhanced fluorescence, CHEF), heavy metal ion effect (spin-orbit coupling) and fluorescence quenching mechanism. It has been established from comparative fluorescence spectra of 4-ethylphenol, H2L and 1 that H2L can be reasonably considered as a PET species in which the fluorophore is 4-ethylphenol. The binding constants, as determined from titration experiments, qualitatively corroborate the results of metal ion competition studies. The modulation of the absorption spectra and color of the H2L-HgII solution in the presence of various diamagnetic metal ions has been explored. Significant aspects of structures and spectroscopic properties have been discussed.


Fatal intentional drowning in Australia: A systematic literature review of rates and risk factors.
Unintentional drowning deaths are only part of the drowning profile, with little attention being paid to intentional drowning in Australia. Strategies for the prevention of intentional drowning deaths are likely to be different from unintentional. Quality documentation, analysis and dissemination of intentional deaths data is crucial for developing appropriate strategies for prevention. To conduct a systematic literature review to investigate the mortality rates and risk factors of intentional drowning deaths in Australia. A systematic search guided by PRISMA was performed using Ovid MEDLINE, CINAHL, PsycINFO (ProQuest), Scopus, Google Scholar, and BioMed Central databases to locate relevant original research articles published between 2007 and 2018. Ten papers reporting the mortality rates and risk factors of intentional drowning deaths in Australia published between 2007 and 2018, with study periods of the included articles spanning from 1907 to 2012, were reviewed. Most studies investigated suicidal drowning deaths in Australia, none reported homicidal drowning deaths. The downward trend of fatal suicide drowning was identified in Australia. The annual rate of intentional drowning between 1994 and 2012 can be inferred from eight studies, ranging from 0.06 to 0.21 for nation-wide mortality rates. The highest annual state-wide mortality rate was identified in the state of Queensland, ranging from 0.02 to 0.11 per 100,000 individuals. Of four studies examining the risk factors of fatal intentional drowning in Australia, being of older age groups, being female, and the presence of substance use were identified as important factors for suicidal drowning deaths. The national-scale proportion of suicide drowning in Australia, ranging from 2% to 3% of all intentional self-harm deaths, was also identified. Limited publications reporting the mortality rates and risk factors of intentional drowning deaths in Australia were identified. Being of older age groups and being female were recognised as factors for suicide drowning deaths, and psychoactive substances were widely identified amongst cases. Future research on improving death reporting systems and the legal framework for medico-legal death investigation, along with the investigation of the risk factors of intentional drowning, are required to inform the planning, implementation, and evaluation of prevention interventions for intentional drowning deaths in Australia.


Denaturing gradient gel electrophoresis used to monitor the enrichment culture of aerobic chemoorganotrophic bacteria from a hot spring cyanobacterial mat.
Previous studies investigating microbial diversity in the Octopus Spring cyanobacterial mat community (Yellowstone National Park) have shown a discrepancy between bacterial populations observed by molecular retrieval and cultivation techniques. To investigate how selective enrichment culture techniques affect species composition, we used denaturing gradient gel electrophoresis (DGGE) separation of PCR-amplified 16S rRNA gene fragments to monitor the populations contained within enrichment cultures of aerobic chemoorganotrophic bacteria from the ca. 50 degrees C region of the mat community. By varying the degree of dilution of the inoculum, medium composition, and enrichment conditions and duration and by analyzing the cultures by DGGE, we detected 14 unique 16S rRNA sequence types. These corresponded to alpha-, beta-, gamma-, and delta-proteobacteria, Thermus relatives, and gram-positive bacteria with high G + C ratio and, at the highest inoculum dilutions, Chloroflexus aurantiacus relatives, which were estimated to still be approximately 300 times less abundant than cells of the mat primary producer, Synechococcus spp. Only three of these populations were previously cultivated on solidified medium after similar enrichment. Only two of these population have 16S rRNA sequences which were previously cloned directly from the mat. These results reveal a diversity of bacterial populations in enrichment culture which were not detected by either molecular retrieval or strain purification techniques.


Toward photorealism in endoscopic sinus surgery simulation.
Endoscopic sinus surgery (ESS) is the surgical standard treatment for chronic rhinitis/rhinosinusitis and nasal polyposis. There is a reported complication rate of 5-10% associated with this type of surgery. Simulation has been advocated as a means to improve surgical training and minimize the rates of complication and medical error. This study aimed to show how a virtual reality ESS simulator was developed, with particular emphasis on achieving satisfactory photorealism and surgical verisimilitude. Sinus computed tomography scans were processed to create a triangle-based three-dimensional mesh model; this was incorporated into a spring-damper model of thousands of interconnected nodes, which is allowed to deform in response to user interactions. Dual haptic handpiece devices were programmed to simulate an endoscope and various surgical instruments. Textures and lighting effects were added to the mesh model to provide an accurate representation of the surgical field. Effects such as vasoconstriction in response to "virtual" decongestant were added. The final simulated endoscopic view of the sinuses accurately simulates the moist and glossy appearance of the sinuses. The interactive tissue simulation system enables the user to interactively cut and remove tissue while receiving accurate haptic feedback. A working prototype of the simulator has been developed that leverages recent advances in computer hardware to deliver a realistic user experience, both visually and haptically. This new computer-based training tool for practicing ESS provides a risk-free environment for surgical trainees to practice and develop core skills. The novel use of customized precision force feedback (haptic) devices enables trainees to use movements during training that closely mimic those used during the actual procedure, which we anticipate will improve learning, retention, and recall.


