Return to play after an initial or recurrent concussion in a prospective study of physician-observed junior ice hockey concussions: implications for return to play after a concussion.
The authors investigated return-to-play duration for initial and recurrent concussion in the same season in 2 teams of junior (16-21-year-old) ice hockey players during a regular season. The authors conducted a prospective cohort study during 1 junior regular season (2009-2010) of 67 male fourth-tier ice hockey players (mean age 18.2 ± 1.2 years [SD], range 16-21 years) from 2 teams. Prior to the start of the season, every player underwent baseline assessments that were determined using the Sideline Concussion Assessment Tool 2 (SCAT2) and the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). The study protocol also required players who entered the study during the season to complete a baseline SCAT2 and ImPACT. If the protocol was not followed, the postinjury test results of a player without true baseline test results were compared with previously established age- and sex-matched group normative levels. Each game was directly observed by a physician and at least 1 neutral nonphysician observer. Players suspected of suffering a concussion were evaluated by the physician during the game. If a concussion was diagnosed, the player underwent clinical evaluation at the physician's office within 24 hours. The return-to-play decision was based on clinical evaluation guided by the Zurich return-to-play protocol (contained in the consensus statement of international expert opinion at the 3rd International Conference on Concussion in Sport held in Zurich, November 2008). This clinical evaluation and return-to-play protocol was augmented by the 2 tests (SCAT2 and ImPACT) also recommended by the Zurich consensus statement, for which baseline values had been obtained. Seventeen players sustained a physician-observed or self-reported, physician-diagnosed concussion during a physician-observed ice hockey game. The mean clinical return-to-play duration (in 15 cases) was 12.8 ± 7.02 days (median 10 days, range 7-29 days); the mean number of physician office visits by players who suffered a concussion (15 cases) was 2.1 ± 1.29 (median 1.5 visits). Five of the 17 players who sustained a concussion also suffered a recurrent or second concussion. One of the 5 individuals who suffered a repeat concussion sustained his initial concussion in a regular season game that was not observed by a physician, and as a result this single case was not included in the total of 21 concussions. This initial concussion of the player was identified during baseline testing 2 days after the injury and was subsequently medically diagnosed and treated. The mean interval between the first and second concussions in these 5 players was 78.6 ± 39.8 days (median 82 days), and the mean time between the return-to-play date of the first and second concussions was 61.8 ± 39.7 days (median 60 days). The mean rates of return to play for single and recurrent concussions were higher than rates cited in recent studies involving sport concussions. The time interval between the first and second concussions was also greater than previously cited. This difference may be the result of the methodology of direct independent physician observation, diagnosis, and adherence to the Zurich return-to-play protocol.


Patients with a first symptomatic unprovoked deep vein thrombosis are at higher risk of recurrent venous thromboembolism than patients with a first unprovoked pulmonary embolism.
Previous studies are mixed as to whether patients with unprovoked pulmonary embolism (PE) have a higher rate of venous thromboembolism (VTE) recurrence after anticoagulation is discontinued than patients with unprovoked deep vein thrombosis (DVT). To determine whether patients with unprovoked PE have a higher rate of VTE recurrence than patients with unprovoked DVT in a prospective multicenter cohort study. Six hundred and forty-six patients with a first episode of symptomatic unprovoked VTE were treated with heparin and subsequent oral anticoagulation for 5-7 months, and were followed every 6 months for recurrent VTE after their anticoagulant therapy was discontinued. Of 646 patients, 194 had isolated PE, 339 had isolated DVT, and 113 had both DVT and PE. After a mean of 18 months of follow-up, there were 91 recurrent VTE events (9.5% annualized risk of recurrent VTE in the total population). The crude recurrent VTE rate for the isolated PE, isolated DVT and DVT and PE groups were 7.7%, 16.5% and 17.7%, respectively. The relative risk of recurrent VTE for isolated DVT vs. isolated PE was 2.1 (95% confidence interval 1.2-3.7). This study has demonstrated that patients with a first episode of unprovoked isolated DVT are 2.1 times more likely to have a recurrent VTE episode than patients with a first episode of unprovoked isolated PE. These findings need to be considered when determining the optimal duration of anticoagulant therapy for patients with unprovoked VTE.


Dietary Patterns and CKD Progression.
Chronic kidney disease (CKD) patients and their clinicians seek ways to mitigate the risk of CKD progression and its associated complications. Emerging data suggest that dietary modifications may be beneficial adjuvant approaches to reducing the risk of adverse CKD outcomes. This review focuses on several different dietary patterns, including the Dietary Approaches to Stop Hypertension and Mediterranean diets, and their kidney health benefits. We discuss how healthful dietary patterns are lower in dietary acid load and how improving diet quality may slow the progression of CKD. We also discuss some barriers that may impede socially disadvantaged individuals from following healthful diets. Dietary patterns low in dietary acid load might slow the progression of CKD. Current evidence suggests that a reduction in dietary acid load could be beneficial in patients with CKD, but the supremacy of any particular diet is yet to be established. Additional randomized controlled dietary interventions among CKD patients are needed to inform evidence-based recommendations, which can be tailored to an individual's preferences and ability to access healthful foods.


Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/- mast cells.
The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/-) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1-/-) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/- mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration. Thus, these studies identify a novel interaction between Nf1-/- Schwann cells and Nf1+/- mast cells that is likely to be important in neurofibroma formation.


Identifying adolescent sleep problems.
To examine the efficacy of self-report and parental report of adolescent sleep problems and compare these findings to the incidence of adolescents who fulfill clinical criteria for a sleep problem. Sleep and daytime functioning factors that predict adolescents' self-identification of a sleep problem will also be examined. 308 adolescents (aged 13-17 years) from eight socioeconomically diverse South Australian high schools participated in this study. Participants completed a survey battery during class time, followed by a 7-day Sleep Diary and the Flinders Fatigue Scale completed on the final day of the study. Parents completed a Sleep, Medical, Education and Family History Survey. The percentage of adolescents fulfilling one or more of the criteria for a sleep problem was inordinately high at 66%. Adolescent self-reporting a sleep problem was significantly lower than the adolescents who had one or more of the clinical criteria for a sleep problem (23.1% vs. 66.6%; χ(2) = 17.46, p<.001). Parental report of their adolescent having a sleep problem was significantly lower than adolescent self-report (14.3% vs. 21.1%, p<.001). Adolescents who reported unrefreshing sleep were 4.81 times more likely to report a sleep problem. For every hour that bedtime was delayed, the odds of self-reporting a sleep problem increased by 1.91 times, while each additional 10 minutes taken to fall asleep increased the odds 1.40 times. While many adolescents were found to have sleep patterns indicative of a sleep problem, only a third of this number self-identify having a sleep problem, while only a sixth of this number are indicated by parental report. This study highlights important features to target in future sleep education and intervention strategies for both adolescents and parents.


Shared decision-making, health choices and the menopause.
The growing influence of the mass media on public understanding of health care matters has increased both information and misinformation in patients seeking help with menopausal symptoms. The use of shared decision-making strategies provides the opportunity to engage the patient in taking some responsibility for their own treatment. It also allows the identification and correction of any distortions in the perceived balance of evidence for and against any particular treatment. Shared decision-making balances the need to respect patients' values and autonomy with the drive towards evidence-based medicine and clinical cost-effectiveness. Although ways of achieving such a balance are much discussed, the current need is for research which can identify effective strategies that allow the principles of "shared decision-making" and "evidence-based patient choice" to be validated and applied in clinical practice. Previous research focused on hormone replacement therapy indicates that the patient's decision is the outcome of the way they balance the pros and cons of taking (or not taking) it, and that their satisfaction with the decision is strongly associated with the perception that they have been given information about the full range of treatment available. It therefore seems likely that patients will respond more positively to consultations which include discussion of hormone replacement therapy alongside alternative strategies such as natural remedies and dietary/lifestyle changes. Psychological factors influencing treatment choice and the decision making process are discussed, and clinical and research implications for clinical practice in the menopause clinic examined.


An Improved Melon Reference Genome With Single-Molecule Sequencing Uncovers a Recent Burst of Transposable Elements With Potential Impact on Genes.
The published melon (Cucumis melo L.) reference genome assembly (v3.6.1) has still 41.6 Mb (Megabases) of sequences unassigned to pseudo-chromosomes and about 57 Mb of gaps. Although different approaches have been undertaken to improve the melon genome assembly in recent years, the high percentage of repeats (~40%) and limitations due to read length have made it difficult to resolve gaps and scaffold's misassignments to pseudomolecules, especially in the heterochromatic regions. Taking advantage of the PacBio single- molecule real-time (SMRT) sequencing technology, an improvement of the melon genome was achieved. About 90% of the gaps were filled and the unassigned sequences were drastically reduced. A lift-over of the latest annotation v4.0 allowed to re-collocate protein-coding genes belonging to the unassigned sequences to the pseudomolecules. A direct proof of the improvement reached in the new melon assembly was highlighted looking at the improved annotation of the transposable element fraction. By screening the new assembly, we discovered many young (inserted less than 2Mya), polymorphic LTR-retrotransposons that were not captured in the previous reference genome. These elements sit mostly in the pericentromeric regions, but some of them are inserted in the upstream region of genes suggesting that they can have regulatory potential. This improved reference genome will provide an invaluable tool for identifying new gene or transposon variants associated with important phenotypes.


