Health information technology and digital innovation for national learning health and care systems.
Health information technology can support the development of national learning health and care systems, which can be defined as health and care systems that continuously use data-enabled infrastructure to support policy and planning, public health, and personalisation of care. The COVID-19 pandemic has offered an opportunity to assess how well equipped the UK is to leverage health information technology and apply the principles of a national learning health and care system in response to a major public health shock. With the experience acquired during the pandemic, each country within the UK should now re-evaluate their digital health and care strategies. After leaving the EU, UK countries now need to decide to what extent they wish to engage with European efforts to promote interoperability between electronic health records. Major priorities for strengthening health information technology in the UK include achieving the optimal balance between top-down and bottom-up implementation, improving usability and interoperability, developing capacity for handling, processing, and analysing data, addressing privacy and security concerns, and encouraging digital inclusivity. Current and future opportunities include integrating electronic health records across health and care providers, investing in health data science research, generating real-world data, developing artificial intelligence and robotics, and facilitating public-private partnerships. Many ethical challenges and unintended consequences of implementation of health information technology exist. To address these, there is a need to develop regulatory frameworks for the development, management, and procurement of artificial intelligence and health information technology systems, create public-private partnerships, and ethically and safely apply artificial intelligence in the National Health Service.


Neuroimaging overuse is more common in Medicare compared with the VA.
To inform initiatives to reduce overuse, we compared neuroimaging appropriateness in a large Medicare cohort with a Department of Veterans Affairs (VA) cohort. Separate retrospective cohorts were established in Medicare and in VA for headache and neuropathy from 2004 to 2011. The Medicare cohorts included all patients enrolled in the Health and Retirement Study (HRS) with linked Medicare claims (HRS-Medicare; n = 1,244 for headache and 998 for neuropathy). The VA cohorts included all patients receiving services in the VA (n = 93,755 for headache and 183,642 for neuropathy). Inclusion criteria were age over 65 years and an outpatient visit for incident neuropathy or a primary headache. Neuroimaging use was measured with Current Procedural Terminology codes and potential overuse was defined using published criteria for use with administrative data. Increasingly specific appropriateness criteria excluded nontarget conditions for which neuroimaging may be appropriate. For both peripheral neuropathy and headache, potentially inappropriate imaging was more common in HRS-Medicare compared with the VA. Forty-nine percentage of all headache patients received neuroimaging in HRS-Medicare compared with 22.1% in the VA (p < 0.001) and differences persist when analyzing more specific definitions of overuse. A total of 23.7% of all HRS-Medicare incident neuropathy patients received neuroimaging compared with 9.0% in the VA (p < 0.001), and the difference persisted after excluding nontarget conditions. Overuse of neuroimaging is likely less common in the VA than in a Medicare population. Better understanding the reasons for the more selective use of neuroimaging in the VA could help inform future initiatives to reduce overuse of diagnostic testing.


The mediating role of coping strategy in the association between family functioning and nonsuicidal self-injury among Taiwanese adolescents.
Nock's (2009) integrated theoretical model suggests that both intrapersonal and interpersonal factors contribute to the development of nonsuicidal self-injury (NSSI). Based on this model, the present study examined the roles of family functioning and coping strategy in predicting NSSI, as well as the mediating effect of coping strategy in the relationship between family functioning and NSSI. Gender differences on the associations of these variables were also examined. A sample of 1,989 secondary school students (52.0% females) in Taiwan was assessed by self-report measures of perceived family functioning, coping strategy, and NSSI. Results showed that both family functioning and avoidance/emotion-focused coping strategy predicted NSSI. Additionally, the association between family functioning and NSSI was mediated by avoidance/emotion-focused coping strategy. Gender differences were not found on the associations among these study variables. These data provided evidences that the Nock's (2009) integrated theoretical model may help to explain how coping strategy mediates the effect of family functioning on NSSI. The implications of the findings for future research and intervention were discussed.


Intervening in global markets to improve access to HIV/AIDS treatment: an analysis of international policies and the dynamics of global antiretroviral medicines markets.
Universal access to antiretroviral therapy (ART) in low- and middle-income countries faces numerous challenges: increasing numbers of people needing ART, new guidelines recommending more expensive antiretroviral (ARV) medicines, limited financing, and few fixed-dose combination (FDC) products. Global initiatives aim to promote efficient global ARV markets, yet little is known about market dynamics and the impact of global policy interventions. We utilize several data sources, including 12,958 donor-funded, adult first-line ARV purchase transactions, to describe the market from 2002-2008. We examine relationships between market trends and: World Health Organization (WHO) HIV/AIDS treatment guidelines; WHO Prequalification Programme (WHO Prequal) and United States (US) Food and Drug Administration (FDA) approvals; and procurement policies of the Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM), US President's Emergency Plan for AIDS Relief (PEPFAR) and UNITAID. WHO recommended 7, 4, 24, and 6 first-line regimens in 2002, 2003, 2006 and 2009 guidelines, respectively. 2009 guidelines replaced a stavudine-based regimen ($88/person/year) with more expensive zidovudine- ($154-260/person/year) or tenofovir-based ($244-465/person/year) regimens. Purchase volumes for ARVs newly-recommended in 2006 (emtricitabine, tenofovir) increased >15-fold from 2006 to 2008. Twenty-four generic FDCs were quality-approved for older regimens but only four for newer regimens. Generic FDCs were available to GFATM recipients in 2004 but to PEPFAR recipients only after FDA approval in 2006. Price trends for single-component generic medicines mirrored generic FDC prices. Two large-scale purchasers, PEPFAR and UNITAID, together accounted for 53%, 84%, and 77% of market volume for abacavir, emtricitabine, and tenofovir, respectively, in 2008. PEPFAR and UNITAID purchases were often split across two manufacturers. Global initiatives facilitated the creation of fairly efficient markets for older ARVs, but markets for newer ARVs are less competitive and slower to evolve. WHO guidelines shape demand, and their complexity may help or hinder achievement of economies of scale in pharmaceutical manufacturing. Certification programs assure ARV quality but can delay uptake of new formulations. Large-scale procurement policies may decrease the numbers of buyers and sellers, rendering the market less competitive in the longer-term. Global policies must be developed with consideration for their short- and long-term impact on market dynamics.


A pathway for tumor necrosis factor-alpha-induced Bcl10 nuclear translocation. Bcl10 is up-regulated by NF-kappaB and phosphorylated by Akt1 and then complexes with Bcl3 to enter the nucleus.
Bcl10 overexpression and nuclear translocation were originally identified in mucosa-associated lymphoid tissue lymphoma with t(1;14)(p32;q32) chromosome translocation. DNA amplification of Bcl10 was also found in other solid tumors. We have recently shown that nuclear translocation of Bcl10 is a specific molecular determinant of Helicobacter pylori-independent mucosa-associated lymphoid tissue lymphoma (Kuo, S.-H., Chen, L. T., Yeh, K.-H., Wu, M. S., Hsu, H. C., Yeh, P. Y., Mao, T. L., Chen, C. L., Doong, S. L., Lin, J. T., and Cheng, A.-L. (2004) J. Clin. Oncol. 22, 3491-3497). However, the molecular mechanism of Bcl10 nuclear translocation remains unknown. In this study, we observed that tumor necrosis factor-alpha (TNFalpha) up-regulates the expression of Bcl10 and induces a fraction of Bcl10 nuclear translocation in human breast carcinoma MCF7 cells. Chromatin immunoprecipitation assays and electrophoretic mobility shift assays indicated that an NF-kappaB-binding site resides in the Bcl10 5 '-untranslated region. This study also demonstrates that Akt1, activated by TNFalpha, phosphorylates Bcl10 at Ser218 and Ser231 and that phosphorylated Bcl10 subsequently complexes with Bcl3 to enter the nucleus. Either inhibition of Akt1 or depletion of Bcl3 blocks Bcl10 nuclear translocation. In summary, these findings characterize a molecular linkage that directs Bcl10 nuclear translocation in response to TNFalpha treatment.


Removing constraints to sustainable food production: new ways to exploit secondary metabolism from companion planting and GM.
The entire process of agricultural and horticultural food production is unsustainable as practiced by current highly intensive industrial systems. Energy consumption is particularly intensive for cultivation, and for fertilizer production and its incorporation into soil. Provision of nitrogen contributes a major source of the greenhouse gas, N2 O. All losses due to pests, diseases and weeds are of food for which the carbon footprint has already been committed and so crop protection becomes an even greater concern. The rapidly increasing global need for food and the aggravation of associated problems by the effects of climate change create a need for new and sustainable crop protection. The overall requirement for sustainability is to remove seasonal inputs, and consequently all crop protection will need to be delivered via the seed or other planting material. Although genetic modification (GM) has transformed the prospects of sustainable crop protection, considerably more development is essential for the realisation of the full potential of GM and thereby consumer acceptability. Secondary plant metabolism offers wider and perhaps more robust new crop protection via GM and can be accomplished without associated yield loss because of the low level of photosynthate diverted for plant defence by secondary metabolism. Toxic mechanisms can continue to be targeted but exploiting non-toxic regulatory and signalling mechanisms should be the ultimate objective. There are many problems facing these proposals, both technical and social, and these are discussed but it is certainly not possible to stay where we are in terms of sustainability. The evidence for success is mounting and the technical opportunities from secondary plant metabolism are discussed here. © 2019 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Effect of chronic hydroxychloroquine use on COVID-19 risk in patients with rheumatoid arthritis and systemic lupus erythematosus: a multicenter retrospective cohort.
Hydroxychloroquine (HCQ) has been used during the coronavirus disease 2019 (COVID-19) pandemic because of its reported anti-viral activity. This study examined the association of chronic HCQ use with the incidence and complications of COVID-19. This retrospective cohort study included adults with rheumatoid arthritis and/or systemic lupus erythematosus who visited rheumatology clinics in three tertiary hospitals in Riyadh, Saudi Arabia between January 2019 and December 2020. Patients were categorized into two groups based on HCQ use. Data were obtained from the electronic health record and by interviews with patients. The primary study objective was the incidence of COVID-19 and its complications from March 2020 to February 2021. Almost 11% of the study cohort was positive for COVID-19, and the incidence of COVID-19 was similar between HCQ users (11.11%) and nonusers (10.86%). Disease complication rates were similar in the study arms, and they mainly included fever, dry cough, fatigue, and breathing difficulty. This study revealed no significant association between chronic HCQ use and the incidence of COVID-19, and disease complications were similar in the study arms.