Comparison among model estimates of critical loads of acidic deposition using different sources and scales of input data.
The critical load (CL) of acidic atmospheric deposition represents the load of acidity deposited from the atmosphere to the earth's surface at which harmful acidification effects on sensitive biological receptors are thought to occur. In this study, the CL for forest soils was estimated for 27 watersheds throughout the United States using a steady-state mass balance approach based on both national and site-specific data and using different approaches for estimating base cation weathering. Results suggested that the scale and source of input data can have large effects on the calculated CL and that the most important parameter in the steady-state model used to estimate CL is base cation weathering. These results suggest that the data and approach used to estimate weathering must be robust if the calculated CL is to be useful for its intended purpose.


Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1.
The Myc oncoprotein is a transcriptional regulator whose function is essential for normal development. Myc is capable of binding to 10% of the mammalian genome, and it is unclear how a developing embryo controls the DNA binding of its abundant Myc proteins in order to avoid Myc's potential for inducing tumorigenesis. To identify chromatin binding proteins with a potential role in controlling Myc activity, we established a genetic assay for dMyc activity in Drosophila. We conducted a genome-wide screen using this assay, and identified the Trithorax Group protein Ash1 as a modifier of dMyc activity. Ash1 is a histone methyltransferase known for its role in opposing repression by Polycomb. Using RNAi in the embryo and Affymetrix microarrays, we show that ash1 RNAi causes the increased expression of many genes, suggesting that it is directly or indirectly required for repression in the embryo, in contrast to its known role in maintenance of activation. Many of these genes also respond similarly upon depletion of Pc and pho transcripts, as determined by concurrent microarray analysis of Pc and pho RNAi embryos, suggesting that the three are required for low levels of expression of a common set of targets. Further, many of these overlapping targets are also activated by Myc overexpression. We identify a second group of genes whose expression in the embryo requires Ash1, consistent with its previously established role in maintenance of activation. We find that this second group of Ash1 targets overlaps those activated by Myc and that ectopic Myc overcomes their requirement for Ash1. Genetic, genomic and chromatin immunoprecipitation data suggest a model in which Pc, Ash1 and Pho are required to maintain a low level of expression of embryonic targets of activation by Myc, and that this occurs, directly or indirectly, by a combination of disparate chromatin modifications.


Seven-coordinate lanthanide complexes with a tripodal redox active ligand: structural, electrochemical and spectroscopic investigations.
The tripodal ligand TREN-(3,5-di-tert-butylsalicylidene)3 (H3L) was synthesized and its tris(phenolato) lanthanide complexes L-Ln (Ln = NdIII, EuIII, TbIII, GdIII, ErIII, YbIII and LuIII) were prepared. The X-Ray crystal structures confirm that each metal ion resides in a similar monocapped octahedral geometry, excluding water molecules from the coordination sphere. The coordination bond distances are in agreement with the lanthanide contraction, with Ln-O bond lengths in the range 2.139-2.216 Å. The complexes show three reversible monoelectronic oxidation waves, which are assigned to the successive oxidation of the phenolate moieties to phenoxyl radicals. The L-Nd complex is the easiest to oxidize, with E = 0.11, E = 0.21 and E = 0.34 V vs. Fc+/Fc, due to the larger size of the lanthanide ion. The ΔE1/2 value (ΔE1/2 = E-E) is correlated to the lanthanide radius, with values of 0.10 V for L-Nd and 0.22 V for L-Lu. The monoradical species were persistent in solution, allowing for their characterisation. All exhibit a distinct absorption band at around 445 nm due to the phenoxyl π-π* transitions. The EPR spectrum of L-Lu+ consists of a single resonance at giso = 1.999, confirming the radical nature of the oxidized product. Most of the other complexes (L-Gd, L-Er, L-Yb) show a quenching of the LnIII-based resonances upon oxidation, indicative of magnetic interactions between the metal and the radical spins. The L-Ln (L = Nd, Er, Yb) complexes exhibit a metal-based luminescence upon excitation of the ligand. A significant quenching of the luminescence was observed upon radical formation: 92%, 83% and 79% respectively for L-Nd+, L-Er+ and L-Yb+.


Early increase in glomerular leucocyte number after a reduction in renal mass: implications for the pathogenesis of glomerulosclerosis.
1. Adult female Wistar rats underwent uninephrectomy (n = 8) through a flank incision, or a sham operation (n = 7). One to two weeks later the kidney was perfused in situ and glomeruli were isolated from cortical tissue by sequential sieving, and partially digested. Glomerular leucocytes were labelled with a mouse monoclonal antibody against leucocyte common antigen followed by a fluorescein-labelled anti-mouse immunoglobulin to allow counting. 2. In a further group of animals 24 h albumin excretion and glomerular size were measured 2 weeks after either uninephrectomy (n = 6) or sham operation (n = 6). 3. Glomerular leucocyte number was significantly increased in uninephrectomized animals (15.7 +/- 0.9 versus 8.9 +/- 0.4, P < 0.001), with some glomeruli having leucocyte numbers comparable with those seen in glomerulonephritis. 4. Albuminuria was not increased 2 weeks after uninephrectomy (233 +/- 35 versus 170 +/- 42 micrograms/24 h, not significant), and glomerular size was unchanged. Light microscopical appearance was normal. 5. An increase in glomerular leucocyte number is an early response in what was previously considered a non-immunological lesion. It precedes the development of renal scarring and may be important in the pathogenesis of this process.


Pharmacokinetic properties of artemether, dihydroartemisinin, lumefantrine, and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in Uganda.
Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.


Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.
In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.