The global burden of non-typhoidal salmonella invasive disease: a systematic analysis for the Global Burden of Disease Study 2017.
Non-typhoidal salmonella invasive disease is a major cause of global morbidity and mortality. Malnourished children, those with recent malaria or sickle-cell anaemia, and adults with HIV infection are at particularly high risk of disease. We sought to estimate the burden of disease attributable to non-typhoidal salmonella invasive disease for the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. We did a systematic review of scientific databases and grey literature, and estimated non-typhoidal salmonella invasive disease incidence and mortality for the years 1990 to 2017, by age, sex, and geographical location using DisMod-MR, a Bayesian meta-regression tool. We estimated case fatality by age, HIV status, and sociodemographic development. We also calculated the HIV-attributable fraction and estimated health gap metrics, including disability-adjusted life-years (DALYs). We estimated that 535 000 (95% uncertainty interval 409 000-705 000) cases of non-typhoidal salmonella invasive disease occurred in 2017, with the highest incidence in sub-Saharan Africa (34·5 [26·6-45·0] cases per 100 000 person-years) and in children younger than 5 years (34·3 [23·2-54·7] cases per 100 000 person-years). 77 500 (46 400-123 000) deaths were estimated in 2017, of which 18 400 (12 000-27 700) were attributable to HIV. The remaining 59 100 (33 300-98 100) deaths not attributable to HIV accounted for 4·26 million (2·38-7·38) DALYs in 2017. Mean all-age case fatality was 14·5% (9·2-21·1), with higher estimates among children younger than 5 years (13·5% [8·4-19·8]) and elderly people (51·2% [30·2-72·9] among those aged ≥70 years), people with HIV infection (41·8% [30·0-54·0]), and in areas of low sociodemographic development (eg, 15·8% [10·0-22·9] in sub-Saharan Africa). We present the first global estimates of non-typhoidal salmonella invasive disease that have been produced as part of GBD 2017. Given the high disease burden, particularly in children, elderly people, and people with HIV infection, investigating the sources and transmission pathways of non-typhoidal salmonella invasive disease is crucial to implement effective preventive and control measures. Bill & Melinda Gates Foundation.


Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing.
Analysis of the Kv3 subfamily of K(+) channel subunits has lead to the discovery of a new class of neuronal voltage-gated K(+) channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height. The short spike duration and the rapid deactivation of the Kv3 currents after spike repolarization maximize the quick recovery of resting conditions after an action potential. Several neurons in the mammalian CNS have incorporated into their repertoire of voltage-dependent conductances a relatively large number of Kv3 channels to enable repetitive firing at high frequencies - an ability that crucially depends on the special properties of Kv3 channels and their impact on excitability.


Undergraduate healthcare ethics education, moral resilience, and the role of ethical theories.
This article combines foundational and empirical aspects of healthcare education and develops a framework for teaching ethical theories inspired by pragmatist learning theory and recent work on the concept of moral resilience. It describes an exemplary implementation and presents data from student evaluation. After a pilot implementation in a regular ethics module, the feasibility and acceptance of the novel framework by students were evaluated. In addition to the regular online module evaluation, specific questions referring to the teaching of ethical theories were added using simple (yes/no) and Likert rating answer formats. At the Bern University of Applied Sciences, a total of 93 students from 2 parallel sub-cohorts of the bachelor's program in nursing science were sent the online survey link after having been exposed to the same modular contents. A total of 62% of all students participated in the survey. The survey was voluntary and anonymous. Students were free to write their name and additional comments. Students consider ethical theories-as taught within the proposed framework-as practically applicable, useful, and transferable into practice. Teaching ethical theories within the proposed framework overcomes the shortcomings described by current research. Students do not consider the mutually exclusive character of ethical theories as an insurmountable problem. The proposed framework is likely to promote the effectiveness of healthcare ethics education. Inspired by pragmatist learning theory, it enables students to consider ethical theories as educative playgrounds that help them to "frame" and "name" the ethical issues they encounter in daily practice, which is seen as an expression of moral resilience. Since it does not advocate a single ethical theory, but is open to the diversity of traditions that shape ethical thinking, it promotes a culturally sensitive, ethically reflected healthcare practice.


Genetic diversity and stability of the porA allele as a genetic marker in human Campylobacter infection.
The major outer-membrane protein (MOMP) of Campylobacter jejuni and Campylobacter coli, encoded by the porA gene, is extremely genetically diverse. Conformational MOMP epitopes are important in host immunity, and variation in surface-exposed regions probably occurs as a result of positive immune selection during infection. porA diversity has been exploited in genotyping studies using highly discriminatory nucleotide sequences to identify potentially epidemiologically linked cases of human campylobacteriosis. To understand the overall nature and extent of porA diversity and stability in C. jejuni and C. coli we investigated sequences in isolates (n=584) obtained from a defined human population (approx. 600,000) over a defined time period (1 year). A total of 196 distinct porA variants were identified. Regions encoding putative extracellular loops were the most variable in both nucleotide sequence and length. Phylogenetic analysis identified three porA allele clusters that originated in (i) predominantly C. jejuni and a few C. coli, (ii) solely C. jejuni or (iii) predominantly C. coli and a few C. jejuni. The stability of porA within an individual human host was investigated using isolates cultured longitudinally from 64 sporadic cases, 27 of which had prolonged infection lasting between 5 and 98 days (the remainder having illness of normal duration, 0-4 days), and 20 cases from family outbreaks. Evidence of mutation was detected in two patients with prolonged illness. Despite demonstrable positive immune selection in these two unusual cases, the persistence of numerous variants within the population indicated that the porA allele is a valuable tool for use in extended typing schemes.


Lack of a role for type I and type II interferons in the resolution of rotavirus-induced diarrhea and infection in mice.
Rotavirus infects the intestinal epithelium of most mammalian species and causes diarrhea in infants. Previously, we have shown that both type I and II human interferons (IFNs) have potent and mechanistically discreet antiviral effects in vitro against rotavirus. We have also shown that adult IFN-gamma knockout (-/-) mice have no alteration in clearance of primary rotavirus infection. In the present studies, we wished to determine the importance of both IFN types in modulation of degree and duration of disease and infection in mice. Immunocompetent suckling mice were treated orally (5,000 IU) or parenterally (500 IU) with type I and II murine IFNs before and after challenge with virulent murine rotavirus. Treated animals developed diarrhea indistinguishable from that observed in untreated control mice. In other experiments, type I IFN receptor -/- suckling mice and IFN-gamma-/- suckling mice developed diarrhea of similar characteristics and duration and had comparable quantities of viral antigen in their intestines as did immunocompetent mice. Furthermore, type I IFN receptor -/- adult mice infected with rotavirus shed equivalent quantities of viral antigen and with similar kinetics as the control mice. Thus, IFNs do not seem to be major inhibitors of rotavirus diarrhea or replication in mice.


Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats.
Vampire bats (Desmodus rotundus) are obligate blood feeders that have evolved specialized systems to suit their sanguinary lifestyle. Chief among such adaptations is the ability to detect infrared radiation as a means of locating hotspots on warm-blooded prey. Among vertebrates, only vampire bats, boas, pythons and pit vipers are capable of detecting infrared radiation. In each case, infrared signals are detected by trigeminal nerve fibres that innervate specialized pit organs on the animal's face. Thus, vampire bats and snakes have taken thermosensation to the extreme by developing specialized systems for detecting infrared radiation. As such, these creatures provide a window into the molecular and genetic mechanisms underlying evolutionary tuning of thermoreceptors in a species-specific or cell-type-specific manner. Previously, we have shown that snakes co-opt a non-heat-sensitive channel, vertebrate TRPA1 (transient receptor potential cation channel A1), to produce an infrared detector. Here we show that vampire bats tune a channel that is already heat-sensitive, TRPV1, by lowering its thermal activation threshold to about 30 °C. This is achieved through alternative splicing of TRPV1 transcripts to produce a channel with a truncated carboxy-terminal cytoplasmic domain. These splicing events occur exclusively in trigeminal ganglia, and not in dorsal root ganglia, thereby maintaining a role for TRPV1 as a detector of noxious heat in somatic afferents. This reflects a unique organization of the bat Trpv1 gene that we show to be characteristic of Laurasiatheria mammals (cows, dogs and moles), supporting a close phylogenetic relationship with bats. These findings reveal a novel molecular mechanism for physiological tuning of thermosensory nerve fibres.


Developing an academic health department in Northeast Tennessee: a sustainable approach through student leadership.
In an effort to bridge the gap between public health practice and academia, the Health Resources and Services Administration-funded Tennessee Public Health Training Center (LIFEPATH) has supported establishment of an academic health department (AHD) involving the East Tennessee State University College of Public Health (COPH) and the Sullivan County Regional Health Department (SCRHD). The SCRHD identified a need to increase internal capacity to conduct ongoing community health assessment and community-centered practice. Similarly, the COPH recognized the need to expand evidence-based practice implementation and evaluation opportunities for public health students. Personnel from the SCRHD, LIFEPATH, and the COPH developed a formal AHD agreement during the summer of 2012 and launched the program the subsequent fall semester. One aspect of the COPH/SCRHD/LIFEPATH model that addresses financial barriers experienced by other AHDs is the competitive awarding of the coordinator position to a doctor of public health student from the COPH, demonstrating investment in the model by the college. The doctor of public health student gains leadership experience through project management, coordination of the local health council, and day-to-day facilitation of undergraduate and master's student interns. The SCRHD benefits from the formal academic background of graduate-level interns dedicated to working in the community. This AHD framework offers an opportunity for doctoral-level students to develop practical leadership skills in a health department while enhancing the capacity of the SCRHD and the COPH to serve their community and stakeholders.


AACR-FDA-NCI Cancer Biomarkers Collaborative consensus report: advancing the use of biomarkers in cancer drug development.
Recent discoveries in cancer biology have greatly increased our understanding of cancer at the molecular and cellular level, but translating this knowledge into safe and effective therapies for cancer patients has proved to be challenging. There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost. Biomarkers are central to accelerating the identification and adoption of new therapies, but currently, many barriers impede their use in drug development and clinical practice. In 2007, the AACR-FDA-NCI Cancer Biomarkers Collaborative stepped into the national effort to bring together disparate stakeholders to clearly delineate these barriers, to develop recommendations for integrating biomarkers into the cancer drug development enterprise, and to set in motion the necessary action plans and collaborations to see the promise of biomarkers come to fruition, efficiently delivering quality cancer care to patients.