Oxidative damage in unfertilized eggs of Chinese rare minnow (Gobiocypris rarus) exposed to nonylphenol.
In the present study, female Chinese rare minnows (Gobiocypris rarus) were used as in vivo models and exposed to nonylphenol (NP) at concentrations of 1 to 200 microg/L for 21 d under semistatic conditions. Molecular biomarkers of oxidative stress were measured in unfertilized eggs and included reactive oxygen species (ROS), lipid peroxidation products (thiobarbituric acid- reactive substances [TBARS] and protein carbonyl), superoxide dismutase activity, and glutathione. Cathepsin D activity as an indicator of egg viability also was assayed. Nonylphenol induced ROS formation in unfertilized eggs in all exposed groups compared to the controls. The levels of protein carbonyl and TBARS in unfertilized eggs were significantly increased (p < 0.05) at 10 to 200 and 100 to 200 microg/L, respectively. Good positive correlations were shown between ROS induction and levels of TBARS and protein carbonyl in eggs (R = 0.918, p < 0.05 and R = 0.784, p < 0.05, respectively). Superoxide dismutase activity in eggs was significantly inhibited (p < 0.05) in the 50 to 200 microg/L exposure groups. Glutathione levels in eggs were significantly depleted (p < 0.05) at 100 to 200 microg/L concentrations. In addition, ROS induction resulted in oxidative damage to lipid and protein in chorions. Significant reductions (p < 0.05) of the protein and lipid contents in chorions were both found in the 50 to 200 microg/L exposure groups. A previous study found that NP exposure could lead to chorion thinning in zebra fish. Thus, the reductions in protein and lipid contents in chorion could be the reason for chorion thinning by NP exposure. Meanwhile, cathepsin D activity was significantly inhibited (p < 0.05) in all exposure groups. The results demonstrated that NP-induced oxidative stress could damage the chorion of unfertilized eggs and lead to a decline in gamete quality in female Chinese rare minnow.


Impact of new cancer therapies on outpatient treatment delivery for colorectal cancer: A population-based study.
We investigated the impact of new systemic therapies approved in Canada for colorectal cancer on the frequency, intensity and duration of oncology clinic and infusion visits over five treatment phases from diagnosis (P1, P3) to treatment (P2, P4) of primary and metastatic disease, respectively, and during the last 6 months of life (P5). In total, 15,157 adult patients with newly diagnosed colorectal cancer and referred between 2000 and 2012 to any cancer clinic in British Columbia, Canada, were included. Frequency, intensity and duration of medical oncology clinic visits (CVs), oncology infusions (OIs) and oncology prescriptions (OPs) were measured by treatment phase. Mean, total and adjusted total duration for CVs increased for P1-5. CVs increased in P1-5, and in P1-4 when adjusted by treatment length. Adjusted and unadjusted OIs decreased in P1 coinciding with the introduction of an oral treatment option, but increased in P2-5. Mean OI duration increased in P1-5, while total and adjusted total decreased in P1 and increased in P2-5. OPs increased in P2-4, but were unchanged in P1 and P5. Multi-fold increases in resources and time required per patient were also observed, which have significant implications for demand projections in cancer care planning and delivery. In conclusion, patients required more visits in almost all treatment phases, visits on average took longer and patients were in treatment for longer periods of time.


Low-cost, frequency-domain, fluorescence lifetime confocal microscopy.
We describe the theory and implementation of a frequency-domain fluorescence lifetime confocal microscope using switched diode laser illumination. Standard, communications-type, radio-frequency electronics are used to provide inexpensive modulation references and to perform phase-sensitive detection. This allows the rapid acquisition of fluorescence intensity and lifetime images and their display in real time. We show fluorescence lifetime images of bead objects and fluorescence lifetime images of biological specimens from a single confocal scan.


Selection for nonspecific adhesion is a driver of FimH evolution increasing Escherichia coli biofilm capacity.
Bacterial interactions with surfaces rely on the coordinated expression of a vast repertoire of surface-exposed adhesins. However, how bacteria dynamically modulate their adhesion potential to achieve successful surface colonization is not yet well understood. Here, we investigated changes in adhesion capacity of an initially poorly adherent Escherichia coli strain using experimental evolution and positive selection for mutations improving adhesion and biofilm formation on abiotic surfaces. We showed that all identified evolved populations and clones acquired mutations located almost exclusively in the lectin domain of fimH, the gene coding for the α-d-mannose-specific tip adhesin of type 1 fimbriae, a key E. coli virulence factor. While most of these fimH mutants showed reduced mannose-binding ability, they all displayed enhanced binding to abiotic surfaces, indicating a trade-off between FimH-mediated specific and nonspecific adhesion properties. Several of the identified mutations were already reported in the FimH lectin domain of pathogenic and environmental E. coli, suggesting that, beyond pathoadaptation, FimH microevolution favoring nonspecific surface adhesion could constitute a selective advantage for natural E. coli isolates. Consistently, although E. coli deleted for the fim operon still evolves an increased adhesion capacity, mutants selected in the ∆fim background are outcompeted by fimH mutants revealing clonal interference for adhesion. Our study therefore provides insights into the plasticity of E. coli adhesion potential and shows that evolution of type 1 fimbriae is a major driver of the adaptation of natural E. coli to colonization.


Oral health and obesity in the SAYCARE study: reliability and internal validity of diagnostic methods.
The aim of this pilot study was to address the reliability, internal validity and viability of oral health methods used in the South American Youth/Child cARdiovascular and Environmental study. South American Youth/Child cARdiovascular and Environmental study was a multicentre feasibility observational study and conducted in seven South American cities. The training sessions were performed in two steps before data collection: the first verified the inter-rater reproducibility between the examiners of the six centres in relation to the gold standard, and the second one verified the inter-rater reproducibility between the examiners at each centre in relation to the main rater. The diagnostic methods used were International Caries Detection and Assessment System II and Pulpal Involvement, Ulceration, Fistula and Abscess for dental caries and Periodontal Screening and Recording and Index Plaque for periodontal disease. Anthropometric variables were measured and used to calculate the body mass index and were classified according to the cut-off points defined by the International Obesity Task Force. Cohen's kappa coefficient and proportions of agreement were calculated to report inter-rater and intra-rater reliability in the calibration process and pilot study. The inter-rater weight kappa ranged from 0.78 to 0.88 and proportion of agreement from 96.07% to 98.10% for the International Caries Detection and Assessment System II and for the Periodontal Screening and Recording, 0.68 to 0.95 and 94.40% to 98.33%, respectively, in the calibration process. At the pilot study, a total of 490 children (40.8% overweight and 12.9% obese) and 364 adolescents (23.4% overweight and 4.3% obese) were examined. The prevalence of dental caries was 66% in children and 78% in adolescents, and gingival bleeding was 49% and 58.20%, respectively. The results demonstrated good reliability and internal validity after the examiners were trained, as well as the feasibility of using the methods chosen for this multicentre study.


Intestinal homeostasis and its breakdown in inflammatory bowel disease.
Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease.


Direct and indirect genetic effects in life-history traits of flour beetles (Tribolium castaneum).
Indirect genetic effects (IGEs) are the basis of social interactions among conspecifics, and can affect genetic variation of nonsocial and social traits. We used flour beetles (Tribolium castaneum) of two phenotypically distinguishable populations to estimate genetic (co)variances and the effect of IGEs on three life-history traits: development time (DT), growth rate (GR), and pupal body mass (BM). We found that GR was strongly affected by social environment with IGEs accounting for 18% of the heritable variation. We also discovered a sex-specific social effect: male ratio in a group significantly affected both GR and BM; that is, beetles grew larger and faster in male-biased social environments. Such sex-specific IGEs have not previously been demonstrated in a nonsocial insect. Our results show that beetles that achieve a higher BM do so via a slower GR in response to social environment. Existing models of evolution in age-structured or stage-structured populations do not account for IGEs of social cohorts. It is likely that such IGEs have played a key role in the evolution of developmental plasticity shown by Tenebrionid larvae in response to density. Our results document an important source of genetic variation for GR, often overlooked in life-history theory.


Vitamin C intervention may lower the levels of persistent organic pollutants in blood of healthy women - A pilot study.
Emerging evidence suggests that exposure to endocrine-disrupting chemicals including persistent organic pollutants (POPs) such as organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) has a long term impact on human health. The goal of this pilot study was to test whether antioxidant intervention by vitamin C supplementation may be a remedial approach to decrease body burden of POPs in humans. Using solid phase extraction coupled with a triple quadrupole mass spectrometer and a gas chromatography high resolution mass spectrometry, we measured 18 PCBs, 7 OCPs, and 5 PBDEs in the blood of 15 healthy California women (8 were obese/overweight and 7 had normal weight) before and after 2 months of vitamin C supplementation (1000 mg/day). We observed higher PBDE levels than PCBs and OCPs, but only PCB and OCP levels were strongly and positively correlated with participant's BMI and age. We also found statistically significant decreases in 6 PCBs (PCB-74, PCB-118, PCB-138, PCB-153, PCB-180, and PCB-187), and 2 OCPs (4,4'-DDE, and 4,4'-DDT), but not PBDEs after vitamin C supplementation. Pending confirmation of this pilot finding in a larger study of both sexes, vitamin C intervention may have important public health implications in protecting health by reducing body burdens of POPs.