Complete Genome Sequence of Pseudomonas stutzeri Type Strain SGAir0442, Isolated from Singapore Air Samples.
Pseudomonas stutzeri strain SGAir0442 was isolated from tropical air samples collected in Singapore. It is a Gram-negative denitrifying bacterium and an opportunistic human pathogen. Its complete genome consists of one chromosome of 4.52 Mb, containing 4,129 protein-coding genes, 12 rRNA subunits, and 62 tRNAs.


Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy.
Aging of white adipose tissue (WAT) is associated with reduced insulin sensitivity, which contributes to whole-body glucose intolerance. WAT aging in mice impairs cold-induced beige adipocyte recruitment (beiging), which has been attributed to the senescence of adipose progenitor cells. Tumor suppressor p53 has also been implicated in WAT aging. However, whether p53-related cellular aging in mature white adipocytes is causative of age-impaired WAT beiging remains unknown. It is also unclear whether transient p53 inhibition can rescue WAT beiging. Herein, we report that p53 increased in adipose tissues of 28-wk-old (aged) mice with impaired beiging capability. Cold exposure decreased p53 in beiging WAT of young mice but not in aged mice. In aged mice, inducible p53 ablation in differentiated adipocytes restored cold-induced WAT beiging and augmented whole-body energy expenditure and insulin sensitivity. Transient pharmacological inhibition of p53 led to the same beneficial effects. Mechanistically, cold exposure repressed autophagy in beiging WAT of young mice yet increased autophagy in aged WAT. p53-ablation reduced microtubule-associated protein light chain 3-mediated mitochondria clearance (mitophagy) and hence facilitated the increase of mitochondria during beiging. These findings suggest that p53-induced mitophagy in aged white adipocytes impedes WAT beiging and may be therapeutically targeted to improve insulin sensitivity in aged WAT.-Fu, W., Liu, Y., Sun, C., Yin, H. Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy.


First Report of Spot Type of Barley Net Blotch Caused by Pyrenophora teres f. sp. maculata in Uruguay.
In September 2003, leaves exhibiting spot-type lesions similar to those produced by Cochliobolus sativus Drechs. ex Dastur were widely observed in six commercial barley crops of cvs. Norteña Daymán, Norteña Carumbé, and MUSA 936 in Soriano and Río Negro provinces, the main barley production region in western Uruguay. Spot lesions were tan to dark brown, circular to elliptical, and 3 to 10 mm in diameter. Larger lesions were surrounded by a chlorotic margin of varying width. Affected leaf pieces (10 to 15) from each field were placed in a moist chamber for 2 days to promote sporulation. A fungus identified morphologically as Pyrenophora teres (Died.) Drechs. (1) was consistently isolated from infected leaves. However, symptoms did not correspond to the net-type lesions of net blotch commonly produced by P. teres f. sp. teres in Uruguay. Three monoconidial cultures were obtained by transferring single conidia to potato dextrose agar and then to 10% V8 juice agar and incubated at 20 to 22°C with a 12-h photoperiod for 10 days. Adding sterile water to each plate and gently rubbing the surface with a microscope slide prepared inoculum for pathogenicity tests. Conidia concentration was adjusted to 1 × 104 conidia per ml. Sixty-eight barley genotypes from Uruguay, ICARDA/CIMMYT, and North Dakota were grown in the greenhouse for 2 weeks at 20 to 22°C with a 14-h photoperiod. For each monoconidial isolate, three seedlings of each genotype were inoculated at the three-leaf stage 15 to 16 days after seeding with 0.4 ml of the inoculum suspension with an airbrush inoculator. A drop of Tween 20 was added per 40 ml of inoculum suspension. One set of each genotype was inoculated with sterile water as a control. Seedlings were placed in a dew chamber at 20°C and 100% relative humidity in the dark for 24 h and then returned to prior conditions. The first lesions developed after 7 to 9 days. Leaves two and three of the plants were visually rated for disease (3) 13 days after inoculation. Control plants were disease free. The most susceptible reactions were observed on cvs. Norteña Daymán, MUSA 936, and line CLE 230 (Uruguay). Symptoms were similar in shape and size to those observed in the fields. The most resistant infection types were observed on several Uruguayan and North Dakota advanced lines. The fungus was consistently reisolated from inoculated plants. On the basis of morphology and symptoms produced, the pathogen was identified (2) as P. teres. f. sp. maculata Smedeg. To our knowledge, this is the first report of this fungus causing spot-like symptoms of net blotch in Uruguay. References: (1) M. B. Ellis. Dematiaceous hyphomycetes, CABI, Oxon, UK, 1971. (2) V. Smedergaard-Petersen. Pages 124-144 in: R. Vet. Agr. Univ. Yearbook, Copenhagen, 1971. (3) A. Tekauz. Can. J. Plant Pathol.7:181, 1985.


Epigenetic reprogramming rewires transcription during the alternation of generations in Arabidopsis.
Alternation between morphologically distinct haploid and diploid life forms is a defining feature of most plant and algal life cycles, yet the underlying molecular mechanisms that govern these transitions remain unclear. Here, we explore the dynamic relationship between chromatin accessibility and epigenetic modifications during life form transitions in Arabidopsis. The diploid-to-haploid life form transition is governed by the loss of H3K9me2 and DNA demethylation of transposon-associated cis-regulatory elements. This event is associated with dramatic changes in chromatin accessibility and transcriptional reprogramming. In contrast, the global loss of H3K27me3 in the haploid form shapes a chromatin accessibility landscape that is poised to re-initiate the transition back to diploid life after fertilisation. Hence, distinct epigenetic reprogramming events rewire transcription through major reorganisation of the regulatory epigenome to guide the alternation of generations in flowering plants.