Biocompatibility issues with modern implants in bone - a review for clinical orthopedics.
Skeletal defects may result from traumatic, infectious, congenital or neoplastic processes and are considered to be a challenge for reconstructive surgery. Although the autologous bone graft is still the "gold standard", there is continuing demand for bone substitutes because of associated disadvantages, such as limited supply and potential donor side morbidity [1]. This is not only true for indications in orthopedic and craniomaxillofacial surgeries, but also in repairing endodontic defects and in dental implantology.Before clinical use all new bone substitute materials have to be validated for their osseoconductive and - depending on the composition of the material also -inductive ability, as well as for their long-term biocompatibility in bone. Serving this purpose various bone healing models to test osteocompatibility and inflammatory potential of a novel material on one hand and, on the other hand, non-healing osseous defects to assess the healing potential of a bone substitute material have been developed. Sometimes the use of more than one implantation site can be helpful to provide a wide range of information about a new material [2].Important markers for biocompatibility and inflammatory responses are the cell types appearing after the implantation of foreign material. There, especially the role of foreign body giant cells (FBGC) is discussed controversial in the pertinent literature, such that it is not clear whether their presence marks an incompatibility of the biomaterial, or whether it belongs to a normal degradation behavior of modern, resorbable biomaterials.This publication is highlighting the different views currently existing about the function of FBGC that appear in response to biomaterials at the implantation sites. A short overview of the general classes of biomaterials, where FBGC may appear as cellular response, is added for clarity, but may not be complete.


Vibrio shiloi sp. nov., the causative agent of bleaching of the coral Oculina patagonica.
The aetiological agent of bleaching of the coral Oculina patagonica was characterized as a new Vibrio species on the basis of 16S rDNA sequence, DNA-DNA hybridization data and phenotypic properties, including the cellular fatty acid profile. Based on its 16S rDNA and DNA-DNA hybridization, the new Vibrio species is closely related to Vibrio mediterranei. The name Vibrio shiloi sp. nov. is proposed for the new coral-bleaching species, the type strain being AK1T (= ATCC BAA-91T = DSM 13774T).


Toxicological aspects of flavonoid interaction with biomacromolecules.
Flavonoids are widely accepted as health promoting phytochemicals, however, some flavonoids show ability of direct interaction with DNA and/or enhance carcinogen activation into DNA modifying agents. Thus, their potential harmful effect on the human body should be examined in detail. Direct interaction of flavonoids (quercetin, rutin) with DNA was examined using square wave voltammetry on carbon paste electrode. Induction effect of selected flavonoids on content of cytochrome P450 1A1, carcinogens activating enzyme, in colon and liver microsomal samples of animals exposed to flavonoids was determined by Western blotting, using anti-cytochrome P450 1A1 specific antibody. Of the natural flavonoids tested, induction of CYP1A1 was elicited by the typical citrus flavonoid naringenin in the colon, as well as by flavone in the liver. Moreover, synthetic beta-naphthoflavone and naturally occurring chrysin, quercetin and diosmin induced CYP1A1 in both tissues. The oxidation signals of guanine and adenine in the DNA molecule were decreased in the presence of flavonoids. Although flavonoids are often considered to be safe because of their "plant origin", ingestion of flavonoids should be taken with caution. Enhanced expression of CYP1A1 in colon tissue might be responsible for increasing incidence of colorectal carcinoma in humans. Electrochemistry can be used to study the interactions of flavonoids and DNA.


Measuring information interactions on the ordinal pattern of stock time series.
The interactions among time series as individual components of complex systems can be quantified by measuring to what extent they exchange information among each other. In many applications, one focuses not on the original series but on its ordinal pattern. In such cases, trivial noises appear more likely to be filtered and the abrupt influence of extreme values can be weakened. Cross-sample entropy and inner composition alignment have been introduced as prominent methods to estimate the information interactions of complex systems. In this paper, we modify both methods to detect the interactions among the ordinal pattern of stock return and volatility series, and we try to uncover the information exchanges across sectors in Chinese stock markets.


Identifying a kinase network regulating FGF14:Nav1.6 complex assembly using split-luciferase complementation.
Kinases play fundamental roles in the brain. Through complex signaling pathways, kinases regulate the strength of protein:protein interactions (PPI) influencing cell cycle, signal transduction, and electrical activity of neurons. Changes induced by kinases on neuronal excitability, synaptic plasticity and brain connectivity are linked to complex brain disorders, but the molecular mechanisms underlying these cellular events remain for the most part elusive. To further our understanding of brain disease, new methods for rapidly surveying kinase pathways in the cellular context are needed. The bioluminescence-based luciferase complementation assay (LCA) is a powerful, versatile toolkit for the exploration of PPI. LCA relies on the complementation of two firefly luciferase protein fragments that are functionally reconstituted into the full luciferase enzyme by two interacting binding partners. Here, we applied LCA in live cells to assay 12 kinase pathways as regulators of the PPI complex formed by the voltage-gated sodium channel, Nav1.6, a transmembrane ion channel that elicits the action potential in neurons and mediates synaptic transmission, and its multivalent accessory protein, the fibroblast growth factor 14 (FGF14). Through extensive dose-dependent validations of structurally-diverse kinase inhibitors and hierarchical clustering, we identified the PI3K/Akt pathway, the cell-cycle regulator Wee1 kinase, and protein kinase C (PKC) as prospective regulatory nodes of neuronal excitability through modulation of the FGF14:Nav1.6 complex. Ingenuity Pathway Analysis shows convergence of these pathways on glycogen synthase kinase 3 (GSK3) and functional assays demonstrate that inhibition of GSK3 impairs excitability of hippocampal neurons. This combined approach provides a versatile toolkit for rapidly surveying PPI signaling, allowing the discovery of new modular pathways centered on GSK3 that might be the basis for functional alterations between the normal and diseased brain.


Marital coitus across the life course.
It remains unclear whether the frequency of marital coitus does in fact decline universally across the life course, what shape that decay normally takes, and what best accounts for it: increasing marriage duration, women's age or age of their partners. Using cross-sectional Demographic and Health Survey (DHS) data of 91,744 non-abstaining women in their first marriage, a generalized linear model is used to determine if there is a consistent pattern in the life course pattern of degradation in the frequency of marital coitus. Datasets were drawn from nineteen countries in Asia, Africa and the Americas. Use of very large samples allows proper disentangling of the effects of women's age, husband's age and marital duration, and use of samples from multiple countries allows consideration of the influence of varied prevailing fertility regimes and fertility-related practices on life course trajectories. It is found that declining coital frequency over time seems a shared demographic feature of human populations, but whether marriage duration, wife's age or husband's age is most responsible for that decline varies by country. In many cases, coital frequency actually increases with women's age into their thirties, once husband's age and marriage duration are taken into account, but in most cases coital frequency declines with husband's age and marital duration.


Dipstick proteinuria is an independent predictor of high on treatment platelet reactivity in patients on clopidogrel, but not aspirin, admitted for major adverse cardiovascular events.
The effectiveness of aspirin and clopidogrel in patients with chronic kidney disease (CKD) suffering from acute cardiovascular events is unclear. High on treatment platelet reactivity (HTPR) has been associated with worse outcomes. Here, we assessed the association of dipstick proteinuria (DP) and renal function on HTPR and clinical outcomes. Retrospective cohort analysis of 261 consecutive, non-dialysis patients admitted for Major Adverse Cardiovascular Events (MACE) that had VerifyNow P2Y12 and VerifyNow Aspirin assays performed. HTPR was defined as P2Y12 reactivity unit (PRU) > 208 for clopidogrel and aspirin reaction units (ARU) > 550 for aspirin. Renal function was classified based on the estimated glomerular filtration rate (eGFR), and dipstick proteinuria was defined as ≥ 30 mg/dl of albumin detected on a spot analysis. All cause mortality, readmissions, and cardiac catheterizations were reviewed over 520 days. In patients on clopidogrel (n = 106), DP was associated with HTPR, independent of eGFR, diabetes mellitus, smoking or use of proton pump inhibitor (AOR = 4.76, p = 0.03). In patients with acute coronary syndromes, HTPR was associated with more cardiac catheterizations (p = 0.009) and readmissions (p = 0.032), but no differences in in-stent thrombosis or re-stenosis were noted in this cohort. In patients on aspirin (n = 155), no associations were seen between DP and HTPR. However, all cause mortality was significantly higher with HTPR in this group (p = 0.038). In this cohort, DP is an independent predictor of HTPR in patients on clopidogrel, but not aspirin, admitted to the hospital for MACE.


Routine laboratory tests can predict in-hospital mortality in acute exacerbations of COPD.
Chronic obstructive pulmonary disease (COPD) has a rising global incidence and acute exacerbation of COPD (AECOPD) carries a high health-care economic burden. Classification and regression tree (CART) analysis is able to create decision trees to classify risk groups. We analysed routinely collected laboratory data to identify prognostic factors for inpatient mortality with AECOPD from our large district hospital. Data from 5,985 patients with 9,915 admissions for AECOPD over a 7-year period were examined. Randomly allocated training (n = 4,986) or validation (n = 4,929) data sets were developed and CART analysis was used to model the risk of all-cause death during admission. Inpatient mortality was 15.5%, mean age was 71.5 (±11.5) years, 56.2% were male, and mean length of stay was 9.2 (±12.2) days. Of 29 variables used, CART analysis identified three (serum albumin, urea, and arterial pCO(2)) to predict in-hospital mortality in five risk groups, with mortality ranging from 3.0 to 23.4%. C statistic indices were 0.734 and 0.701 on the training and validation sets, respectively, indicating good model performance. The highest-risk group (23.4% mortality) had serum urea >7.35 mmol/l, arterial pCO(2) >6.45 kPa, and normal serum albumin (>36.5 g/l). It is possible to develop clinically useful risk prediction models for mortality using laboratory data from the first 24 h of admission in AECOPD.