Challenges of Prevention for a Sustainable Personalized Medicine.
The development and implementation of the approaches of personalized medicine for disease prevention are still at infancy, although preventive activities in healthcare represent a key pillar to guarantee health system sustainability. There is an increasing interest in finding informative markers that indicate the disease risk before the manifestation of the disease (primary prevention) or for early disease detection (secondary prevention). Recently, the systematic collection and study of clinical phenotypes and biomarkers consented to the advance of Rehabilomics in tertiary prevention. It consents to identify relevant molecular and physiological factors that can be linked to plasticity, treatment response, and natural recovery. Implementation of these approaches would open avenues to identify people at high risk and enable new preventive lifestyle interventions or early treatments targeted to their individual genomic profile, personalizing prevention and rehabilitation. The integration of personalized medicine into prevention may benefit citizens, patients, healthcare professionals, healthcare authorities, and industry, and ultimately will seek to contribute to better health and quality of life for Europe's citizens.


Core-level transient absorption spectroscopy as a probe of electron hole relaxation in photoionized H+(H2O)n.
There is fundamental interest in understanding the coupled nuclear and electronic dynamics associated with charge transfer processes in complex molecules and materials, which are often mediated by electron, electron hole or proton motion. With dramatic improvements in the techniques to generate extreme ultraviolet (XUV) and X-ray femtosecond pulses, it now becomes possible to trigger and probe these kinds of processes in real time. Here we study the dynamics of an electron hole created by photoionization in the valence shell of protonated water clusters H(+)(H(2)O)(n). We demonstrate that the electron hole is strongly correlated with the protons forming the hydrogen bond network. We show that it is possible to probe key aspects of the valence electron hole dynamics and the coupled nuclear motion with femtosecond time resolution by resonantly exciting K-shell 1s electrons to fill the electron hole. This represents an opportunity for X-ray transient absorption spectroscopy.


Identification of hemostatic genes expressed in human and rat leg muscles and a novel gene (LPP1/PAP2A) suppressed during prolonged physical inactivity (sitting).
Partly because of functional genomics, there has been a major paradigm shift from solely thinking of skeletal muscle as contractile machinery to an understanding that it can have roles in paracrine and endocrine functions. Physical inactivity is an established risk factor for some blood clotting disorders. The effects of inactivity during sitting are most alarming when a person develops the enigmatic condition in the legs called deep venous thrombosis (DVT) or "coach syndrome," caused in part by muscular inactivity. The goal of this study was to determine if skeletal muscle expresses genes with roles in hemostasis and if their expression level was responsive to muscular inactivity such as occurs in prolonged sitting. Microarray analyses were performed on skeletal muscle samples from rats and humans to identify genes associated with hemostatic function that were significantly expressed above background based on multiple probe sets with perfect and mismatch sequences. Furthermore, we determined if any of these genes were responsive to models of physical inactivity. Multiple criteria were used to determine differential expression including significant expression above background, fold change, and non-parametric statistical tests. These studies demonstrate skeletal muscle tissue expresses at least 17 genes involved in hemostasis. These include the fibrinolytic factors tetranectin, annexin A2, and tPA; the anti-coagulant factors TFPI, protein C receptor, PAF acetylhydrolase; coagulation factors, and genes necessary for the posttranslational modification of these coagulation factors such as vitamin K epoxide reductase. Of special interest, lipid phosphate phosphatase-1 (LPP1/PAP2A), a key gene for degrading prothrombotic and proinflammatory lysophospholipids, was suppressed locally in muscle tissue within hours after sitting in humans; this was also observed after acute and chronic physical inactivity conditions in rats, and exercise was relatively ineffective at counteracting this effect in both species. These findings suggest that skeletal muscle may play an important role in hemostasis and that muscular inactivity may contribute to hemostatic disorders not only because of the slowing of blood flow per se, but also potentially because of the contribution from genes expressed locally in muscles, such as LPP1.


Optimization of preprocessing strategies in Positron Emission Tomography (PET) neuroimaging: A [11C]DASB PET study.
Positron Emission Tomography (PET) is an important neuroimaging tool to quantify the distribution of specific molecules in the brain. The quantification is based on a series of individually designed data preprocessing steps (pipeline) and an optimal preprocessing strategy is per definition associated with less noise and improved statistical power, potentially allowing for more valid neurobiological interpretations. In spite of this, it is currently unclear how to design the best preprocessing pipeline and to what extent the choice of each preprocessing step in the pipeline minimizes subject-specific errors. To evaluate the impact of various preprocessing strategies, we systematically examined 384 different pipeline strategies in data from 30 healthy participants scanned twice with the serotonin transporter (5-HTT) radioligand [11C]DASB. Five commonly used preprocessing steps with two to four options were investigated: (1) motion correction (MC) (2) co-registration (3) delineation of volumes of interest (VOI's) (4) partial volume correction (PVC), and (5) kinetic modeling. To quantitatively compare and evaluate the impact of various preprocessing strategies, we used the performance metrics: test-retest bias, within- and between-subject variability, the intraclass-correlation coefficient, and global signal-to-noise ratio. We also performed a power analysis to estimate the required sample size to detect either a 5% or 10% difference in 5-HTT binding as a function of preprocessing pipeline. The results showed a complex downstream dependency between the various preprocessing steps on the performance metrics. The choice of MC had the most profound effect on 5-HTT binding, prior to the effects caused by PVC and kinetic modeling, and the effects differed across VOI's. Notably, we observed a negative bias in 5-HTT binding across test and retest in 98% of pipelines, ranging from 0 to 6% depending on the pipeline. Optimization of the performance metrics revealed a trade-off in within- and between-subject variability at the group-level with opposite effects (i.e. minimization of within-subject variability increased between-subject variability and vice versa). The sample size required to detect a given effect size was also compromised by the preprocessing strategy, resulting in up to 80% increases in sample size needed to detect a 5% difference in 5-HTT binding. This is the first study to systematically investigate and demonstrate the effect of choosing different preprocessing strategies on the outcome of dynamic PET studies. We provide a framework to show how optimal and maximally powered neuroimaging results can be obtained by choosing appropriate preprocessing strategies and we provide recommendations depending on the study design. In addition, the results contribute to a better understanding of methodological uncertainty and variability in preprocessing decisions for future group- and/or longitudinal PET studies.


Randomised crossover trial of four nasal respiratory support systems for apnoea of prematurity in very low birthweight infants.
Apnoea of prematurity (AOP) is a common problem in preterm infants which can be treated with various modes of nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive pressure ventilation (NIPPV). It is not known which mode of NCPAP or NIPPV is most effective for AOP. To assess the effect of four NCPAP/NIPPV systems on the rate of bradycardias and desaturation events in very low birthweight infants. Sixteen infants (mean gestational age at time of study 31 weeks, 10 males) with AOP were enrolled in a randomised controlled trial with a crossover design. The infants were allocated to receive nasal pressure support using four different modes for 6 h each: NIPPV via a conventional ventilator, NIPPV and NCPAP via a variable flow device, and NCPAP delivered via a constant flow underwater bubble system. The primary outcome was the cumulative event rate of bradycardias (< or =80 beats per minute) and desaturation events (< or =80% arterial oxygen saturation), which was obtained from cardio-respiratory recordings. The median event rate was 6.7 per hour with the conventional ventilator in NIPPV mode, and 2.8 and 4.4 per hour with the variable flow device in NCPAP and NIPPV mode, respectively (p value<0.03 for both compared to NIPPV/conventional ventilator). There was no significant difference between the NIPPV/conventional ventilator and the underwater bubble system. A variable flow NCPAP device may be more effective in treating AOP in preterm infants than a conventional ventilator in NIPPV mode. It remains unclear whether synchronised NIPPV would be even more effective.


Activity of striatal neurons reflects social action and own reward.
Social interactions provide agents with the opportunity to earn higher benefits than when acting alone and contribute to evolutionary stable strategies. A basic requirement for engaging in beneficial social interactions is to recognize the actor whose movement results in reward. Despite the recent interest in the neural basis of social interactions, the neurophysiological mechanisms identifying the actor in social reward situations are unknown. A brain structure well suited for exploring this issue is the striatum, which plays a role in movement, reward, and goal-directed behavior. In humans, the striatum is involved in social processes related to reward inequity, donations to charity, and observational learning. We studied the neurophysiology of social action for reward in rhesus monkeys performing a reward-giving task. The behavioral data showed that the animals distinguished between their own and the conspecific's reward and knew which individual acted. Striatal neurons coded primarily own reward but rarely other's reward. Importantly, the activations occurred preferentially, and in approximately similar fractions, when either the own or the conspecific's action was followed by own reward. Other striatal neurons showed social action coding without reward. Some of the social action coding disappeared when the conspecific's role was simulated by a computer, confirming a social rather than observational relationship. These findings demonstrate a role of striatal neurons in identifying the social actor and own reward in a social setting. These processes may provide basic building blocks underlying the brain's function in social interactions.