Inferomedial displacement of the meniscal free fragment: MR findings.
To define the accuracy of Magnetic Resonance (MR) in the diagnosis of inferomedial displacement of the meniscal fragment. The MR examinations of the knee performed between December 2002 and April 2004 on 676 patients (mean age 32 years) with knee trauma and subsequently subjected to arthroscopy were retrospectively reviewed to assess the presence of bucket-handle meniscal tear and inferomedial displacement of the meniscal free fragment. The MR examinations were performed using a superconductive 0.5 T MR unit with a transmitting/receiving coil dedicated for the extremities. The MR images were acquired with SE T1 and GE T2* sequences in the sagittal, coronal and axial planes with 3 mm thickness and 1 mm gap. The images were independently reviewed by two authors blinded to the arthroscopic findings. In case of disagreement, a third author, unaware of the arthroscopic findings, gave his judgment. On MR images a bucket-handle meniscal tear was identified in 54/676 patients. In 6 out of 54 patients, an inferomedial meniscal fragment displacement of the medial meniscus with associated inflammatory synovial reaction around the fragment was detected. In one case an associated inflammatory bursal reaction with effusion around the distal insertion of the medial homolateral collateral ligament was detected. All cases were confirmed by arthroscopy and no statistical differences between the two authors were observed. MR allows the detection of the inferomedial meniscal fragment displacement and a more correct planning of arthroscopy with a strong reduction of repeat interventions.


Necessity for LH in selection and continued growth of the bovine dominant follicle.
Previous research demonstrated that acute treatment with GnRH antagonist, Acyline, allowed follicle growth until ~8.5 mm and no dominant follicle was selected. This study evaluated whether deficient LH was the underlying mechanism for Acyline effects by replacing LH action, using human chorionic gonadotropin (hCG), during Acyline treatment. Holstein heifers (n = 24) during first follicular wave were evaluated by ultrasound and randomized into one of three treatments: Control (saline treatments), Acyline (5 µg/kg Acyline), or Acyline+hCG (Acyline plus 50 IU of hCG at start then 100 IU every 12 h). Pulses of LH were present in Control heifers (9 Pulses/10 h) but not during Acyline treatment. Data were normalized to the transition to diameter deviation (day 0; F1 ~7.5 mm). Diameter deviation of the largest (F1) and the second largest (F2) follicle was not observed in Acyline-treated heifers, whereas control heifers had decreased growth of F2 at F1 ~7.5 mm, indicating deviation. Selection of a single dominant follicle was restored by providing LH activity in Acyline+hCG heifers, as evidenced by F1 and F2 deviation, continued growth of F1, and elevated circulating estradiol. Separation of F1 and F2 occurred 12 h (~7.0 mm) earlier in Acyline+hCG heifers than Controls. Circulating FSH was greater in Acyline than Controls, but lower in Acyline+hCG than Controls after day 1.5. In conclusion, dominant follicle selection and growth after follicle deviation is due to LH action as shown by inhibition of this process during ablation of GnRH-stimulated LH pulses with Acyline and restoration of it after replacement of LH action by hCG treatment.


Vital dye labelling demonstrates a sacral neural crest contribution to the enteric nervous system of chick and mouse embryos.
We have used the vital dye, DiI, to analyze the contribution of sacral neural crest cells to the enteric nervous system in chick and mouse embryos. In order to label premigratory sacral neural crest cells selectively, DiI was injected into the lumen of the neural tube at the level of the hindlimb. In chick embryos, DiI injections made prior to stage 19 resulted in labelled cells in the gut, which had emerged from the neural tube adjacent to somites 29-37. In mouse embryos, neural crest cells emigrated from the sacral neural tube between E9 and E9.5. In both chick and mouse embryos, DiI-labelled cells were observed in the rostral half of the somitic sclerotome, around the dorsal aorta, in the mesentery surrounding the gut, as well as within the epithelium of the gut. Mouse embryos, however, contained consistently fewer labelled cells than chick embryos. DiI-labelled cells first were observed in the rostral and dorsal portion of the gut. Paralleling the maturation of the embryo, there was a rostral-to-caudal sequence in which neural crest cells populated the gut at the sacral level. In addition, neural crest cells appeared within the gut in a dorsal-to-ventral sequence, suggesting that the cells entered the gut dorsally and moved progressively ventrally. The present results resolve a long-standing discrepancy in the literature by demonstrating that sacral neural crest cells in both the chick and mouse contribute to the enteric nervous system in the postumbilical gut.


Implementing evidence-based recommended practices for the management of patients with mild traumatic brain injuries in Australian emergency care departments: study protocol for a cluster randomised controlled trial.
Mild head injuries commonly present to emergency departments. The challenges facing clinicians in emergency departments include identifying which patients have traumatic brain injury, and which patients can safely be sent home. Traumatic brain injuries may exist with subtle symptoms or signs, but can still lead to adverse outcomes. Despite the existence of several high quality clinical practice guidelines, internationally and in Australia, research shows inconsistent implementation of these recommendations. The aim of this trial is to test the effectiveness of a targeted, theory- and evidence-informed implementation intervention to increase the uptake of three key clinical recommendations regarding the emergency department management of adult patients (18 years of age or older) who present following mild head injuries (concussion), compared with passive dissemination of these recommendations. The primary objective is to establish whether the intervention is effective in increasing the percentage of patients for which appropriate post-traumatic amnesia screening is performed. The design of this study is a cluster randomised trial. We aim to include 34 Australian 24-hour emergency departments, which will be randomised to an intervention or control group. Control group departments will receive a copy of the most recent Australian evidence-based clinical practice guideline on the acute management of patients with mild head injuries. The intervention group will receive an implementation intervention based on an analysis of influencing factors, which include local stakeholder meetings, identification of nursing and medical opinion leaders in each site, a train-the-trainer day and standardised education and interactive workshops delivered by the opinion leaders during a 3 month period of time. Clinical practice outcomes will be collected retrospectively from medical records by independent chart auditors over the 2 month period following intervention delivery (patient level outcomes). In consenting hospitals, eligible patients will be recruited for a follow-up telephone interview conducted by trained researchers. A cost-effectiveness analysis and process evaluation using mixed-methods will be conducted. Sample size calculations are based on including 30 patients on average per department. Outcome assessors will be blinded to group allocation. Australian New Zealand Clinical Trials Registry ACTRN12612001286831 (date registered 12 December 2012).