Anatomical Analysis and Feasibility Study of Next-Generation Fenestrated or Branched Stent-Grafts for the Treatment of Arch Aneurysms.
Purpose: To analyze the anatomical characteristics of arch aneurysms and evaluate the anatomical feasibility of 4 next-generation stent-grafts with either branched or fenestrated configurations. Materials and Methods: A retrospective analysis was conducted of 213 patients (mean age 75.0±7.1 years; 179 men) with arch aneurysms treated using total arch replacement or zone 0 or 1 thoracic endovascular aortic repair (TEVAR) from 2007 to 2017 at 2 Japanese hospitals. Anatomical analyses were performed using the centerline of flow technique on a 3-dimensional workstation. The anatomical feasibility of the Zenith A-branch, TAG Thoracic Branch Endoprosthesis (TBE), Terumo Aortic Relay Plus Double Branched (DB), and fenestrated Najuta stent-grafts were evaluated based on the instructions for use (IFU). Results: The mean lengths from the sinotubular junction (STJ) to the innominate artery (IA) and from the IA to the left common carotid artery were 114.9±15.9 and 12.8±5.6 mm, respectively. The mean aortic diameters at the STJ and IA were 31.3±3.4 and 34.1±5.3 mm, respectively. In terms of feasibility, 5.2% of patients were within the Zenith A-branch IFU, 40.8% for the TAG TBE, 24.9% for the Relay Plus DB, and 13.6% for the Najuta. Significant (>50% circumference) thrombus/calcification at the sealing zone affected nearly half of the patients, but there is currently no standardized definition or evaluation method for "significant" thrombus/calcification. Conclusion: Only 5% to 41% of arch aneurysm patients are anatomically suitable for TEVAR using any one of the next-generation branched or fenestrated stent-grafts. Furthermore, a definitive method of evaluating the thrombus/calcification burden needs to be established in future IFU.


Quantifying aromaticity with electron delocalisation measures.
Aromaticity cannot be measured directly by any physical or chemical experiment because it is not a well-defined magnitude. Its quantification is done indirectly from the measure of different properties that are usually found in aromatic compounds such as bond length equalisation, energetic stabilisation, and particular magnetic behaviour associated with induced ring currents. These properties have been used to set up the myriad of structural-, energetic-, and magnetic-based indices of aromaticity known to date. The cyclic delocalisation of mobile electrons in two or three dimensions is probably one of the key aspects that characterise aromatic compounds. However, it has not been until the last decade that electron delocalisation measures have been widely employed to quantify aromaticity. Some of these new indicators of aromaticity such as the PDI, FLU, ING, and INB were defined in our group. In this paper, we review the different existing descriptors of aromaticity that are based on electron delocalisation properties, we compare their performance with indices based on other properties, and we summarise a number of applications of electronic-based indices for the analysis of aromaticity in interesting chemical problems.


Characterization and cloning of a bovine insulin-like growth factor-binding protein.
The primary structure of the insulin-like growth factor-binding protein (IGFBP) produced by the bovine kidney cell line, MDBK, has been deduced from the cDNA clone. The MDBK binding protein precursor consists of a hydrophobic pre-peptide of at least 26 amino acids and a mature protein of 284 amino acids. The predicted protein sequence shares extensive sequence similarity with both the rat (82%) and human (89%) IGFBP-2s, so that the MDBK binding protein is clearly the bovine counterpart of IGFBP-2. The protein has limited similarity with classes 1 (31%) and 3 (31%) human IGFBPs, except that all 18 cysteine residues are conserved. Other features deduced from the bovine IGFBP-2 cDNA include: an abundance of leucine in the pre-peptide, an Arg-Gly-Asp sequence, absence of N-linked glycosylation sites, and an imperfect polyadenylation signal as well as an ATTTA motif in the 3' non-coding DNA. Western blotting indicated that this binding protein is widely distributed in bovine fluids as well as in media conditioned by bovine cell lines. Proteins immunologically related to bovine IGFBP-2 were detected not only in sheep, but also in chickens, indicating that this IGFBP is not exclusively mammalian.


Expansion of the aspartate beta-semialdehyde dehydrogenase family: the first structure of a fungal ortholog.
The enzyme aspartate semialdehyde dehydrogenase (ASADH) catalyzes a critical transformation that produces the first branch-point intermediate in an essential microbial amino-acid biosynthetic pathway. The first structure of an ASADH isolated from a fungal species (Candida albicans) has been determined as a complex with its pyridine nucleotide cofactor. This enzyme is a functional dimer, with a similar overall fold and domain organization to the structurally characterized bacterial ASADHs. However, there are differences in the secondary-structural elements and in cofactor binding that are likely to cause the lower catalytic efficiency of this fungal enzyme. Alterations in the dimer interface, through deletion of a helical subdomain and replacement of amino acids that participate in a hydrogen-bonding network, interrupt the intersubunit-communication channels required to support an alternating-site catalytic mechanism. The detailed functional information derived from this new structure will allow an assessment of ASADH as a possible target for antifungal drug development.


HMGB1 A box protects neurons by potently inhibiting both microglia and T cell-mediated inflammation in a mouse Parkinson's disease model.
In the subacute Parkinson's disease (PD) mice model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), injection of HMGB1 competitive inhibitor protein HMGB1 A box and the ethyl pyruvate (EP) that inhibit the release of HMGB1 from cells restored the number of dopaminergic neurons and TH+ fibers in the SN and striatum. Our data show that A box up-regulated CD200-CD200R signal of microglia inhibited the activation of microglia mediated by HMGB1, and the production of TNF-α, IL-1β and IL-6 in vivo and in vitro mixed culture system. Microglia overexpressing CD200R produced less inflammatory chemokines and reduced the loss of TH+ neurons. In addition, HMGB1 A box decreased the level of CCL5 and significantly inhibited the infiltration of almost all T cells including Th17 and the proportion of Th17 in CD4+ T cells. In vitro MPP+ induced model and HMGB1-stimulated mesencephalic cell system activated microglia induced the differentiation of naïve T cells to Th17, and A box significantly inhibited this process. To sum up, our results show that HMGB1 A box targeting HMGB1, which effectively reduces the activation of microglia in MPTP PD model by restoring CD200-CD200R signal inhibit microglia mediated neuroinflammation and the differentiation of T cells to Th17.


Anal fistula plug versus surgeon's preference for surgery for trans-sphincteric anal fistula: the FIAT RCT.
The aim of fistula surgery is to eradicate the disease while preserving anal sphincter function. The efficacy of the Surgisis® anal fistula plug (Cook Medical, Bloomington, IN, USA) in the treatment of trans-sphincteric fistula-in-ano has been variably reported. To undertake a randomised comparison of the safety and efficacy of the Surgisis anal fistula plug in comparison with surgeon's preference for the treatment of trans-sphincteric anal fistulas. A randomised, unblinded, parallel-arm, prospective, multicentre clinical trial. Hospitals in the UK NHS involving colorectal surgeons accredited by the Association of Coloproctology of Great Britain and Ireland. Adult patients suffering from trans-sphincteric fistula-in-ano of cryptoglandular origin. Patients were randomised on a 1 : 1 basis to either the fistula plug or the surgeon's preference [e.g. fistulotomy, cutting seton, advancement flap or ligation of intersphincteric fistula tract (LIFT) procedure]. The primary outcome measure was quality of life as measured by the Faecal Incontinence Quality of Life (FIQoL) questionnaire at 12-month follow-up. Secondary outcome measures included clinical and radiological fistula healing rates, faecal incontinence rates, complications rates, reintervention rates and cost-effectiveness. Between May 2011 and March 2016, 304 participants were recruited (152 fistula plug vs. 152 surgeon's preference). No difference in FIQoL score between the two trial groups was seen at the 6-week, 6-month or 12-month follow-up. Clinical evidence of fistula healing was reported in 66 of 122 (54%) participants in the fistula plug group and in 66 of 119 (55%) participants in the surgeon's preference group at 12 months. Magnetic resonance imaging (MRI) showed fistula healing in 54 of 110 (49%) participants in the fistula plug group and in 63 of 112 (56%) participants in the surgeon's preference group. Variation in 12-month clinical healing rates was observed: 55%, 64%, 75%, 53% and 42% for fistula plug, cutting seton, fistulotomy, advancement flap and LIFT procedure, respectively. Faecal incontinence rates were low at baseline, with small improvement in both groups post treatment. Complications and reinterventions were frequent. The mean total costs were £2738 [standard deviation (SD) £1151] in the fistula plug group and £2308 (SD £1228) in the surgeon's preference group. The average total quality-adjusted life-years (QALYs) gain was much smaller in the fistula plug group (0.829, SD 0.174) than in the surgeon's preference group (0.790, SD 0.212). Using multiple imputation and probabilistic sensitivity analysis, and adjusting for differences in baseline EuroQol-5 Dimensions, three-level version utility, there was a 35-45% chance that the fistula plug was as cost-effective as surgeon's preference over a range of thresholds of willingness to pay for a single QALY of £20,000-30,000. Limitations include a smaller sample size than originally calculated, a lack of blinding that perhaps biased patient-reported outcomes and a lower compliance rate with MRI at 12-month follow-up. The Surgisis anal fistula plug is associated with similar FIQoL score to surgeon's preference at 12-month follow-up. The higher costs and highly uncertain and small gains in QALYs associated with the fistula plug mean that this technology is unlikely to be considered a cost-effective use of resources in the UK NHS. Further in-depth analysis should consider the clinical and MRI characteristics of fistula-in-ano in an attempt to identify predictors of fistula response to treatment. Current Controlled Trials ISRCTN78352529. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 21. See the NIHR Journals Library website for further project information.


The new BMI criteria for asians by the regional office for the western pacific region of WHO are suitable for screening of overweight to prevent metabolic syndrome in elder Japanese workers.
Obesity occurs less frequently in Japanese than in various other ethnic populations. A person with abnormal glucose tolerance is often found to have one or more of the other cardiovascular disease risk factors, such as obesity, hypertension and hyperlipidemia. This clustering has been labeled as metabolic syndrome (WHO, 1998). It was suggested that Japanese, categorized as having normal weight (BMI of less than 25.0), as defined by the WHO (2000), have an increasing tendency toward metabolic syndrome. Our objective was to analyze metabolic syndrome in "Overweight" with BMI of 23.0-24.9 in Japanese workers, and to assess the suitability for Asians of the Regional Office for the Western Pacific Region of WHO criteria pertaining to obesity (WPRO criteria, 2000). We conducted a cross-sectional study in the workplace setting and investigated the relationship between BMI classification based on WPRO criteria and metabolic syndrome by gender and age group (18-44 yr vs. 45-60 yr). Three hundred seventy-nine men and 432 women Japanese workers participated in this study. BMI were categorized as 20% "Overweight" (23.0-24.9 BMI), 20% "Obese I" (25.0-29.9 BMI) and 2% "Obese II" (over 30.0 BMI), based on WPRO criteria. Graded increases in BMI were positively associated with body fat percentage, waist circumference, hip circumference and waist/hip ratio in both genders and age groups. A progressively increasing BMI category in the elder group aged 45-60 yr in both genders was positively related with parameters constituting metabolic syndrome. Graded increases in BMI classes in elder workers based on WPRO criteria were positively associated with prevalence of metabolic syndrome, and "Overweight" elder women had significantly higher prevalence of metabolic syndrome. The present investigation, based on the increasing risks of "Overweight" with a BMI of 23.0-24.9, suggests that WPRO criteria are suitable for Japanese workers aged over 45 yr.


Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1.
We report 4 cases of malignant peripheral nerve sheath tumors (MPNST) with neurofibromatosis type 1 (NF1). Mean age was 29.5. Two of them had a family history. Three of them were male. All of them had enlarging mass and pain in the background of neurofibromas. Locations were popliteal, thigh and forearm. The masses were greater than 5 cm in diameter in each case. In two cases the mass was showing continuity with a nerve. One patient had a nonossifying fibroma as well as a MPNST. Wide excision and radiotherapy were applied to three of the patients. One of them did not take any therapy after surgical resection. Two of the patients died of lung metastases after a mean period of 12.5 months. In a majority of NF1 patients MPNST emerges from a preexisting neurofibroma. The patients with NF1 are at greatest risk for developing sarcomas, so they should be followed closely.


Association between 24-hour urine sodium and potassium excretion and diet quality in six-year-old children: a cross sectional study.
Limited data is available on sodium (Na) and potassium (K) intake in young children estimated by 24 hour (24h) excretion in urine. The aim was to assess 24h urinary excretion of Na and K in six-year-old children and its relationship with diet quality. The study population was a subsample of a national dietary survey, including six-year-old children living in the greater Reykjavik area (n=76). Three day weighed food records were used to estimate diet quality. Diet quality was defined as adherence to the Icelandic food based dietary guidelines. Na and K excretion was analyzed from 24h urine collections. PABA check was used to validate completeness of urine collections. The associations between Na and K excretion and diet quality were estimated by linear regression, adjusting for gender and energy intake. Valid urine collections and diet registrations were provided by 58 children. Na and K excretion was, mean (SD), 1.64 (0.54) g Na/24h (approx. 4.1 g salt/24h) and 1.22 (0.43) g K/24h. In covariate adjusted models Na excretion decreased by 0.16 g Na/24h (95% CI: 0.31, 0.06) per 1-unit increase in diet quality score (score range: 1-4) while K excretion was increased by 0.18 g K/24h (95% CI: 0.06, 0.29). Na intake, estimated by 24h urinary excretion was on average higher than recommended. Increased diet quality was associated with lower Na excretion and higher K excretion in six-year-old children.


Recent advances in SALDI-MS techniques and their chemical and bioanalytical applications.
Although laser desorption mass spectrometry was introduced in the 1960s, the potential of laser mass spectrometry was not realised until the introduction of matrix-assisted laser desorption/ionisation (MALDI) in the 1980s. The technique relies on light-absorbing compounds called matrices that are co-crystallised with the analyte to achieve high ionisation and desorption efficiencies. MALDI offers a lot of advantages and is an indispensable tool in macromolecule analysis. However, the presence of the matrix also produces a high chemical background in the region below m/z 700 in the mass spectrum. Surface-assisted laser desorption/ionisation (SALDI) substitutes the chemical matrix of MALDI for an active surface, which means that matrix interference can be eliminated. SALDI mass spectrometry has evolved in recent years into a technique with great potential to provide insight into many of the challenges faced in modern research, including the growing interest in "omics" and the demands of pharmaceutical science. A great variety of materials have been reported to work in SALDI. Examples include a number of nanomaterials and surfaces. The unique properties of nanomaterials greatly facilitate analyte desorption and ionisation. This article reviews recent advances made in relation to carbon- and semiconductor-based SALDI strategies. Examples of their environmental, chemical and biomedical applications are discussed with the aim of highlighting progression in the field and the robustness of the technique, as well as to evaluate the strengths and weaknesses of individual approaches. In addition, this article describes the physical and chemical processes involved in SALDI and explains how the unique physical and electronic properties of nanostructured surfaces allow them to substitute for the matrix in energy transfer processes.


Prevalence and childhood antecedents of depersonalization syndrome in a UK birth cohort.
Depersonalization syndrome is characterised by a sense of unreality about the self [depersonalization (DP)] and/or the outside world [derealization (DR)]. Prevalence estimates vary widely. Little is known about childhood antecedents of the disorder although emotional abuse is thought to play a role. Longitudinal data from 3,275 participants of a UK population-based birth cohort (the MRC National Survey of Health and Development) were used to: (1) assess the prevalence of DP syndrome at age 36, measured by the Present State Examination (PSE); and (2) examine the effects of a range of socio-demographic, childhood adversity and emotional responses as potential risk factors for DP. Thirty three survey members were classified with DP, yielding a prevalence of 0.95% [95% confidence intervals (CI) 0.56-1.34]. There were no associations with socio-economic status, parental death or divorce; self-reported accidents, childhood depression, tendency to daydream or reactions to criticism. However, teacher-estimated childhood anxiety was a strong independent predictor of adult depersonalization, and there were strong cross-sectional relationships between DP and anxiety and depression caseness. To our knowledge this is the first study assessing nationwide prevalence of the DP syndrome and uses longitudinal data to explore childhood risk factors for adult DP. The prevalence of adult DP was slightly lower than reported by other surveys. The study found that childhood anxiety was the only significant predictor of the adult DP syndrome, supporting the view that depersonalisation disorder forms part of the spectrum of responses to anxiety.


Effects of early antiretroviral treatment on HIV-1 RNA in blood and lymphoid tissue: a randomized trial of double versus triple therapy. Swiss HIV Cohort Study.
To assess the effects of early initiation of antiretroviral therapy on cell-free and cell-associated viral load in blood and lymphoid tissue, we performed a randomized, open-label, multicenter trial comparing a double (zidovudine + lamivudine) and triple (zidovudine + lamivudine + ritonavir) drug combination in treatment-naive, asymptomatic patients with CD4 counts >400 cells/microl. HIV-1 RNA was measured in plasma, peripheral blood mononuclear cells, and sequential tonsil or lymph node biopsies (27 patients); the study follow-up was 2 years. Among 42 randomized patients, the proportion with plasma HIV-1 RNA <50 copies/ml was 16% and 74% at week 24 (p<.001) in those randomized to double and triple therapy, respectively, necessitating frequent treatment intensification in the double arm. After a rapid decline within 4 weeks in both arms, cell-associated HIV-1 RNA decreased further only in those patients with sustained suppression of plasma viral load, but remained almost always detectable at low levels, indicating persisting transcription of viral RNA. CD4 counts increased by 200 to 250 cells/microl at week 96 in both arms without significant differences (intent-to-treat analyses). Thus, even if treatment is initiated early in asymptomatic patients with preserved CD4 counts, three drugs are necessary to achieve sustained decreases of HIV load in blood and lymphoid tissue.


Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin.
Aberrant activation of signaling by the Wnt pathway is strongly implicated in the onset and progression of numerous types of cancer. Owing to the persistent dependence of these tumors on Wnt signaling for growth and survival, inhibition of this pathway is considered an attractive mechanism-based therapeutic approach. Oncogenic activation of Wnt signaling can ensue from a variety of distinct aberrations in the signaling pathway, but most share the common feature of causing increased cellular levels of β-catenin by interfering with its constitutive degradation. β-Catenin serves as a central hub in Wnt signaling by engaging in crucial protein-protein interactions with both negative and positive effectors of the pathway. Direct interference with these protein-protein interactions is a biologically compelling approach toward suppression of β-catenin hyperactivity, but such interactions have proven intransigent with respect to small-molecule targeting. Hence β-catenin remains an elusive target for translational cancer therapy. Here we report the discovery of a hydrocarbon-stapled peptide that directly targets β-catenin and interferes with its ability to serve as a transcriptional coactivator for T-cell factor (TCF) proteins, the downstream transcriptional regulators of the Wnt pathway.


A Review of the Hemodynamic Factors Believed to Contribute to Vascular Access Dysfunction.
A vascular access (VA) is used to facilitate hemodialysis in patients that suffer from end-stage renal disease. However, they suffer from high failure rates due to non-maturation and venous stenosis, with intimal hyperplasia (IH) the underlying cause of both conditions. Abnormal hemodynamic profiles, which arise following VA creation, are believed to lead to the development of IH. However, the exact physiological response that initiates this process is unknown. This review evaluates the different hemodynamic parameters that are hypothesised to correlate with the development of IH. Review studies that examine the correlation between hemodynamic parameters and the onset of IH using computational fluid dynamics. These studies are divided into groups depending on the type of analysis conducted; longitudinal studies, patient specific arteriovenous fistula (AVF) studies, arteriovenous graft studies, idealised AVF studies and studies that analyse the bulk flow. Studies that conduct longitudinal analysis identify an overall reduction in wall shear stress (WSS) as the VA matures. This is further associated with outward remodelling and the successful maturation of the VA. The majority of studies that conduct a transversal analysis find that low/oscillating shear is associated with the development of IH. However, a number of studies find a link between high shear and high spatial and temporal WSS gradients and the onset of IH. This review highlights the lack of unanimity between studies and emphasises the fact that the exact physiological response that leads to the development of IH remains unknown. This accentuates the need for a single, precise hypothesis capable of accurately predicting the onset of IH. If computational modelling is to assist in this process, the number of longitudinal studies conducted must increase. This will provide a better understanding of the effect that hemodynamic parameters have on the remodelling process and potentially identify a single/group of parameter/s that can accurately predict the onset of IH.


MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors.
MicroRNAs (miRNAs) regulate gene expression. It has been suggested that obtaining miRNA expression profiles can improve classification, diagnostic, and prognostic information in oncology. Here, we sought to comprehensively identify the miRNAs that are overexpressed in lung cancer by conducting miRNA microarray expression profiling on normal lung versus adjacent lung cancers from transgenic mice. We found that miR-136, miR-376a, and miR-31 were each prominently overexpressed in murine lung cancers. Real-time RT-PCR and in situ hybridization (ISH) assays confirmed these miRNA expression profiles in paired normal-malignant lung tissues from mice and humans. Engineered knockdown of miR-31, but not other highlighted miRNAs, substantially repressed lung cancer cell growth and tumorigenicity in a dose-dependent manner. Using a bioinformatics approach, we identified miR-31 target mRNAs and independently confirmed them as direct targets in human and mouse lung cancer cell lines. These targets included the tumor-suppressive genes large tumor suppressor 2 (LATS2) and PP2A regulatory subunit B alpha isoform (PPP2R2A), and expression of each was augmented by miR-31 knockdown. Their engineered repression antagonized miR-31-mediated growth inhibition. Notably, miR-31 and these target mRNAs were inversely expressed in mouse and human lung cancers, underscoring their biologic relevance. The clinical relevance of miR-31 expression was further independently and comprehensively validated using an array containing normal and malignant human lung tissues. Together, these findings revealed that miR-31 acts as an oncogenic miRNA (oncomir) in lung cancer by targeting specific tumor suppressors for repression.


Oxidative damage is the earliest event in Alzheimer disease.
Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.


Increased TIMP-3 expression alters the cellular secretome through dual inhibition of the metalloprotease ADAM10 and ligand-binding of the LRP-1 receptor.
The tissue inhibitor of metalloproteinases-3 (TIMP-3) is a major regulator of extracellular matrix turnover and protein shedding by inhibiting different classes of metalloproteinases, including disintegrin metalloproteinases (ADAMs). Tissue bioavailability of TIMP-3 is regulated by the endocytic receptor low-density-lipoprotein receptor-related protein-1 (LRP-1). TIMP-3 plays protective roles in disease. Thus, different approaches have been developed aiming to increase TIMP-3 bioavailability, yet overall effects of increased TIMP-3 in vivo have not been investigated. Herein, by using unbiased mass-spectrometry we demonstrate that TIMP-3-overexpression in HEK293 cells has a dual effect on shedding of transmembrane proteins and turnover of soluble proteins. Several membrane proteins showing reduced shedding are known as ADAM10 substrates, suggesting that exogenous TIMP-3 preferentially inhibits ADAM10 in HEK293 cells. Additionally identified shed membrane proteins may be novel ADAM10 substrate candidates. TIMP-3-overexpression also increased extracellular levels of several soluble proteins, including TIMP-1, MIF and SPARC. Levels of these proteins similarly increased upon LRP-1 inactivation, suggesting that TIMP-3 increases soluble protein levels by competing for their binding to LRP-1 and their subsequent internalization. In conclusion, our study reveals that increased levels of TIMP-3 induce substantial modifications in the cellular secretome and that TIMP-3-based therapies may potentially provoke undesired, dysregulated functions of ADAM10 and LRP-1.


Low-energy-density diets are associated with high diet quality in adults in the United States.
This study investigated food choices made by individuals consuming diets differing in energy density and explores relationships between energy density and diet quality. Cross-sectional, nationally representative survey. 7,500 adults (older than 19 years) in the 1994-1996 Continuing Survey of Food Intakes by Individuals. Energy density values were calculated from reported food intake. Subjects were classified as consuming a low-energy-density diet, medium-energy-density diet, or high-energy-density diet using tertile cutoffs. For each group, the percentage consuming various foods/beverages and the mean amount of foods/beverages they consumed was determined along with mean nutrient intakes. Compared with participants consuming a high-energy-density diet, those with a low-energy-density diet had a lower energy intake but consumed more food, by weight, from most food groups. A low-energy-density diet included a relatively high proportion of foods high in micronutrients and water and low in fat, such as fruits and vegetables. Subjects with a low-energy-density diet consumed fewer (nonwater) beverages such as caloric carbonated beverages. They also consumed less fat and had higher intakes of several important micronutrients, including vitamins A, C, and B-6, folate, iron, calcium, and potassium. These analyses further demonstrate the beneficial effects of a low-energy-density diet, which was associated with lower energy intakes, higher food intakes, and higher diet quality than a high-energy-density diet. To achieve a low-energy-density diet, individuals should be encouraged to eat a variety of fruits and vegetables as well as low-fat/reduced-fat, nutrient-dense, and/or water-rich grains, dairy products, and meats/meat alternatives.


Single-replication BM2SR vaccine provides sterilizing immunity and cross-lineage influenza B virus protection in mice.
Both influenza A and B viruses cause outbreaks of seasonal influenza resulting in significant morbidity and mortality. There are two antigenically distinct lineages of influenza B virus, Yamagata lineage (YL) and Victoria lineage (VL). Since both B lineages have been co-circulating for years, more than 70% of influenza vaccines currently manufactured are quadrivalent consisting of influenza A (H1N1), influenza A (H3N2), influenza B (YL) and influenza B (VL) antigens. Although quadrivalent influenza vaccines tend to elevate immunity to both influenza B lineages, estimated overall vaccine efficacy against influenza B is still only around 42%. Thus, a more effective influenza B vaccine is needed. To meet this need, we generated BM2-deficient, single-replication (BM2SR) influenza B vaccine viruses that encode surface antigens from influenza B/Wisconsin/01/2010 (B/WI01, YL) and B/Brisbane/60/2008 (B/Bris60, VL) viruses. The BM2SR-WI01 and BM2SR-Bris60 vaccine viruses are replication-deficient in vitro and in vivo, and can only replicate in a cell line that expresses the complementing BM2 protein. Both BM2SR viruses were non-pathogenic to mice, and vaccinated animals showed elevated mucosal and serum antibody responses to both Yamagata and Victoria lineages in addition to cellular responses. Serum antibody responses included lineage-specific hemagglutinin inhibition antibody (HAI) responses as well as responses to the stem region of the hemagglutinin (HA). BM2SR vaccine viruses provided apparent sterilizing immunity to mice against intra- and inter-lineage drifted B virus challenge. The data presented here support the feasibility of BM2SR as a platform for next-generation trivalent influenza vaccine development.


Transthoracic versus transhiatal esophagectomy: a prospective study of 945 patients.
Debate continues as to whether transhiatal esophagectomy results in lower morbidity and mortality than transthoracic esophagectomy. Most data addressing this issue are derived from single-institution studies. To investigate this question from a nationwide multicenter perspective, we used the Veterans Administration National Surgical Quality Improvement Program to prospectively analyze risk factors for morbidity and mortality in patients undergoing transthoracic esophagectomy or transhiatal esophagectomy from 1991 to 2000. Univariate and multivariate analyses were performed on 945 patients (mean age, 63 +/- 10 years). There were 562 transthoracic esophagectomies and 383 transhiatal esophagectomies in 105 hospitals, with complete 30-day outcomes recorded. There were no differences in recorded preoperative variables between the groups that might bias any comparisons. Overall mortality was 10.0% (56/562) for transthoracic esophagectomy and 9.9% (38/383) for transhiatal esophagectomy (P =.983). Morbidity occurred in 47% (266/562) of patients after transthoracic esophagectomy and in 49% (188/383) of patients after transhiatal esophagectomy (P =.596). Risk factors for mortality common to both groups included a serum albumin value of less than 3.5 g/dL, age greater than 65 years, and blood transfusion of greater than 4 units (P <.05). When comparing transthoracic esophagectomy with transhiatal esophagectomy, there was no difference in the incidence of respiratory failure, renal failure, bleeding, infection, sepsis, anastomotic complications, or mediastinitis. Wound dehiscence occurred in 5% (18/383) of patients undergoing transhiatal esophagectomy and only 2% (12/562) of patients undergoing transthoracic esophagectomy (P =.036). These data demonstrate no significant differences in preoperative variables and postoperative mortality or morbidity between transthoracic esophagectomy and transhiatal esophagectomy on the basis of a 10-year, prospective, multi-institutional, nationwide study.


Effects of chronic renal disease on the transport of vitamin A in plasma and urine of dogs.
To determine plasma and urine concentrations of retinol, retinyl esters, retinol-binding protein (RBP), and Tamm-Horsfall protein (THP) in dogs with chronic renal disease (CRD). 17 dogs with naturally developing CRD and 21 healthy control dogs. A diagnosis of CRD was established on the basis of clinical signs, plasma concentrations of creatinine and urea, and results of urinalysis. Concentrations of retinol and retinyl esters were measured by use of reverse-phase high-performance liquid chromatography. Concentrations of RBP and THP were measured by use of sensitive ELISA systems. Dogs with CRD had higher plasma concentrations of retinol, which were not paralleled by differences in plasma concentrations of RBP. Calculated ratio of urinary total vitamin A (sum of concentrations of retinol and retinyl esters to creatinine concentration) and ratio of the concentration of urinary retinyl esters to creatinine concentration did not differ between groups. However, we detected a significantly higher retinol-to-creatinine ratio in the urine of dogs with CRD, which was paralleled by a higher urinary RBP-to-creatinine ratio. Thus, in dogs with CRD, the estimated fractional clearance of total vitamin A, retinol, and RBP was increased. Furthermore, dogs with CRD had a reduced urinary THP-to-creatinine ratio. Results of this study documented that CRD affects the concentrations of retinol in plasma and urine of dogs. Analysis of the data indicates that measurement of urinary RBP and urinary THP concentrations provides valuable information that can be helpful in follow-up monitoring of dogs with CRD.