Differential mTOR and ERK pathway utilization by effector CD4 T cells suggests combinatorial drug therapy of arthritis.
The signaling pathways utilized by naïve and experienced effector CD4 T cells during activation and proliferation were evaluated. While inhibition of either mTOR or MAPK alone was able to inhibit naïve T cell proliferation, both mTOR and MAPK (ERK) pathway inhibition was required to efficiently block experienced, effector CD4 T cell proliferation. This was demonstrated both in vitro, and in vivo by treating mice with collagen-induced arthritis using mTOR and/or ERK inhibitors. The combination of mTOR and ERK inhibition prevented or treated disease more efficiently than either agent alone. These data illustrate the different requirements of naïve and experienced effector CD4 T cells in the use of the mTOR and MAPK pathways in proliferation, and suggest that therapies targeting both the mTOR and MAPK pathways may be more effective than targeting either pathway alone in the treatment of CD4 T cell-mediated autoimmunity.


Rapid detection of mecA-positive and mecA-negative coagulase-negative staphylococci by an anti-penicillin binding protein 2a slide latex agglutination test.
A rapid slide latex agglutination (LA) test, MRSA-Screen (Denka Seiken Co., Niigata, Japan), which detects PBP 2a, was tested for its ability to differentiate between mecA-positive and -negative coagulase-negative staphylococci. A total of 463 isolates from 13 species were included in the study. The mecA gene was detected by PCR, and the oxacillin MIC was determined by the agar dilution method according to the guidelines of the National Committee for Clinical Laboratory Standards (NCCLS). The LA test was performed with oxacillin-induced isolates. The true-positive and true-negative results were defined on the basis of the presence or the absence of the mecA gene. By PCR, 251 isolates were mecA positive and 212 were mecA negative. The sensitivities, specificities, and positive and negative predictive values for the LA test compared to the NCCLS breakpoint for oxacillin resistance (>/=0.5 mg/liter) were as follows: for the LA test, 100, 99.5, 99.6, and 100%, respectively; for the NCCLS breakpoint, 100, 60.8, 75.1, and 100%, respectively. One hundred twenty-five mecA-positive isolates were also tested by the LA test without induction of PBP 2a; only 72 (57.6%) gave a positive result and required 3 to 15 min for reaction. With induction, all 251 isolates were positive within 3 min. The LA test was reliable in classifying mecA-negative isolates, but it classified isolates for which the oxacillin MIC was >/=0.5 mg/liter as oxacillin susceptible. For the reliable detection of oxacillin resistance by the MRSA-Screen in coagulase-negative staphylococci, induction of the mecA gene appears to be necessary.


Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population.
Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. Its development is a multistep process that spans more than 15 years, thereby providing an opportunity for prevention and early detection. The high incidence and mortality rates emphasise the need for prevention and screening. Many countries have therefore introduced CRC screening programmes. It is expected, and preliminary evidence in some countries suggests, that this screening effort will decrease CRC-related mortality rates. CRC prevention involves a healthy lifestyle and chemoprevention-more specifically, oral chemoprevention that can interfere with progression from a normal colonic mucosa to adenocarcinoma. This preventive effect is important for individuals with a genetic predisposition, but also in the general population. The ideal chemopreventive agent, or combination of agents, remains unknown, especially when considering safety during long-term use. This review evaluates the evidence across 80 meta-analyses of interventional and observational studies of CRC prevention using medications, vitamins, supplements and dietary factors. This review suggests that the following factors are associated with a decreased incidence of CRC: aspirin, non-steroidal anti-inflammatory drugs, magnesium, folate, a high consumption of fruits and vegetables, fibre and dairy products. An increased incidence of CRC was observed with frequent alcohol or meat consumption. No evidence of a protective effect for tea, coffee, garlic, fish and soy products was found. The level of evidence is moderate for aspirin, β-carotene and selenium, but is low or very low for all other exposures or interventions.


Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair.
Heart disease is a leading cause of death in newborn children and in adults. Efforts to promote cardiac repair through the use of stem cells hold promise but typically involve isolation and introduction of progenitor cells. Here, we show that the G-actin sequestering peptide thymosin beta4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta4. We found that thymosin beta4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt (also known as protein kinase B). After coronary artery ligation in mice, thymosin beta4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival and improved cardiac function. These findings suggest that thymosin beta4 promotes cardiomyocyte migration, survival and repair and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage.


The Potyviridae cylindrical inclusion helicase: a key multipartner and multifunctional protein.
A unique feature shared by all plant viruses of the Potyviridae family is the induction of characteristic pinwheel-shaped inclusion bodies in the cytoplasm of infected cells. These cylindrical inclusions are composed of the viral-encoded cylindrical inclusion helicase (CI protein). Its helicase activity was characterized and its involvement in replication demonstrated through different reverse genetics approaches. In addition to replication, the CI protein is also involved in cell-to-cell and long-distance movements, possibly through interactions with the recently discovered viral P3N-PIPO protein. Studies over the past two decades demonstrate that the CI protein is present in several cellular compartments interacting with viral and plant protein partners likely involved in its various roles in different steps of viral infection. Furthermore, the CI protein acts as an avirulence factor in gene-for-gene interactions with dominant-resistance host genes and as a recessive-resistance overcoming factor. Although a significant amount of data concerning the potential functions and subcellular localization of this protein has been published, no synthetic review is available on this important multifunctional protein. In this review, we compile and integrate all information relevant to the current understanding of this viral protein structure and function and present a mode of action for CI, combining replication and movement.


The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon.
Klf4 (formerly GKLF) is a zinc-finger transcription factor expressed in the epithelia of the skin, lungs, gastrointestinal tract and several other organs. In vitro studies have suggested that Klf4 plays an important role in cell proliferation and/or differentiation. Mice homozygous for a null mutation in Klf4 die within 15 hours of birth and show selective perturbation of late-stage differentiation structures in the epidermis, but the function of Klf4 in the gastrointestinal tract has not been investigated. To address this issue, we have generated Klf4(-/-) mice by homologous recombination in embryonic stem cells. In this study, we provide the first in vivo evidence that Klf4 is a goblet cell-specific differentiation factor in the colon. Klf4(-/-) mice exhibit normal cell proliferation and cell death rates in the colon on postnatal day 1. However, Klf4(-/-) mice demonstrate a 90% decrease in the number of goblet cells in the colon, show abnormal expression of the goblet cell-specific marker Muc2 by in situ hybridization, have abnormal staining of the colonic epithelium with Alcian Blue for acidic mucins, and lack normal goblet cell morphology by ultrastructural analysis. All other epithelial cell types are present in the colon of Klf4(-/-) mice. In summary, Klf4 plays a crucial role in colonic epithelial cell differentiation in vivo.


Transplant Professionals' Perceptions of Long-Term Care Residents' Candidacy for Kidney Transplantation.
Given the aging end-stage renal disease (ESRD) population, kidney transplant (KTx) centers may experience an increase in referrals of patients living in long-term care (LTC) settings (eg, skilled nursing facilities, assisted living facilities, group homes, and boarding homes). To identify best practices among KTx professionals when considering individuals in LTC settings for transplantation. A cross-sectional survey administered online to US transplant professionals via e-mail LISTSERVs and other professional networks. One hundred twenty-six KTx professionals working in the United States. The survey was composed of demographic questions and 6 hypothetical scenarios. These scenarios asked participants to assess transplant candidacy of patients with ESRD living in LTC settings based on the information provided in the scenario. Each scenario presented a different variable that necessitated LTC placement, including lack of social support, moderate intellectual disability, stable neurological condition, mild dementia, a psychiatric condition controlled on medications, and limited mobility. The only scenario that elicited an overwhelmingly negative response was mild dementia with 73.9% of participants unwilling to consider such patients for KTx. By contrast, the proportion of KTx professionals reluctant to proceed with KTx in the remaining scenarios ranged between 40.0% and 50.6%. This survey of a large number of KTx professionals suggests that there is presently no best practice consensus regarding offering KTx to patients living in LTC settings. Further research should include a broader range of KTx professionals and should also include a study of outcomes with KTx in this particular patient population.


Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis.
Purpose Regulatory T cells (Tregs) have been implicated in the pathogenesis of several autoimmune disorders and used in adoptive cell transfer therapies. Neither have been explored in patients with autoimmune encephalitis where treated patient outcomes remain suboptimal with frequent relapses. Here, to identify new treatment strategies for autoimmune encephalitis, we sought to evaluate the proportion of circulating Tregs and Treg subpopulations in peripheral blood of patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis (NMDAR-Ab-E) and compared this with healthy controls. We compared the phenotype of peripheral blood Tregs in four adult NMDAR-Ab-E patients and four age- and sex-matched healthy controls using an 11-color flow cytometry assay panel for characterization of Tregs (CD4+ CD25+ FoxP3+) cells into naïve (chemokine receptor [CCR] 7+ CD45RA+), central memory (CCR7+ CD45RA-), and effector memory (CCR7- CD45RA-) cells. We also examined and compared the expression of the CCR6 by circulating Tregs and the respective Treg subpopulations between the study groups. The proportion of circulating Tregs was similar between patients with NMDAR-Ab-E and healthy controls but the proportion of naïve Tregs was lower in NMDAR-Ab-E patients (p = 0.0026). Additionally, the frequency of circulating effector memory Tregs was higher, and the proportion of circulating effector memory Tregs expressing CCR6 was lower, in NMDAR-Ab-E patients compared with healthy controls (p = 0.0026). Altered Treg homeostasis may be a feature of patients with NMDAR-Ab-E. Future studies with larger samples are warranted to validate these findings.