Prior knowledge driven Granger causality analysis on gene regulatory network discovery.
Our study focuses on discovering gene regulatory networks from time series gene expression data using the Granger causality (GC) model. However, the number of available time points (T) usually is much smaller than the number of target genes (n) in biological datasets. The widely applied pairwise GC model (PGC) and other regularization strategies can lead to a significant number of false identifications when n>>T. In this study, we proposed a new method, viz., CGC-2SPR (CGC using two-step prior Ridge regularization) to resolve the problem by incorporating prior biological knowledge about a target gene data set. In our simulation experiments, the propose new methodology CGC-2SPR showed significant performance improvement in terms of accuracy over other widely used GC modeling (PGC, Ridge and Lasso) and MI-based (MRNET and ARACNE) methods. In addition, we applied CGC-2SPR to a real biological dataset, i.e., the yeast metabolic cycle, and discovered more true positive edges with CGC-2SPR than with the other existing methods. In our research, we noticed a " 1+1>2" effect when we combined prior knowledge and gene expression data to discover regulatory networks. Based on causality networks, we made a functional prediction that the Abm1 gene (its functions previously were unknown) might be related to the yeast's responses to different levels of glucose. Our research improves causality modeling by combining heterogeneous knowledge, which is well aligned with the future direction in system biology. Furthermore, we proposed a method of Monte Carlo significance estimation (MCSE) to calculate the edge significances which provide statistical meanings to the discovered causality networks. All of our data and source codes will be available under the link https://bitbucket.org/dtyu/granger-causality/wiki/Home.


Do more with less: a surgery directed institutional model for resident central line training.
Simulation training can improve proficiency in central line placement, but it is expensive and resource intensive. The authors developed a 3-phase approach to central venous catheter placement training, including an online module, mannequin-based simulation using a single faculty member, followed by department directed clinical observation. The hypothesis was that standardizing institutional central venous catheter placement training would maintain training efficiency and reduce faculty and resource demands. Preintervention and postintervention assessments of the trainees' performance were collected to evaluate program effectiveness. Program surveys were collected to evaluate residents' satisfaction and comfort with the procedure. Resource utilization was compared between the period before program implementation and the 2 following years. Mean pretest to posttest scores for the online module improved significantly from 7.0 to 8.4 in 2010 and from 7.1 to 8.4 in 2011. Video evaluation demonstrated significant improvement across all postgraduate year levels. Surveys revealed high resident satisfaction and increased procedural confidence. Overall resource costs and faculty requirements decreased. A standardized training program for an entire institution can maintain quality while being more cost effective than traditional central venous catheter placement training.


Changing the culture around end-of-life care in the trauma intensive care unit.
Ten percent to 20% of trauma patients admitted to the intensive care unit (ICU) will die from their injuries. Providing appropriate end-of-life care in this setting is difficult and often late in the patients' course. Patients are young, prognosis uncertain, and conflict common around goals of care. We hypothesized that early, structured communication in the trauma ICU would improve end-of-life care practice. Prospective, observational, prepost study on consecutive trauma patients admitted to the ICU before and after a structured palliative care intervention was integrated into standard ICU care. The program included part I, early (at admission) family bereavement support, assessment of prognosis, and patient preferences, and part II (within 72 hours) interdisciplinary family meeting. Data on goals of care discussions, do-not-resuscitate (DNR) orders and withdrawal of life support (W/D) were collected from physician rounds, family meetings, and medical records. Eighty-three percent of patients received part I and 69% part II intervention. Discussion of goals of care by physicians on rounds increased from 4% to 36% of patient-days. During intervention, rates of mortality (14%), DNR (43%), and W/D (24%) were unchanged, but DNR orders and W/D were instituted earlier in hospital course. ICU length of stay was decreased in patients who died. Structured communication between physician and families resulted in earlier consensus around goals of care for dying trauma patients. Integration of early palliative care alongside aggressive trauma care can be accomplished without change in mortality and has the ability to change the culture of care in the trauma ICU.


Terahertz birefringence for orientation analysis.
A terahertz time-domain spectrometer is employed to study different birefringent samples. We develop a method based on the temporal waveform and the impulse response of a sample to map the anisotropy of their inner structure. To validate our algorithm, we study the polarization-affecting structure of various classes of materials such as crystals, plastics, and natural products. Among all samples we observe the largest birefringence for a rutile crystal with Deltan=3.3 at 1 THz.