Segmentation of short keying sequences does not spontaneously transfer to other sequences.
Previous research suggested that highly practiced discrete 6-key sequences are spontaneously segmented, sometimes even differently for different persons. This suggests there is some limit in the length of motor chunks that are assumed to underlie the segments in the sequence. The present experiment examined whether a segmentation pattern induced in one 6-key sequence (the prestructured sequence) determines segmentation in other 6-key sequences. The results are in line with segmentation, but showed neither transfer from the prestructured to a concurrently practiced unstructured sequence, nor to two new sequences that were carried out in a subsequent phase. Moreover, segmentation of these two new sequences was mutually different. Hence, while segmentation seems a phenomenon affecting all 6-element keying sequences, the exact segmentation pattern is not determined by that of a familiar keying sequence. Another result of the present research is that using different fingers of the same hand did slow execution rate (thus indicating effector-specific sequence learning), but the rate reduction was clearly smaller than in a previous study in which transfer to fingers of the other hand was assessed (Verwey & Wright, 2004). This is more in line with effector-specific learning being a result of sequence learning in terms of a hand-based reference frame than learning to directly trigger particular effectors (i.e., the fingers).


The genetic history of Europeans.
The evolutionary history of modern humans is characterized by numerous migrations driven by environmental change, population pressures, and cultural innovations. In Europe, the events most widely considered to have had a major impact on patterns of genetic diversity are the initial colonization of the continent by anatomically modern humans (AMH), the last glacial maximum, and the Neolithic transition. For some decades it was assumed that the geographical structuring of genetic diversity within Europe was mainly the result of gene flow during and soon after the Neolithic transition, but recent advances in next-generation sequencing (NGS) technologies, computer simulation modeling, and ancient DNA (aDNA) analyses are challenging this simplistic view. Here we review the current knowledge on the evolutionary history of humans in Europe based on archaeological and genetic data.


Towards curative cancer immunotherapy: overcoming posttherapy tumor escape.
The past decade has witnessed the evolvement of cancer immunotherapy as an increasingly effective therapeutic modality, evidenced by the approval of two immune-based products by the FDA, that is, the cancer vaccine Provenge (sipuleucel-T) for prostate cancer and the antagonist antibody against cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for advanced melanoma. In addition, the clinical evaluations of a variety of promising immunotherapy drugs are well under way. Benefiting from more efficacious immunotherapeutic agents and treatment strategies, a number of recent clinical studies have achieved unprecedented therapeutic outcomes in some patients with certain types of cancers. Despite these advances, however, the efficacy of most cancer immunotherapies currently under clinical development has been modest. A recurring scenario is that therapeutic maneuvers initially led to measurable antitumor immune responses in cancer patients but ultimately failed to improve patient outcomes. It is increasingly recognized that tumor cells can antagonize therapy-induced immune attacks through a variety of counterregulation mechanisms, which represent a fundamental barrier to the success of cancer immunotherapy. Herein we summarize the findings from some recent preclinical and clinical studies, focusing on how tumor cells advance their survival and expansion by hijacking therapy-induced immune effector mechanisms that would otherwise mediate their destruction.


Genotypic analysis of the TGF beta-509 allele in patients with systemic lupus erythematosus and Sjogren's syndrome.
Transforming growth factor beta (TGFbeta) is a secreted protein present in the circulation and is a critical regulator of the body's immune system. TGFbeta is believed to control several components of the immune system and inhibit autoimmune reactions. Systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) are prototypical human autoimmune diseases characterized by the circulating autoantibodies directed against nuclear antigens and immune complex deposition in various tissues leading to target organ inflammation and damage. Although the etiology of SLE is unknown, it has been observed that patients with SLE have lower levels of circulating TGFbeta than healthy individuals. In addition, mice lacking the TGFbeta1 gene develop a severe autoimmune disease that has features of both SS and SLE. Polymorphisms in the TGFbeta1 gene may alter the mRNA expression levels and influence the plasma protein concentration. Of the known TGFbeta 1 polymorphisms, only the C-509T polymorphism in the promoter region has been shown to be significantly associated with the plasma concentrations of TGFbeta 1. In this study, we have conducted a blinded study to determine if the -509 TGFbeta1 gene polymorphism is associated with SS or SLE. Genomic PCR and RFLP analysis of a 441 bp sequence encompassing the -509 polymorphism of the TGFbeta gene indicated that there were no statistically significant clinical correlations.


Single capacitive discharge utilizing an auxiliary shock in the coronary venous system reduces the defibrillation threshold.
Auxiliary shocks (AS) from electrodes sutured to the left ventricle (LV) prior to primary biphasic shocks (PS) have been shown to reduce defibrillation thresholds (DFT). Two capacitors are required to generate these waveforms. We investigate delivery of AS from one capacitor using a novel waveform. The epicardial surface of the LV is accessed transvenously via the middle cardiac vein (MCV) avoiding a thoracotomy. A defibrillation electrode was placed in the right ventricle (RV) and superior vena cava (SVC) in 12 pigs (37+/-2 kg). A 50x1.8 mm electrode was inserted in the MCV through a guide catheter. A can was placed in the left pectoral region. A monophasic AS (100 microF, 1.5 J) was delivered along one pathway before switching to deliver a biphasic waveform (40% tilt, 2 ms phase 2) along another. DFTs (PS+AS) were assessed using a binary search. Two configurations not incorporating AS acted as controls. DFTs were compared using repeated measures analysis of variance. DFTs of the four novel configurations (AS/PS) were: RV-->Can/MCV-->Can=14.9+/-3.7 J, MCV-->Can/RV-->Can=17.2+/-5.7 J, RV-->SVC+Can/MCV-->SVC+Can=13.4+/-4.6 J, MCV-->SVC+Can/RV-->SVC+Can=17.1+/-5.9 J. Delivering AS in the RV followed by PS in the MCV reduced the DFT (RV-->Can (19.9+/-7.3 J, P<0.01) and RV-->SVC+Can (19.2+/-6.0 J, P<0.05)). Delivering AS prior to PS in the MCV reduces the DFT by up to a third compared to conventional configurations of RV-->Can and RV-->SVC+Can. This is possible using only a single capacitor and an entirely transvenous approach to the LV.


The Effectiveness of Parent Training Programs for Child Maltreatment and Their Components: A Meta-Analysis.
This is the first meta-analytic review investigating what components and techniques of parent training programs for preventing or reducing child maltreatment are associated with program effectiveness. A literature search yielded 51 studies (N = 6670) examining the effectiveness of parent training programs for preventing or reducing child maltreatment. From these studies, 185 effect sizes were extracted and more than 40 program components and techniques were coded. A significant and small overall effect size was found (d = 0.416, 95% CI (0.334, 0.498), p < 0.001). No significant moderating effects were found for contextual factors and structural elements (i.e., program duration, delivery location, and delivery setting). Further, no significant moderating effects were found for most of the coded program components and techniques, indicating that these components are about equally effective. Only a few program components and techniques moderated program effectiveness, however these effects were negative. These results indicated that improving parental personal skills, improving problem solving skills, and stimulating children's prosocial behavior should not be the main focus of parental training programs for preventing and reducing child maltreatment. This also holds for practicing new skills by rehearsal and giving direct feedback in program sessions. Further clinical implications and directions for future research are discussed.


Multiple component patient safety intervention in English hospitals: controlled evaluation of second phase.
To independently evaluate the impact of the second phase of the Health Foundation's Safer Patients Initiative (SPI2) on a range of patient safety measures. Design A controlled before and after design. Five substudies: survey of staff attitudes; review of case notes from high risk (respiratory) patients in medical wards; review of case notes from surgical patients; indirect evaluation of hand hygiene by measuring hospital use of handwashing materials; measurement of outcomes (adverse events, mortality among high risk patients admitted to medical wards, patients' satisfaction, mortality in intensive care, rates of hospital acquired infection). Setting NHS hospitals in England. Nine hospitals participating in SPI2 and nine matched control hospitals. The SPI2 intervention was similar to the SPI1, with somewhat modified goals, a slightly longer intervention period, and a smaller budget per hospital. One of the scores (organisational climate) showed a significant (P = 0.009) difference in rate of change over time, which favoured the control hospitals, though the difference was only 0.07 points on a five point scale. Results of the explicit case note reviews of high risk medical patients showed that certain practices improved over time in both control and SPI2 hospitals (and none deteriorated), but there were no significant differences between control and SPI2 hospitals. Monitoring of vital signs improved across control and SPI2 sites. This temporal effect was significant for monitoring the respiratory rate at both the six hour (adjusted odds ratio 2.1, 99% confidence interval 1.0 to 4.3; P = 0.010) and 12 hour (2.4, 1.1 to 5.0; P = 0.002) periods after admission. There was no significant effect of SPI for any of the measures of vital signs. Use of a recommended system for scoring the severity of pneumonia improved from 1.9% (1/52) to 21.4% (12/56) of control and from 2.0% (1/50) to 41.7% (25/60) of SPI2 patients. This temporal change was significant (7.3, 1.4 to 37.7; P = 0.002), but the difference in difference was not significant (2.1, 0.4 to 11.1; P = 0.236). There were no notable or significant changes in the pattern of prescribing errors, either over time or between control and SPI2 hospitals. Two items of medical history taking (exercise tolerance and occupation) showed significant improvement over time, across both control and SPI2 hospitals, but no additional SPI2 effect. The holistic review showed no significant changes in error rates either over time or between control and SPI2 hospitals. The explicit case note review of perioperative care showed that adherence rates for two of the four perioperative standards targeted by SPI2 were already good at baseline, exceeding 94% for antibiotic prophylaxis and 98% for deep vein thrombosis prophylaxis. Intraoperative monitoring of temperature improved over time in both groups, but this was not significant (1.8, 0.4 to 7.6; P = 0.279), and there were no additional effects of SPI2. A dramatic rise in consumption of soap and alcohol hand rub was similar in control and SPI2 hospitals (P = 0.760 and P = 0.889, respectively), as was the corresponding decrease in rates of Clostridium difficile and meticillin resistant Staphylococcus aureus infection (P = 0.652 and P = 0.693, respectively). Mortality rates of medical patients included in the case note reviews in control hospitals increased from 17.3% (42/243) to 21.4% (24/112), while in SPI2 hospitals they fell from 10.3% (24/233) to 6.1% (7/114) (P = 0.043). Fewer than 8% of deaths were classed as avoidable; changes in proportions could not explain the divergence of overall death rates between control and SPI2 hospitals. There was no significant difference in the rate of change in mortality in intensive care. Patients' satisfaction improved in both control and SPI2 hospitals on all dimensions, but again there were no significant changes between the two groups of hospitals. Many aspects of care are already good or improving across the NHS in England, suggesting considerable improvements in quality across the board. These improvements are probably due to contemporaneous policy activities relating to patient safety, including those with features similar to the SPI, and the emergence of professional consensus on some clinical processes. This phenomenon might have attenuated the incremental effect of the SPI, making it difficult to detect. Alternatively, the full impact of the SPI might be observable only in the longer term. The conclusion of this study could have been different if concurrent controls had not been used.