Development of a shuttle walking test of disability in patients with chronic airways obstruction.
The aim was to develop a standardised and externally paced field walking test, incorporating an incremental and progressive structure, to assess functional capacity in patients with chronic airways obstruction. The usefulness of two different shuttle walking test protocols was examined in two separate groups of patients. The initial 10 level protocol (group A, n = 10) and a subsequent, modified, 12 level protocol (group B, n = 10) differed in the number of increments and in the speeds of walking. Patients performed three shuttle walking tests one week apart. Then the performance of patients (group C, n = 15) in the six minute walking test was compared with that in the second (modified) shuttle walking test protocol. Heart rate was recorded during all the exercise tests with a short range telemetry device. The 12 level modified protocol provided a measure of functional capacity in patients with a wide range of disability and was reproducible after just one practice walk; the mean difference between trial 2 v 3 was -2.0 (95% CI -21.9 to 17.9) m. There was a significant relation between the distance walked in the six minute walking test and the shuttle walking test (rho = 0.68) but the six minute walking test appeared to overestimate the extent of disability in some patients. The shuttle test provoked a graded cardiovascular response not evident in the six minute test. Moreover, the maximal heart rates attained were significantly higher for the shuttle walking test than for the six minute test. The shuttle walking test constitutes a standardised incremental field walking test that provokes a symptom limited maximal performance. It provides an objective measurement of disability and allows direct comparison of patients' performance.


Molecular simulation study of the competitive adsorption of H2O and CO2 in zeolite 13X.
The presence of H2O in postcombustion gas streams is an important technical issue for deploying CO2-selective adsorbents. Because of its permanent dipole, H2O can interact strongly with materials where the selectivity for CO2 is a consequence of its quadrupole interacting with charges in the material. We performed molecular simulations to model the adsorption of pure H2O and CO2 as well as H2O/CO2 mixtures in 13X, a popular zeolite for CO2 capture processes that is commercially available. The simulations show that H2O reduces the capacity of these materials for adsorbing CO2 by an order of magnitude and that at the partial pressures of H2O relevant for postcombustion capture, 13X will be essentially saturated with H2O .


Physical activity in US youth: effect of race/ethnicity, age, gender, and weight status.
To describe physical activity (PA) levels by race/ethnicity, age, gender, and weight status in a representative sample of US youth. Cross-sectional data from the 2003-2004 and 2005-2006 National Health and Nutrition Examination Survey were combined and analyzed. Youth aged 6-19 yr with at least four 10-h days of PA measured by accelerometry were included (n = 3106). Outcomes included mean counts per minute and minutes spent in moderate-to-vigorous PA (MVPA). Among the groups, the 6- to 11-yr-olds spent more time (88 min·d) in MVPA than the 12- to 15-yr-olds (33 min·d) and 16- to 19-yr-olds (26 min·d; P < 0.001 for both). Females spent fewer minutes per day in MVPA than males (P < 0.001). Overall, obese youth spent 16 fewer minutes per day in MVPA than normal-weight youth. However, non-Hispanic white males spent three to four fewer minutes per day in vigorous PA than Mexican American (MA; P = 0.004) and non-Hispanic black (P < 0.001) males but had lower obesity rates and obese 12- to 15-yr-old MA recorded similar minutes in MVPA per day as normal-weight MA (P > 0.050). There was a significant three-way age-body mass index-race/ethnicity interaction for mean minutes per day in MVPA (P < 0.001). Adjustment for total energy intake did not qualitatively alter these results. Females and older youth were the least active groups. Obese youth were generally less active, but this did not hold uniformly across race/ethnic groups. Cultural or biological factors could moderate the association between PA and obesity in youth.


Exosomal neurofilament light: A prognostic biomarker for remote symptoms after mild traumatic brain injury?
To measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms. Exosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1-2 mTBIs, and repetitive (3 or more) mTBIs. Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF. Repetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.


From the Ground Up: Establishing a Centre for Universal Design in Australia.
The universal design movement arrived in Australia well before the turn of the century. A handful of individuals, often working as lone voices, are doing their best to incorporate the concepts into their everyday work and promote the concepts more widely. As is often the case elsewhere, the term "universal design" is misunderstood and confused with special and separate designs for people with disability rather than inclusion for everyone. Compliance to legislated disability access standards has created further confusion and as a consequence many myths about universal design have emerged. Such myths have held back the implementation and understanding of universal design and inclusive practice. Australian governments at all levels have shown little interest in promoting universal design principles, save for a casual mention of the term in policy documents. This is in spite of changes to disability and ageing policies promoting more autonomy and independence for individuals. When political leadership is absent, leadership often defaults to the community, or to be precise, to a handful of people with a passion for the cause. In 2013 a chance meeting of two unrelated individuals set the wheels in motion to establish a centre for universal design in Australia. This paper charts the development and progress of the organisation through volunteer effort, harnessing community support, maintaining international connections, using social media, and establishing a resource-rich website and newsletter.


Multiple haplotypes of Echinococcus granulosus sensu stricto in single naturally infected intermediate hosts.
Cystic echinococcosis is a disease that affects both humans and animals, caused by cryptic species complex belonging to the platyhelminth Echinococcus granulosus sensu lato (s.l.). This disease is distributed worldwide, with E. granulosus sensu stricto (s.s.) being the most widespread of the species. High genetic variability has been demonstrated within E. granulosus s.s. studying single cyst per infected animal identifying a number of different haplotypes. However, few studies have addressed the genetic diversity of this parasite within a single intermediate host with multiple Echinococcus cysts. To date, it remains unknown if specific haplotypes of E. granulosus s.s. produce differences in biological features of the cyst. Here, we use the full length of the mitochondrial gene cox1 to determine E. granulosus s.s. haplotypes in samples from both cattle and sheep which harboured more than one cyst in different areas in Chile, where this parasite is endemic. We found 16 different haplotypes in 66 echinococcal cysts from 10 animals, and both cattle and sheep can harbour up to five different haplotypes of E. granulosus s.s. in the same animal. Regarding cyst fertility, five animals had both fertile and infertile Echinococcus cysts in both single and multiple haplotype infections. There was no association between haplotype and cyst fertility, size, or adventitial layer characteristics. Sampling and sequencing every Echinococcus cyst found in the intermediate host reveals a high molecular variability. We speculate that multiple haplotype infections could also suggest that intermediate hosts come from hyperendemic areas.


Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract.
It has long been known that differentiated cells can switch fates, especially in vitro, but only recently has there been a critical mass of publications describing the mechanisms adult, postmitotic cells use in vivo to reverse their differentiation state. We propose that this sort of cellular reprogramming is a fundamental cellular process akin to apoptosis or mitosis. Because reprogramming can invoke regenerative cells from mature cells, it is critical to the long-term maintenance of tissues like the pancreas, which encounter large insults during adulthood but lack constitutively active adult stem cells to repair the damage. However, even in tissues with adult stem cells, like the stomach and intestine, reprogramming may allow mature cells to serve as reserve ("quiescent") stem cells when normal stem cells are compromised. We propose that the potential downside to reprogramming is that it increases risk for cancers that occur late in adulthood. Mature, long-lived cells may have years of exposure to mutagens. Mutations that affect the physiological function of differentiated, postmitotic cells may lead to apoptosis, but mutations in genes that govern proliferation might not be selected against. Hence, reprogramming with reentry into the cell cycle might unmask those mutations, causing an irreversible progenitor-like, proliferative state. We review recent evidence showing that reprogramming fuels irreversible metaplastic and precancerous proliferation in the stomach and pancreas. Finally, we illustrate how we think reprogrammed differentiated cells are likely candidates as cells of origin for cancers of the intestine.


Object detectability at increased ambient lighting conditions.
Under typical dark conditions encountered in diagnostic reading rooms, a reader's pupils will contract and dilate as the visual focus intermittently shifts between the high luminance display and the darker background wall, resulting in increased visual fatigue and the degradation of diagnostic performance. A controlled increase of ambient lighting may, however, reduce the severity of these pupillary adjustments by minimizing the difference between the luminance level to which the eyes adapt while viewing an image (L(adp)) and the luminance level of diffusely reflected light from the area surrounding the display (L(s)). Although ambient lighting in reading rooms has conventionally been kept at a minimum to maintain the perceived contrast of film images, proper Digital Imaging and Communications in Medicine (DICOM) calibration of modern medical-grade liquid crystal displays can compensate for minor lighting increases with very little loss of image contrast. This paper describes two psychophysical studies developed to evaluate and refine optimum reading room ambient lighting conditions through the use of observational tasks intended to simulate real clinical practices. The first study utilized the biologic contrast response of the human visual system to determine a range of representative L(adp) values for typical medical images. Readers identified low contrast horizontal objects in circular foregrounds of uniform luminance (5, 12, 20, and 30 cd/m2) embedded within digitized mammograms. The second study examined the effect of increased ambient lighting on the detection of subtle objects embedded in circular foregrounds of uniform luminance (5, 12, and 35 cd/m2) centered within a constant background of 12 cd/m2 luminance. The images were displayed under a dark room condition (1 lux) and an increased ambient lighting level (50 lux) such that the luminance level of the diffusely reflected light from the background wall was approximately equal to the image L(adp) value of 12 cd/m2. Results from the first study demonstrated that observer true positive and false positive detection rates and true positive detection times were considerably better while viewing foregrounds at 12 and 20 cd/m2 than at the other foreground luminance levels. Results from the second study revealed that under increased room illuminance, the average true positive detection rate improved a statistically significant amount from 39.3% to 55.6% at 5 cd/m2 foreground luminance. Additionally, the true positive rate increased from 46.4% to 56.6% at 35 cd/m2 foreground luminance, and decreased slightly from 90.2% to 87.5% at 12 cd/m2 foreground luminance. False positive rates at all foreground luminance levels remained approximately constant with increased ambient lighting. Furthermore, under increased room illuminance, true positive detection times declined at every foreground luminance level, with the most considerable decrease (approximately 500 ms) at the 5 cd/m2 foreground luminance. The first study suggests that L(adp) of typical mammograms lies between 12 and 20 cd/m2, leading to an optimum reading room illuminance of approximately 50-80 lux. Findings from the second study provide psychophysical evidence that ambient lighting may be increased to a level within this range, potentially improving radiologist comfort, without deleterious effects on diagnostic performance.


Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments.
Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan. Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.


Comparison of the Hirshfeld-I and iterated stockholder atoms in molecules schemes.
Two recently introduced self-consistent Hirshfeld procedures for obtaining atoms in molecules are compared in detail. The Hirshfeld-I scheme introduces self consistency by requiring that the atomic population of the promolecular atom is equal to that of the atom-in-the-molecule. In the iterated stockholder atoms (ISA) approach, self consistency is obtained by requiring that for every value of the radius of a sphere around every nucleus, the average electron density on the surface of this sphere is the same in the promolecular atom and in the atom in the molecule. The relationships between the two schemes are examined, and common backgrounds and differences are discussed. Whereas it can be argued that the Hirshfeld-I approach has a stronger physical background, the ISA scheme avoids having to define what states of the atoms are to be considered when constructing the promolecule.


Single ion channel models incorporating aggregation and time interval omission.
We present a general theoretical framework, incorporating both aggregation of states into classes and time interval omission, for stochastic modeling of the dynamic aspects of single channel behavior. Our semi-Markov models subsume the standard continuous-time Markov models, diffusion models and fractal models. In particular our models allow for quite general distributions of state sojourn times and arbitrary correlations between successive sojourn times. Another key feature is the invariance of our framework with respect to time interval omission: that is, properties of the aggregated process incorporating time interval omission can be derived directly from corresponding properties of the process without it. Even in the special case when the underlying process is Markov, this leads to considerable clarification of the effects of time interval omission. Among the properties considered are equilibrium behavior, sojourn time distributions and their moments, and auto-correlation and cross-correlation functions. The theory is motivated by ion channel mechanisms drawn from the literature, and illustrated by numerical examples based on these.


Molecular genetic contributions to socioeconomic status and intelligence.
Education, socioeconomic status, and intelligence are commonly used as predictors of health outcomes, social environment, and mortality. Education and socioeconomic status are typically viewed as environmental variables although both correlate with intelligence, which has a substantial genetic basis. Using data from 6815 unrelated subjects from the Generation Scotland study, we examined the genetic contributions to these variables and their genetic correlations. Subjects underwent genome-wide testing for common single nucleotide polymorphisms (SNPs). DNA-derived heritability estimates and genetic correlations were calculated using the 'Genome-wide Complex Trait Analyses' (GCTA) procedures. 21% of the variation in education, 18% of the variation in socioeconomic status, and 29% of the variation in general cognitive ability was explained by variation in common SNPs (SEs ~ 5%). The SNP-based genetic correlations of education and socioeconomic status with general intelligence were 0.95 (SE 0.13) and 0.26 (0.16), respectively. There are genetic contributions to intelligence and education with near-complete overlap between common additive SNP effects on these traits (genetic correlation ~ 1). Genetic influences on socioeconomic status are also associated with the genetic foundations of intelligence. The results are also compatible with substantial environmental contributions to socioeconomic status.


Microlepidogaster negomata, a new hypoptopomatine catfish (Loricariidae: Hypoptopomatinae) from Rio São Francisco basin, southeastern Brazil.
The number of species of Microlepidogaster recently increased considerably, the genus presently comprises six species distributed in the Paraná, São Francisco, and Jequitinhonha river basins. A new species of Microlepidogaster is herein described from the upper Rio São Francisco basin, which can be distinguished from all congeners by having two exclusive features within the genus: skin over swimbladder opening with two to five reduced unperforated platelets, and ventral laminar expansion of coracoid enclosing completely or almost completely the arrector fossa of the pectoral girdle. In addition, other features to recognize this species are: snout covered by many small plates bearing slender pointed odontodes; presence of iris operculum; exposure of pectoral girdle restricted to the lateral portion; presence of pectoral axillary slit only in juveniles; anterior portion of compound supraneural plus first dorsal-fin proximal radial contacting the neural spine of the eighth or ninth vertebra; first anal-fin pterygiophore covered only by skin; and uninterrupted, long median and mid-dorsal series of lateral plates.


Induction of Genomic Instability in a Primary Human Fibroblast Cell Line Following Low-Dose Alpha-Particle Exposure and the Potential Role of Exosomes.
To study the induction of genomic instability (GI) in the progeny of cell populations irradiated with low doses of alpha-particles and the potential role of exosome-encapsulated bystander signalling. The induction of GI in HF19 normal fibroblast cells was assessed by determining the formation of micronuclei (MN) in binucleate cells along with using the alkaline comet assay to assess DNA damage. Low dose alpha-particle exposure (0.0001-1 Gy) was observed to produce a significant induction of micronuclei and DNA damage shortly after irradiation (assays performed at 5 and 1 h post exposure, respectively). This damage was not only still evident and statistically significant in all irradiated groups after 10 population doublings, but similar trends were observed after 20 population doublings. Exosomes from irradiated cells were also observed to enhance the level of DNA damage in non-irradiated bystander cells at early times. very low doses of alpha-particles are capable of inducing GI in the progeny of irradiated cells even at doses where <1% of the cells are traversed, where the level of response was similar to that observed at doses where 100% of the cells were traversed. This may have important implications with respect to the evaluation of cancer risk associated with very low-dose alpha-particle exposure and deviation from a linear dose response.


Benign gastric polyps: morphological and functional origin.
The most common types of benign gastric polyps are fundic gland polyps, hyperplastic polyps, and adenomas. The aim of this study was to determine on which morphological and functional background benign gastric polyps develop. The study includes 85 consecutive patients with gastric polyps and sex- and age-matched controls without polyps selected at random from a general population sample. The type of polyp was hyperplastic in 52 (61%), fundic gland in 18 (21%), adenoma in 10 (12%), carcinoid in 2 (2%), hamartoma in 2 (2%), and inflammatory fibroid in 1 (1%) of the cases. Routine biopsies from the gastric corpus and antrum were examined for presence of gastritis and H. pylori. Blood samples were analyzed for H. pylori antibodies, H+,K+-ATPase antibodies, gastrin, and pepsinogen I. Patients with hyperplastic polyps had increased P-gastrin concentrations and S-H+,K+-ATPase antibody titers and decreased S-pepsinogen I concentrations with a high prevalence of atrophic corpus gastritis or pangastritis. A similar pattern was observed among patients with adenomas, whereas patients with fundic gland polyps had normal serology and a lower prevalence of gastritis and H. pylori infection than controls. In conclusion, hyperplastic polyps and adenomas are generally associated with atrophic gastritis. Patients with fundic gland polyps seem to have a sounder mucosa than controls. Whereas the risk of malignant gastric neoplasia is increased in patients with hyperplastic polyps or adenomas, this does not seem to be the case in patients with fundic gland polyps.


Finite Element Analysis Examining the Effects of Cam FAI on Hip Joint Mechanical Loading Using Subject-Specific Geometries During Standing and Maximum Squat.
Cam femoroacetabular impingement (FAI) can impose elevated mechanical loading in the hip, potentially leading to an eventual mechanical failure of the joint. Since in vivo data on the pathomechanisms of FAI are limited, it is still unclear how this deformity leads to osteoarthritis. The purpose of this study was to examine the effects of cam FAI on hip joint mechanical loading using finite element analysis, by incorporating subject-specific geometries, kinematics, and kinetics. The research objectives were to address and determine: (1) if hips with cam FAI demonstrate higher maximum shear stresses, in comparison with control hips; (2) the magnitude of the peak maximum shear stresses; and (3) the locations of the peak maximum shear stresses. Using finite element analysis, two patient models were control-matched and simulated during quasi-static positions from standing to squatting. Intersegmental hip forces, from a previous study, were applied to the subject-specific hip geometries, segmented from CT data, to evaluate the maximum shear stresses on the acetabular cartilage and underlying bone. Peak maximum shear stresses were found at the anterosuperior region of the underlying bone during squatting. The peaks at the anterosuperior acetabulum were substantially higher for the patients (15.2 ± 1.8 MPa) in comparison with the controls (4.5 ± 0.1 MPa). Peaks were not situated on the cartilage, but instead located on the underlying bone. The results correspond with the locations of initial cartilage degradation observed during surgical treatment and from MRI. These findings support the pathomechanism of cam FAI. Changes may originate from the underlying subchondral bone properties rather than direct shear stresses to the articular cartilage.


In vitro and in vivo activities of tea catechins against Helicobacter pylori.
The catechin epigallocatechin gallate showed the strongest activity of the six tea catechins tested against Helicobacter pylori (MIC for 50% of the strains tested, 8 microg/ml). It had bactericidal activity at pH 7 but not at pH </=5.0. In infected Mongolian gerbils, H. pylori was eradicated in 10 to 36% of the catechin-treated animals, with significant decreases in mucosal hemorrhage and erosion. Tea catechins, therefore, may have therapeutic effects on H. pylori infection.