Evaluation of IL-28B polymorphisms and serum IP-10 in hepatitis C infected chimpanzees.
In humans, clearance of hepatitis C virus (HCV) infection is associated with genetic variation near the IL-28B gene and the induction of interferon-stimulated genes, like IP-10. Also in chimpanzees spontaneous clearance of HCV is observed. To study whether similar correlations exist in these animals, a direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients was performed. All chimpanzees studied were monomorphic for the human IL-28B SNPs which are associated with spontaneous and treatment induced HCV clearance in humans. As a result, these particular SNPs cannot be used for clinical association studies in chimpanzees. Although these human SNPs were absent in chimpanzees, gene variation in this region was present however, no correlation was observed between different SNP-genotypes and HCV outcome. Strikingly, IP-10 levels in chimpanzees correlated with HCV-RNA load and γGT, while such correlations were not observed in humans. The correlation between IP-10, γGT and virus load in chimpanzees was not found in patients and may be due to the lack of lifestyle-related confounding factors in chimpanzees. Direct comparison of IP-10 and IL-28B polymorphism between chimpanzees and patients in relation to HCV infection, illustrates that the IFN-pathways are important during HCV infection in both species. The Genbank EMBL accession numbers assigned to chimpanzees specific sequences near the IL-28B gene are HE599784 and HE599785.


Surgical choroidal neovascular membrane removal in the era of anti-vascular endothelial growth factor agents.
Intravitreal anti-vascular endothelial growth factor (VEGF) agents have obtained acceptance as the mainstay in the management strategy of subfoveal choroidal neovascular membranes (CNVM) due to varying etiologies. Few drawbacks include need for repeated intravitreal injections, with its adjunct risks, and the lack of a predefined treatment end point, which can cause doubts and uncertainty in the mind of the patient. Furthermore, it remains a significant financial burden for the patient. Herein we report our data of three patients who were reluctant for further re-injections of anti-VEGF agents and were therefore offered surgical removal of the CNVM by submacular surgery as an alternative treatment plan.


Nucleotide sequence of ub52 from the cnidarian Acropora millepora reveals high evolutionary conservation.
We report the cDNA sequence encoding Ub52 from the cnidarian Acropora millepora. As in other eukaryotes, the N-terminal region of the deduced amino-acid sequence is a ubiquitin moiety and the C-terminal region CEP52, a protein component of the large ribosomal subunit. A millepora Ub52 is highly homologous (> 95% identical) with the corresponding Drosophila and vertebrate sequences, the cnidarian sequence having higher identity with these 'higher' metazoan homologs than does the corresponding Caenorhabditis elegans protein. However, the cnidarian sequence contains two unique substitutions in the ubiquitin moiety, Ser22 and Thr28. Northern analysis indicates that A. millepora Ub52 is encoded by a small (< 800 nt) mRNA present in eggs and is first expressed after the early gastrula stage in embryonic development.


Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency.
Human phosphofructokinase (PFK; EC 126.96.36.199) exists in tetrameric isozymic forms. Muscle and liver contain the homotetramers M4 and L4, whereas erythrocytes contain five isozymes composed of M (muscle) and L (liver) subunits, i.e., M4, M3L, M2L2, ML3, and L4. Inherited defects of erythrocyte PFK are usually partial and are described in association with heterogeneous clinical syndromes. To define the molecular basis and pathogenesis of this enzymopathy, we investigated four unrelated individuals manifesting myopathy and hemolysis (glycogenosis type VII), isolated hemolysis, or no symptoms at all. The three symptomatic patients showed high-normal hemoglobin levels, despite hemolysis and early-onset hyperuricemia. They showed total lack of muscle-type PFK and suffered from exertional myopathy of varying severity. In the erythrocytes, a metabolic crossover was evident at the PFK step: the levels of hexose monophosphates were elevated and those of 2,3-diphosphoglycerate (2,3-DPG) were depressed, causing strikingly increased hemoglobin-oxygen affinity. In all cases, the residual erythrocyte PFK consisted exclusively of L4 isozyme, indicating homozygosity for the deficiency of the catalytically active M subunit. However, presence of immunoreactive M subunit was shown in cultured fibroblasts by indirect immunofluorescence with monoclonal anti-M antibody. The fourth individual was completely asymptomatic, had normal erythrocyte metabolism, and had no evidence of hemolysis. His residual erythrocyte PFK showed a striking decrease of the L4, ML3, and M2L2 isozymes, secondary to a mutant unstable L subunit. Identical alterations of erythrocyte PFK were found in his asymptomatic son, indicating heterozygosity for the mutant unstable L subunit in this kindred. These studies show that, except for the varying severity of the myopathic symptoms, glycogenosis type VII has highly uniform clinical and biochemical features and results from homozygosity for mutant inactive M subunit(s). The absence of anemia despite hemolysis may be explained by the low 2,3-DPG levels. The hyperuricemia may result from hyperactivity of the hexose monophosphate shunt. In contrast, the clinically silent carrier state results from heterozygosity for mutant M or L subunit. Of the two, the M subunit appears to be more critical for adequate glycolytic flux in the erythrocyte, since its absence is correlated with hemolysis.