Inhibitory Activity of Avocado Seed Fatty Acid Derivatives (Acetogenins) Against Listeria Monocytogenes.
High standards regarding Listeria monocytogenes control and consumer demands for food products without synthetic additives represent a challenge to food industry. We determined the antilisterial properties of an enriched acetogenin extract (EAE) from avocado seed, compared it to two commercial antimicrobials (one enriched in avocado acetogenins), and tested purified molecules. Acetogenin composition in pulp and seed of Hass avocado was quantified. EAE were obtained by two sequential centrifuge partition chromatography separations and molecules purified by preparative chromatography and quantified by HPLC-MS-TOF and HPLC-PDA. Avocado seed extracts which are the following two: 1) EAE and 2) the commercially available antimicrobial Avosafe®, presented similar inhibition zones and chemical profiles. Minimum inhibitory concentration (MIC) values of extracts and two isolated acetogenins varied between 7.8 and 15.6 mg/L, were effective at 37 and 4 °C, and showed a bactericidal effect probably caused by increased membrane permeability and lytic effects, evidenced by flow cytometry at 10 and 100× MIC. Activity was comparable to Mirenat®. Most potent acetogenins were Persenone C (5) and A (6), and AcO-avocadenyne (1), the latter exclusively present in seed. Common features of bioactive molecules were the acetyl moiety and multiple unsaturations (2 to 3) in the aliphatic chain, some persenones also featured a trans-enone group. Seeds contained 1.6 times higher levels of acetogenins than pulp (5048.1 ± 575.5 and 3107.0 ± 207.2 mg/kg fresh weight, respectively), and total content in pulp was 199 to 398 times higher than MIC values. Therefore, acetogenin levels potentially consumed by humans are higher than inhibitory concentrations. Results document properties of avocado seed acetogenins as natural antilisterial food additives.


Synergy of Sex Differences in Visceral Fat Measured with CT and Tumor Metabolism Helps Predict Overall Survival in Patients with Renal Cell Carcinoma.
Purpose To determine if sex differences in abdominal visceral fat composition, measured by using computed tomography (CT), and tumor glucose metabolism, measured by gene expression, can help predict outcomes in patients with clear cell renal cell carcinoma (RCC). Materials and Methods This retrospective cohort study included 222 patients with clear cell RCC from The Cancer Imaging Atlas. By using CT, body fat was segmented into subcutaneous fat and visceral fat areas (VFAs) and normalized to total fat to obtain the relative VFA (rVFA) and relative subcutaneous fat area. Multivariate Cox proportional hazard regression models were performed to identify effects of rVFA on sex-specific survival. Expression profiles for 39 glycolytic genes in tumors from these patients were obtained from The Cancer Genome Atlas to determine sex differences in metabolism and compared with rVFA. Key mutations in clear cell RCC were analyzed for association with rVFA and tumor glycolytic profiles. Results Women with rVFA greater than 30.9% had an increased risk of death (hazard ratio, 3.66 [95% confidence interval: 1.64, 8.19]) for women vs 1.13 ([95% confidence interval: 0.58, 2.18] for men, P = .028). Glycolytic gene expression stratified both men and women, and the combination of low rVFA and low glycolysis identified 19 women with excellent overall survival (P < .001). SETD2 and BAP1 mutations were uniquely enriched in female tumors with high glycolysis (P = .036 and .001, respectively). No significant differences were identified in tumor mutations between patients with high and low rVFA. Conclusion Sex differences in visceral fat and tumor glucose metabolism may provide a new risk-stratification system for patients with clear cell RCC. © RSNA, 2018 Online supplemental material is available for this article.


Benefit of statin pretreatment in prevention of contrast-induced nephropathy in different adult patient population: systematic review and meta-analysis.
Previous studies have suggested that statin pretreatment prevents contrast-induced nephropathy (CIN). However, single randomised trials are limited in their number of patients. This meta-analysis aims to assess the role of statin use in CIN prevention, as well as to determine patient subgroups that will benefit from statin pre-treatment. We searched PubMed, EMBASE, Web of science and the Cochrane Central Register of Controlled Trials databases for randomised controlled trials (RCT) comparing statin pretreatment versus placebo for preventing CIN. Our main outcome was the risk of CIN within 1-5 days after contrast administration. Data analysed from nine randomised studies with a total of 5143 patients, where 2559 received statins and 2584 received placebo, showed that statin pretreatment was associated with significant reduction in risk of CIN (MH-RR=0.47, 95% CI 0.34 to 0.64, Z=4.49, p<0.00001). This beneficial effect of statin was also seen in patients with baseline renal impairment (MH-RR=0.46, 95% CI 0.29 to 0.72, p=0.0008) and also those who were cotreated with NAC (MH-RR=0.46, 95% CI 0.25 to 0.83, p=0.01). Statin pretreatment leads to significant reduction in CIN, and should be strongly considered in all patients who are planned for diagnostic and interventional procedures involving contrast-media administration.


Netrin-1 Dampens Hypobaric Hypoxia-Induced Lung Injury in Mice.
Background: This study aimed to explore the effects of netrin-1 on hypobaric hypoxia-induced lung injury in mice. Methods: We exposed 6-8-week-old C57BL/6 mice to hypobaric stress at 340 mmHg for 30 minutes followed by 260 mmHg for different periods (6, 12, 18, and 24 hours) to observe the severity of lung injury (O2 concentration, 21%; 54.6 mmHg). The wet/dry weight ratio and protein leakage from the mouse lung were used to determine the suitable exposure time. Netrin-1 was injected into the tail vein of mice before 18-hour decompression. Inflammatory cytokines, lung injury scores, and activity of nuclear factor κB were evaluated. The expression of apoptosis-related proteins was also examined. Results: Protein concentration in the bronchoalveolar lavage fluid was significantly higher in the 18-hour group (p < 0.05). Pulmonary pathology revealed neutrophil infiltration, alveolar septum thickening, and tissue edema. Injury score and macrophage inflammatory protein 2 levels were also increased. Intrinsic apoptosis pathway was activated. Hypoxia decreased the expression of Bcl2 protein, the number of active caspase-3-stained cells, and UNC5HB receptors. Pretreatment with netrin-1 reduced protein leakage, inhibited neutrophil migration, lowered the injury score, attenuated apoptosis, and increased UNC5HB receptor expression. Conclusion: Netrin-1 dampens hypobaric hypoxia-induced lung injury by inhibiting neutrophil migration and attenuating apoptosis.


A review of parametric modelling techniques for EEG analysis.
This review provides an introduction to the use of parametric modelling techniques for time series analysis, and in particular the application of autoregressive modelling to the analysis of physiological signals such as the human electroencephalogram. The concept of signal stationarity is considered and, in the light of this, both adaptive models, and non-adaptive models employing fixed or adaptive segmentation, are discussed. For non-adaptive autoregressive models, the Yule-Walker equations are derived and the popular Levinson-Durbin and Burg algorithms are introduced. The interpretation of an autoregressive model as a recursive digital filter and its use in spectral estimation are considered, and the important issues of model stability and model complexity are discussed.


Link communities reveal multiscale complexity in networks.
Networks have become a key approach to understanding systems of interacting objects, unifying the study of diverse phenomena including biological organisms and human society. One crucial step when studying the structure and dynamics of networks is to identify communities: groups of related nodes that correspond to functional subunits such as protein complexes or social spheres. Communities in networks often overlap such that nodes simultaneously belong to several groups. Meanwhile, many networks are known to possess hierarchical organization, where communities are recursively grouped into a hierarchical structure. However, the fact that many real networks have communities with pervasive overlap, where each and every node belongs to more than one group, has the consequence that a global hierarchy of nodes cannot capture the relationships between overlapping groups. Here we reinvent communities as groups of links rather than nodes and show that this unorthodox approach successfully reconciles the antagonistic organizing principles of overlapping communities and hierarchy. In contrast to the existing literature, which has entirely focused on grouping nodes, link communities naturally incorporate overlap while revealing hierarchical organization. We find relevant link communities in many networks, including major biological networks such as protein-protein interaction and metabolic networks, and show that a large social network contains hierarchically organized community structures spanning inner-city to regional scales while maintaining pervasive overlap. Our results imply that link communities are fundamental building blocks that reveal overlap and hierarchical organization in networks to be two aspects of the same phenomenon.


National survey of UK medical students on the perception of neurology.
Medical students perceive neurology to be a difficult subject, a phenomenon described as "neurophobia". Studies investigating student attitudes towards neurology have so far been limited by small sample sizes as a consequence of being conducted within a single medical school or region. We aimed to conduct the first national survey of the perception of neurology among UK medical students. A 24 question online survey was designed and distributed in the form of a web-link to all UK medical schools. Responses were collected for 10 weeks with reminders sent at 3 and 6 weeks. A prize-draw of £300 was offered upon completion of the survey. 2877 medical students from 25 of 31 medical schools responded. Students found neurology to be significantly more difficult than other specialties and were least comfortable drawing up a neurological differential diagnosis compared to other specialties (p < 0.0001 for neurology vs. each of the other specialties). Neuroanatomy was regarded as the most important factor contributing to neurology being perceived as difficult. The findings of the first national survey addressing this issue are consistent with previous research. The perception of neurology remains unchanged, in contrast to the rapidly changing demands of neurological care in an ageing population. Neurological examination and formulating a differential diagnosis are important skills in any medical specialty, and combatting "neurophobia" in medical students is therefore essential.