Smoking and Mortality in Tianjin, China: A Death Registry-Based Case-Control Study, 2010-2014.
We conducted a mortality case-control study to assess the risks of all-cause and major causes of death attributable to smoking in Tianjin from 2010 through 2014. The death registry-based study used data from The Tianjin All Causes of Death Surveillance System, which collects information routinely on smoking of the deceased in the death certificate of Tianjin Centers for Disease Control and Prevention. Cases (n = 154,086) and controls (n = 25,476) were deaths at 35 to 79 years from smoking-related and nonsmoking-related causes, respectively. Mortality rate ratios (RRs) for ever smokers versus never smokers, with adjustment for sex, 5-year age group, education, marital status, and year of death, and smoking-attributed fractions were calculated. The RRs in men were 1.38 (95% confidence interval [CI], 1.33-1.43) for all causes and 3.07 (95% CI, 2.91-3.24) for lung cancer, and in women were 1.46 (95% CI, 1.39-1.54) and 4.07 (95% CI, 3.81-4.35). The smoking-attributed fractions for all causes and for lung cancer in men were 15.4% and 50.2%, respectively, and in women were 7.3% and 32.7%, respectively. Smoking annually caused an average of 3,756 (9.4%) deaths, mostly from lung cancer in men (47.4%) and women (66.9%). Women who started smoking before 30 had a higher RR (1.79; 95% CI, 1.63-1.97) than men who did so (1.48; 95% CI, 1.41-1.56). Lung cancer was the main cause of smoking-induced deaths in both sexes. Tobacco use is a major cause of premature deaths in men aged 35 to 79 years. Young women must be urged to not start smoking because they could have greater risk of all-cause and lung cancer deaths than men do.


Exploiting Self-organization in Bioengineered Systems: A Computational Approach.
The productivity of bioengineered cell factories is limited by inefficiencies in nutrient delivery and waste and product removal. Current solution approaches explore changes in the physical configurations of the bioreactors. This work investigates the possibilities of exploiting self-organizing vascular networks to support producer cells within the factory. A computational model simulates de novo vascular development of endothelial-like cells and the resultant network functioning to deliver nutrients and extract product and waste from the cell culture. Microbial factories with vascular networks are evaluated for their scalability, robustness, and productivity compared to the cell factories without a vascular network. Initial studies demonstrate that at least an order of magnitude increase in production is possible, the system can be scaled up, and the self-organization of an efficient vascular network is robust. The work suggests that bioengineered multicellularity may offer efficiency improvements difficult to achieve with physical engineering approaches.


Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease.
Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Abeta fibril genesis and deposition remain obscure. Enhanced Abeta synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation. Amyloid accumulation may indirectly exert the greatest pathologic effect on the brain vasculature by destroying smooth muscle cells and creating a cascade of negative impacts on cerebral blood flow. The most visible manifestation of amyloid dis-equilibrium could actually be a defense mechanism employed to avoid serious vascular wall degradation while the major toxic effects to the gray and white matter neurons are mediated by soluble oligomeric Abeta peptides with high beta-sheet content. The recognition that dynamic soluble oligomeric Abeta pools exist in AD and are correlated to disease severity led to neurotoxicity and physical conformation studies. It is now recognized that the most basic soluble Abeta peptides are stable dimers with hydrophobic regions sequestered from the aqueous environment and are capable of higher order aggregations. Time course experiments employing a modified ELISA method able to detect Abeta oligomers revealed dynamic intermolecular interactions and additional experiments physically confirmed the presence of stable amyloid multimers. Amyloid peptides that are rich in beta-sheet structure are capable of creating toxic membrane ion channels and a capacity to self-assemble as annular structures was confirmed in vitro using atomic force microscopy. Biochemical studies have established that soluble Abeta peptides perturb metabolic processes, provoke release of deleterious reactive compounds, reduce blood flow, induce mitochondrial apoptotic toxicity and inhibit angiogenesis. While there is no question that gross amyloid deposition does contribute to AD pathology, the destructive potential now associated with soluble Abeta suggests that treatment strategies that target these molecules may be efficacious in preventing some of the devastating effects of AD.


Sur8/Shoc2 involves both inhibition of differentiation and maintenance of self-renewal of neural progenitor cells via modulation of extracellular signal-regulated kinase signaling.
Sur8/Shoc2 is a scaffold protein that regulates the Ras-extracellular signal-regulated kinase (ERK) pathway. However, the roles of Sur8 in cellular physiologies are poorly understood. In this study, Sur8 was severely repressed in the course of neural progenitor cell (NPC) differentiation in the cerebral cortex of developing rat embryos. Similarly, Sur8 was also critically reduced in cultured NPCs, which were induced differentiation by removal of basic fibroblast growth factor (bFGF). Sur8 regulation occurs at the protein level rather than at the mRNA level as revealed by both in situ hybridization and reverse transcriptase polymerase chain reaction analyses. The role of Sur8 in NPC differentiation was confirmed by lentivirus-mediated Sur8 knockdown, which resulted in increased differentiation, whereas exogenous expression of Sur8 inhibited differentiation. Contrastingly, NPC proliferation was promoted by overexpression, but was suppressed by Sur8 knockdown. The role of Sur8 as an antidifferentiation factor in the developing rat brain was confirmed by an ex vivo embryo culture system combined with the lentivirus-mediated Sur8 knockdown. The numbers and sizes of neurospheres were reduced, but neuronal outgrowth was enhanced by the Sur8 knockdown. The Ras-ERK pathway is involved in Sur8-mediated regulations of differentiation, as the treatment of ERK kinase (MEK) inhibitors blocks the effects of Sur8. The regulations of NPCs' differentiation and proliferation by the Ras-ERK pathway were also shown by the rescues of the effects of bFGF depletion, neuronal differentiation, and antiproliferation by epidermal growth factor. In summary, Sur8 is an antidifferentiation factor that stimulates proliferation for maintenance of self-renewal in NPCs via modulation of the Ras-ERK pathway.


Feasibility and Acceptability of the Youth Aware of Mental Health (YAM) Intervention in US Adolescents.
Suicide is the second leading cause of death among US adolescents, and rates of suicide among youth have been increasing for the past decade. This study assessed the feasibility and acceptability of the universal, school-based Youth Aware of Mental Health (YAM) program, a promising mental health promotion and suicide primary prevention intervention, in US youth. Using an uncontrolled design, the feasibility and acceptability of delivering and studying YAM were assessed in Montana and Texas schools. Thirteen of 16 (81.3%) schools agreed to support YAM delivery, and five Montana and 6 Texas schools were included in analyses. Facilitators delivered YAM in 78 classes (1,878 students) as regular high school curriculum. Of the total number of students who received YAM, 519 (27.6%) provided parental consent and assent. 436 (84.0%) consented students participated in pre- and post-surveys. Students, parents, and school staff found YAM highly acceptable based on satisfaction surveys. In summary, this study found YAM feasible to implement in US schools. Results also suggest students, parents, and school staff supported school-based programs and were highly satisfied with the YAM program. A randomized controlled trial is warranted to test the efficacy of YAM in promoting mental health and preventing suicidal thoughts and behaviors in US adolescents.


Coulomb barrier creation by means of electronic field emission in nanolayer capacitors.
The main mechanism of energy loss in capacitors with nanoscale dielectric films is leakage currents. Using the example of Al-Al2O3-Al, we show that there are two main contributions, namely the cold field emission effect and the hopping conductivity through the dielectric. Our main finding is that an application of a high electric field, ∼0.6-0.7 GV m-1, causes electrons to penetrate the dielectric. If the temperature is sufficiently low, such electrons become permanently trapped in the dielectric. To achieve a strong charging of the dielectric, the voltage needs to be high enough, so that a field emission occurs from the cathode into the dielectric. Such a strongly charged dielectric layer generates a Coulomb barrier and leads to a suppression of the leakage current. Thus, after the dielectric nanolayer of the capacitor is charged, the field emission and the hopping conductivity are both suppressed, and the hysteresis of the I-V curve disappears. The phenomenon is observed at temperatures up to ∼225 K. It would be advantageous to identify insulators in which the phenomenon of the Coulomb barriers persists even up to the room temperature, but at this time it is not known whether such dielectrics exist and/or can be designed.


Enhancing self-regulation as a strategy for obesity prevention in Head Start preschoolers: the growing healthy study.
Nearly one in five 4-year-old children in the United States are obese, with low-income children almost twice as likely to be obese as their middle/upper-income peers. Few obesity prevention programs for low-income preschoolers and their parents have been rigorously tested, and effects are modest. We are testing a novel obesity prevention program for low-income preschoolers built on the premise that children who are better able to self-regulate in the face of psychosocial stressors may be less likely to eat impulsively in response to stress. Enhancing behavioral self-regulation skills in low-income children may be a unique and important intervention approach to prevent childhood obesity. The Growing Healthy study is a randomized controlled trial evaluating two obesity prevention interventions in 600 low-income preschoolers attending Head Start, a federally-funded preschool program for low-income children. Interventions are delivered by community-based, nutrition-education staff partnering with Head Start. The first intervention (n = 200), Preschool Obesity Prevention Series (POPS), addresses evidence-based obesity prevention behaviors for preschool-aged children and their parents. The second intervention (n = 200) comprises POPS in combination with the Incredible Years Series (IYS), an evidence-based approach to improving self-regulation among preschool-aged children. The comparison condition (n = 200) is Usual Head Start Exposure. We hypothesize that POPS will yield positive effects compared to Usual Head Start, and that the combined intervention (POPS + IYS) addressing behaviors well-known to be associated with obesity risk, as well as self-regulatory capacity, will be most effective in preventing excessive increases in child adiposity indices (body mass index, skinfold thickness). We will evaluate additional child outcomes using parent and teacher reports and direct assessments of food-related self-regulation. We will also gather process data on intervention implementation, including fidelity, attendance, engagement, and satisfaction. The Growing Healthy study will shed light on associations between self-regulation skills and obesity risk in low-income preschoolers. If the project is effective in preventing obesity, results can also provide critical insights into how best to deliver obesity prevention programming to parents and children in a community-based setting like Head Start in order to promote better health among at-risk children. Clinicaltrials.gov Identifier: NCT01398358.