Espresso coffee consumption and risk of coronary heart disease in a large Italian cohort.
The relationship between coffee consumption and coronary heart disease (CHD) has been investigated in several studies with discrepant results. We examined the association between Italian-style (espresso and mocha) coffee consumption and CHD risk. We investigated 12,800 men and 30,449 women without history of cardiovascular disease recruited to the EPICOR prospective cohort study. Coffee consumption was assessed at baseline. In a random sub-cohort of 1472 subjects, plasma triglycerides, and total, LDL and HDL cholesterol were determined to investigate the effect of coffee consumption on plasma lipids. After a mean follow up of 10.9 years, 804 cases of CHD (500 acute events, 56 fatal events and 248 revascularizations, all first events) were identified. Multivariable adjusted hazard ratios for CHD were: 1.18 (95% CI 0.87-1.60) for drinking 1-2 cups/day, 1.37 (95% CI 1.03-1.82) for >2-4 cups/day and 1.52 (95% CI 1.11-2.07) for over 4 cups/day (P trend <0.001) compared to reference (<1 cup/day). Plasma triglycerides, and total, LDL and HDL cholesterol did not vary significantly (ANOVA) with coffee consumption. Consumption of over 2 cups/day of Italian-style coffee is associated with increased CHD risk, but coffee consumption was not associated with plasma lipid changes, so the adverse effect of consumption appears unrelated to lipid profile.


Direct Participation in and Indirect Exposure to the Occupy Central Movement and Depressive Symptoms: A Longitudinal Study of Hong Kong Adults.
Despite the extensive history of social movements around the world, the evolution of population mental health before, during, and after a social movement remains sparsely documented. We sought to assess over time the prevalence of depressive symptoms during and after the Occupy Central movement in Hong Kong and to examine the associations of direct and indirect exposures to Occupy Central with depressive symptoms. We longitudinally administered interviews to 909 adults who were randomly sampled from the population-representative FAMILY Cohort at 6 time points from March 2009 to March 2015: twice each before, during, and after the Occupy Central protests. The Patient Health Questionnaire-9 was used to assess depressive symptoms and probable major depression (defined as Patient Health Questionnaire-9 score ≥10). The absolute prevalence of probable major depression increased by 7% after Occupy Central, regardless of personal involvement in the protests. Higher levels of depressive symptoms were associated with online and social media exposure to protest-related news (incidence rate ratio (IRR) = 1.28, 95% confidence interval (CI): 1.06, 1.55) and more frequent Facebook use (IRR = 1.38, 95% CI: 1.12, 1.71). Higher levels of intrafamilial sociopolitical conflict was associated with more depressive symptoms (IRR = 1.05, 95% CI: 1.01, 1.09). The Occupy Central protests resulted in substantial and sustained psychological distress in the community.


Endoscopic sump syndrome secondary to EUS-guided choledocho-duodenostomy with a lumen-apposing metal stent.
Sump syndrome (SS) is associated with choledocho-duodenostomy (CDD) dysfunction, which occurs due to accumulation of detritus, biliary mud and food remains in the suprapapillary distal common bile duct. The prevalence is low after CDD. Currently, biliary drainage endoscopic ultrasound (EUS)-guided with a lumen-apposing metal stent (LAMS) is a new minimally invasive alternative for biliary stenosis for patients in whom endoscopy retrograde cholangial-pancreatography (ERCP) is not feasible. CDD via EUS-guided LAMS is increasing. Thus, SS has become a potential associated complication that was previously unreported in the literature.


O(6)-methylguanine-DNA methyltransferase in equine sarcoids: molecular and epigenetic analysis.
Bovine papillomaviruses (BPVs) types 1 and 2 are the only known papillomaviruses able to jump the species. In fact, BPVs 1/2 induce neoplasia in their natural bovine host but infection is also associated to neoplastic skin lesions in equids termed sarcoids. The equine sarcoid is considered to be the most common equine cutaneous tumour worldwide for which no effective therapy is available. Very little is known about the molecular mechanisms underlying tumourigenesis, although genes contributing to sarcoid development have been identified. Several studies associate the development of cancer to the loss of function of a number of oncosuppressor genes. In this study the putative role of O6-methylguanine-DNA methyltrasferase (MGMT) was investigated for sarcoids. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissues. In addition, the DNA methylation profile was analysed to assess the role of epigenetic mechanism in regulation of MGMT expression. A group of 15 equine sarcoids and two primary sarcoid cell lines (fibroblasts) were analyzed for the expression of MGMT protein by immunohistochemistry, immunofluorescence and Western blotting techniques. The sarcoid cell line EqSO4b and the tumour samples showed a reduction or absence of MGMT expression. To investigate the causes of deregulated MGMT expression, ten samples were analyzed for the DNA methylation profile of the CpG island associated to the MGMT promoter. The analysis of 73 CpGs encompassing the region of interest showed in 1 out of 10 (10%) sarcoids a pronouncedly altered methylation profile when compared to the control epidermal sample. Similarily the EqSO4b cell line showed an altered MGMT methylation pattern in comparison to normal fibroblasts. As previously demonstrated for the oncosuppressor gene FHIT, analysis of MGMT expression in sarcoid tissues and a sarcoid-derived fibroblast cell line further suggests that oncosuppressor silencing may be also involved in BPV-induced equine tumours. Abnormal DNA methylation seems to be one of the possible molecular mechanisms involved in the alteration of MGMT expression. Further studies are required to address other basic molecular mechanisms involved in reduced MGMT expression. This study underlines the possible role of DNA methylation in oncosuppressor inactivation in equine sarcoids.


What happens to the rectus abdominus fascia after laparoscopic ventral hernia repair?
One criticism of laparoscopic ventral hernia repair (LVH) is that the rectus muscles are not re-approximated to the midline, and the effect of LVH repair on the fascial edges is unclear. Progressive migration of the fascial edges toward the midline has been observed anecdotally, but objective evidence remains limited. The purpose of this study is to observe the effect of LVH repair on the rectus abdominus fascia. Patients undergoing LVH repair with defects > 10 cm in horizontal diameter were identified prospectively and enrolled. All were repaired laparoscopically with intraperitoneal placement of mesh (DualMesh, W.L. Gore and Associates) using a standard approach. Radio-opaque clips were placed at the fascial edges intraoperatively to mark the defect, and plain abdominal films were taken postoperatively (Time 1) to establish the initial distance between clips (measured in cm). A subsequent follow-up film was taken (Time 2), and the difference in clip distance per patient was recorded. Results were analyzed using a chi-squared test. Twelve patients qualified for analysis and their results were compared. Mean fascial defect size was 15.1 cm (range 8.3-22.0). With respect to change in clip distance from Times 1 to 2, three events were observed: (1) Diminished (i.e. medialized), (2) Enlarged, or (3) No Change. Ten patients (83%) medialized, one patient enlarged, and one patient showed no change (chi2 (d.f. = 2) 9.17, p < 0.0023). Medialization of the rectus abdominus fascia occurs in the majority of patients undergoing LVH repair. Causes for this phenomenon are unclear: however eliminating intrabdominal pressure with intraperitoneal mesh placement likely plays a role.


Partial-wave microscopic spectroscopy detects subwavelength refractive index fluctuations: an application to cancer diagnosis.
Existing optical imaging techniques offer us powerful tools to directly visualize the cellular structure at the microscale; however, their capability of nanoscale sensitivity is restricted by the diffraction-limited resolution. We show that the mesoscopic light transport theory analysis of the spectra of partial waves propagating within a weakly disordered medium, such as biological cells [i.e., partial wave spectroscopy (PWS)] quantifies refractive index fluctuations at subdiffractional length scales. We validate this nanoscale sensitivity of PWS using experiments with nanostructured models. We also demonstrate the potential of this technique to detect nanoscale alterations in cells from patients with pancreatic cancer who are otherwise classified as normal by conventional microscopic histopathology.


Adherence to long-term surveillance mammography among women with ductal carcinoma in situ treated with breast-conserving surgery.
PURPOSE Breast-conserving surgery (BCS) is an effective treatment for ductal carcinoma in situ (DCIS) but women who undergo BCS remain at risk for recurrences. Whether mammographic surveillance after BCS occurs and by whom is not known. METHODS We reviewed medical records of women diagnosed with DCIS between 1990 and 2001 and treated with BCS. Using descriptive statistics, generalized estimating, and logistic regression modeling, we examined the rates and predictors of surveillance mammography over a 10-year period after BCS. Results The cohort included 3,037 women observed for a median of 4.8 years (range, 0.5 to 15.7). Of the 2,676 women observed for at least 1 year after BCS, most (79%) had at least one surveillance mammogram during the first year of follow-up; 69% in year 5 and 61% in year 10. Among those observed for 5 years, surveillance mammograms were more likely among women age 60 to 69 years (odds ratio [OR], 1.72; 95% CI, 1.26 to 2.34), users of menopausal hormone therapy at diagnosis (OR, 1.26; 95% CI, 1.01 to 1.57) as well as those treated with adjuvant radiation (OR, 1.28; 95% CI, 1.08 to 1.53) and adjuvant radiation with tamoxifen (OR, 1.61; 95% CI, 1.13 to 2.30). Surveillance mammograms were less likely among obese women (OR, 0.70; 95% CI, 0.56 to 0.86). The findings were similar among women observed for 10 years. Only 34% and 15% of women observed for 5 and 10 years, respectively, had a surveillance mammogram during each year of follow-up. CONCLUSION Surveillance mammography after BCS among insured women with DCIS often did not occur yearly and declined over time after treatment. Patients and providers must remain vigilant about surveillance after BCS.


Functional organization of ganglion cells in the salamander retina.
Recently, we reported a novel technique for recording all of the ganglion cells in a retinal patch and showed that their receptive fields cover visual space roughly 60 times over in the tiger salamander. Here, we carry this analysis further and divide the population of ganglion cells into functional classes using quantitative clustering algorithms that combine several response characteristics. Using only the receptive field to classify ganglion cells revealed six cell types, in agreement with anatomical studies. Adding other response measures served to blur the distinctions between these cell types rather than resolve further classes. Only the biphasic off type had receptive fields that tiled the retina. Even when we attempted to split these classes more finely, ganglion cells with almost identical functional properties were found to have strongly overlapping spatial receptive fields. A territorial spatial organization, where ganglion cell receptive fields tend to avoid those of other cells of the same type, was only found for the biphasic off cell. We further studied the functional segregation of the ganglion cell population by computing the amount of visual information shared between pairs of cells under natural movie stimulation. This analysis revealed an extensive mixing of visual information among cells of different functional type. Together, our results indicate that the salamander retina uses a population code in which every point in visual space is represented by multiple neurons with subtly different visual sensitivities.


Quantifying the regression to the mean effect in Poisson processes.
Regression to the mean (RTM) can occur whenever an extreme observation is selected from a population and a later observation is closer to the population mean. A consequence of this phenomenon is that natural variability can be mistaken as real change. Simple expressions are available to quantify RTM when the underlying distribution is bivariate normal. However, there are many real-world situations, which are better approximated as a Poisson process. Examples include the number of hard disk failures during a year, the number of cargo ships damaged by waves, daily homicide counts in California, and the number of deaths per quarter attributable to acquired immune deficiency syndrome in Australia. In this paper, we derive expressions for quantifying RTM effects for the bivariate Poisson distribution for both the homogeneous and inhomogeneous cases. Statistical properties of our derivations have been evaluated through a simulation study. The asymptotic distributions of RTM estimators have been derived. The RTM effect for the number of people killed in road accidents in different regions of New South Wales (Australia) is estimated using maximum likelihood.


New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.