How to Reliably Assess Nodal Status in Distal Pancreatectomy for Adenocarcinoma.
The optimal number of lymph nodes that need to be analyzed to reliably assess nodal status in distal pancreatectomy for adenocarcinoma is still unknown. Two hundred seventy-eight patients who underwent distal pancreatectomy for adenocarcinoma were retrieved from a retrospective French nationwide database. The relations between the number of analyzed lymph nodes and the nodal status of the tumor were studied. The beta-binomial law was used to estimate the probability of being truly node negative depending on the number of analyzed lymph nodes. Cox proportional hazard model was used for the survival analysis. The median number of analyzed lymph nodes was 15. There was a positive correlation between the number of positive lymph nodes and the number of lymph nodes analyzed. The curve reached a plateau at approximately 25 lymph nodes. The beta binomial model demonstrated that an analysis of 21 negative lymph nodes shows a probability to be truly N0 at 95%. N+ status was associated with survival, but the number of lymph node analyzed was not. At least 21 lymph nodes should be analyzed to ensure a reliable assessment of the nodal status, but this number may be hard to reach in distal pancreatectomy.


Deep brain stimulation: preoperative issues.
Numerous factors need to be taken into account in deciding whether a patient with Parkinson's disease (PD) is a candidate for deep brain stimulation. Patient-related personal factors including age and the presence of other comorbid disorders need to be considered. Neuropsychological and neuropsychiatric concerns relate both to the presurgical status of the patient and to the potential for surgery to result in new problems postoperatively. A number of factors related to the underlying PD need to be considered, including the specific parkinsonian motor indications (e.g., tremor, bradykinesia, gait dysfunction), previous medical therapies, including benefit from current therapy and adverse effects, and past surgical treatments. Definable causes of Parkinsonism, particularly atypical Parkinsonisms, should be considered. Finally, methods of evaluating outcomes should be defined and formalized. This is a report from the Consensus on Deep Brain Stimulation for Parkinson's Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society (MDS). The report has been endorsed by the Scientific Issues Committee of the MDS and the American Society of Stereotactic and Functional Neurosurgery. It outlines answers to a series of questions developed to address all aspects of deep brain stimulation preoperative decision-making.


A novel clinicopathological analysis of early stage ovarian Sertoli-Leydig cell tumors at a single institution.
To evaluate the clinical and pathologic characteristics of patients who were diagnosed with ovarian Sertoli-Leydig cell tumors (SLCTs) in a single institution. The medical records of 11 patients who were pathologically diagnosed with SLCTs beginning in 1995 in a single institute was reviewed. The median patient age was 31 years (range, 16 to 70 years). Patient International Federation of Gynecology and Obstetrics stages were IA, IC, and IIB in 3 (27.3%), 6 (54.5%), and 2 (18.2%) patients, respectively. Six patients (54.5%) had grade 3 tumors, 3 patients (27.3%) had grade 2 tumors, and 1 patient (9.1%) had a grade 1 tumor. Four patients without children underwent fertility-sparing surgery, and 7 patients had full staging surgery, including a hysterectomy and bilateral salpingo-oophorectomy, with a laparoscopic approach used in 3. Eight patients underwent pelvic lymph node dissection, and 8 patients were administered adjuvant chemotherapy consisting of bleomycin, etoposide, and cisplatin in 6 cases, a modified bleomycin, etoposide, and cisplatin regimen in 1 case, and a combined paclitaxel and cisplatin regimen in 1 case. Two patients died of disease and were re-diagnosed with Sertoli form endometrioid carcinoma. The other patients remain alive without recurrence at the time of reporting. Our findings suggest that regardless of tumor stage or grade, ovarian SLCT patients have a good prognosis. Close observation and unilateral salpingo-oophorectomy would be beneficial for women who still wish to have children, while hysterectomy and bilateral salpingo-oophorectomy with adjuvant chemotherapy would be the optimal treatment in other cases. Furthermore, meticulous pathologic diagnosis is needed to develop a precise treatment strategy.


Effect of defective collagen synthesis on epithelial implant interface: lathyritic model in dogs. An experimental preliminary study.
Peri-implant mucosa is composed of 2 compartments: a marginal junctional epithelium and a zone of connective tissue attachment. Both structures consist mainly of collagen. Lathyrism is characterized by defective collagen synthesis due to inhibition of lysyl oxidase, an enzyme that is essential for interfibrillar collagen cross-linking. The lathyritic agent beta-aminoproprionitrile (β-APN) is considered a suitable agent to disrupt the connective tissue metabolism. Therefore, the purpose of this study was to assess the effect of defective connective tissue metabolism on epithelial implant interface by using β-APN created chronic lathyrism in the canine model. Two 1-year-old male dogs were included in this study. A β-APN dosage of 5 mg/0.4 mL/volume 100 g/body weight was given to the test dog for 10 months, until lathyritic symptoms developed. After this, the mandibular premolar teeth (p2, p3, p4) of both dogs were atraumatically extracted, and the investigators waited 3 months before implants were placed. In the test dog, 3 implants were placed in the left mandible, and 2 implants were placed in the right mandible. In the control dog, 2 implants were placed in the left mandibular premolar site. The dogs were sacrificed 10 months after healing. Peri-implant tissues obtained from the dogs were examined histomorphologically and histopathologically. Bone to implant contact (BIC) values and bone volumes (BV) were lower in the lathyritic group compared to the control group; however, no statistical significance was found. Significant histologic and histomorphometric changes were observed in peri-implant bone, connective tissue, and peri-implant mucosal width between test and control implants. Defective collagen metabolism such as lathyrism may negatively influence the interface between implant and surrounding soft tissue attachment.


Synthesis and antitumor mechanism of a new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol as ligands.
A new iron(iii) complex with 5,7-dichloro-2-methyl-8-quinolinol (HClMQ) as ligands, i.e., [Fe(ClMQ)2Cl] (1), was synthesized and evaluated for its anticancer activity. Compared to the HClMQ ligand, complex 1 showed a higher cytotoxicity towards a series of tumor cell lines, including Hep-G2, BEL-7404, NCI-H460, A549, and T-24, with IC50 values in the range of 5.04-14.35 μM. Notably, the Hep-G2 cell line was the most sensitive to complex 1. Mechanistic studies indicated that complex 1 is a telomerase inhibitor targeting c-myc G-quadruplex DNA and can trigger cell apoptosis via inducing cell cycle arrest and DNA damage.


The origin recognition complex, SIR1, and the S phase requirement for silencing.
Silencing of transcription in Saccharomyces cerevisiae has several links to DNA replication, including a role for the origin recognition complex (ORC), the DNA replication initiator, in both processes. In addition, the establishment of silencing at the HML and HMR loci requires cells to pass through the S phase of the cell cycle. Passage through S phase was required for silencing of HMR even under conditions in which ORC itself was no longer required. The requirement for ORC in silencing of HMR could be bypassed by tethering the Sir1 protein to the HMR-E silencer. However, ORC had a Sir1-independent role in transcriptional silencing at telomeres. Thus, the role of ORC in silencing was separable from its role in initiation, and the role of S phase in silencing was independent of replication initiation at the silencers.


The Australian Recommended Food Score did not predict weight gain in middle-aged Australian women during six years of follow-up.
To evaluate the relationship between diet quality score, as measured by the Australian Recommended Food Score (ARFS) and six-year weight gain in middle-aged Australian women. Participants were a sub-sample of women from the Australian Longitudinal Study on Women's Health (ALSWH) who were followed up from 2001 to 2007 (n= 7,155, aged 48 to 56 years). The ARFS was derived from responses to a sub-set of questions from a food frequency questionnaire, with possible scores ranging from 0 to 74 (maximum). Absolute weight gain was calculated from the difference in self-reported weight between 2001 and 2007. Linear regression was used to test the relationship between diet score and weight change. On average, women gained weight during follow-up (1.6 ± 6.2 kg) and had a mean baseline ARFS of 32.6 (SD 8.7) which was not optimal. There was no association between ARFS and weight change during follow-up (β= 0.016; p=0.08) in the fully adjusted model that included total energy intake, education, area of residence, baseline weight, physical activity, smoking and menopause status. Weight gain and low ARFS were common. However, diet quality as measured by the ARFS did not predict six-year weight gain. This lack of association may be due to limitations related to AFRS, or may be a false negative finding. Further research is warranted to evaluate the impact of promoting optimal diet quality on weight gain prospectively.


HD1, a thrombin- and prothrombin-binding DNA aptamer, inhibits thrombin generation by attenuating prothrombin activation and thrombin feedback reactions.
HD1, a DNA aptamer, binds exosite 1 on thrombin and blocks its clotting activity. Because HD1 also binds prothrombin and inhibits its activation by prothrombinase, we hypothesised that HD1 would be a more potent inhibitor of coagulation than other exosite 1-directed ligands, such as Hir(54-65)(SO(3)(-)). Supporting this concept, the effect of HD1 on the prothrombin time and activated partial thromboplastin time was two-fold greater than that of Hir(54-65)(SO(3)(-)) even though both agents inhibited thrombin-mediated factor (F) V and FVIII activation to a similar extent. In thrombin generation assays, HD1 (a) delayed the lag time, (b) reduced peak thrombin concentration, and (c) decreased endogenous thrombin potential to a greater extent than Hir54-65(SO(3)(-)). To eliminate thrombin feedback, studies were repeated in FV- and/or FVIII-deficient plasma supplemented with FVa and/or FVIIIa. Only HD1 prolonged the lag time in FV- and FVIII-deficient plasma supplemented with FVa and FVIIIa. In contrast, HD1 and Hir54-65(SO(3)(-)) inhibited the lag time in FVIII-deficient plasma supplemented with FVIIIa and in normal plasma. The more potent anticoagulant properties of HD1, therefore, reflect its capacity to attenuate FV activation by thrombin and inhibit prothrombinase assembly. These findings identify prothrombin as a potential target for new anticoagulants.